Source
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. [email protected]
Abstract
Adolescence is the developmental epoch during which children become adults-intellectually, physically, hormonally and socially. Brain development in critical areas is ongoing. Adolescents are risk-taking and novelty-seeking and they weigh positive experiences more heavily and negative experiences less than adults. This inherent behavioral bias can lead to risky behaviors like drug taking. Most drug addictions start during adolescence and early drug-taking is associated with an increased rate of drug abuse and dependence. The hormonal changes of puberty contribute to physical, emotional, intellectual and social changes during adolescence. These hormonal events do not just cause maturation of reproductive function and the emergence of secondary sex characteristics. They contribute to the appearance of sex differences in non-reproductive behaviors as well. Sex differences in drug use behaviors are among the latter. The male predominance in overall drug use appears by the end of adolescence, while girls develop the rapid progression from first use to dependence (telescoping) that represent a female-biased vulnerability. Sex differences in many behaviors including drug use have been attributed to social and cultural factors. A narrowing gap in drug use between adolescent boys and girls supports this thesis. However, some sex differences in addiction vulnerability reflect biologic differences in brain circuits involved in addiction. The purpose of this review is to summarize the contribution of sex differences in the function of ascending dopamine systems that are critical to reinforcement, to briefly summarize the behavioral, neurochemical and anatomical changes in brain dopaminergic functions related to addiction that occur during adolescence and to present new findings about the emergence of sex differences in dopaminergic function during adolescence.
Copyright 2009 Elsevier Inc. All rights reserved.
Introduction
Adolescence is a critical developmental epoch for addictive disease. Virtually every drug user has his or her first experience with addictive drugs during adolescence. The first regular use of an addictive drug (typically tobacco, alcohol or marijuana) occurs almost always before age 21, and the earlier substance abuse begins, the faster it develops and the more severe it is (Estroff et al. 1989; Myers and Andersen 1991; Clark et al. 1998; Brown et al. 2008; Windle et al. 2008). Adolescence is a time of tremendous change – children are maturing physically, emotionally and socially. Brain development is going through a crucial stage, and the hormonal and physical changes of puberty are ongoing. The present review addresses the contribution of puberty to adolescent changes in the behaviors and neurobiological mechanisms that are most important for the development of drug addiction. We have focused on biologic factors (development of specific neural circuits) rather than the social factors like gender roles and peer influences as contributors to substance abuse. Extensive literature about the latter is already available (Dakof 2000; Waylen and Wolke 2004) while biologic factors that influence gender-specific vulnerabilities are much less discussed. The information we review demonstrates that the enhanced vulnerability to addiction during adolescence reflects mainly gender-independent adolescent brain functions, and that pubertal hormonal changes mediate the emergence of the gender-specific risks for various aspects of addiction that appear by the end of adolescence.
In the following sections we will review the sex differences in drug abuse vulnerability, the important endocrine mediators that have been identified in animal models, the ontogeny of behaviors that enhance addiction risk across adolescence, adolescent development of the dopaminergic neurons innervating the basal ganglia and frontal cortex which mediates drug reinforcement and how puberty influences these processes. Finally, we will provide new preliminary data about the emergence of sex differences in dopaminergic function during adolescence. The chapter ends with a brief mention of several critical neurobehavioral functions including executive function, regulation of emotional behavior and stress-sensitivity which are critical for drug addiction but relatively uncharacterized during puberty. These represent an important target for future research.
Part 1: Sex, Gonadal Steroids and Addiction in Adults
Sex Differences in Addiction Vulnerability
Sex differences in Drug Abuse in Humans
Sex differences in drug sensitivity, drug use patterns and the role of reproductive hormones in these differences have been reviewed in previous articles in the Volume and so these will only be briefly summarized here. There are two sex differences in drug abuse in human populations that are consistently reported. First, more adult males use and abuse addictive drugs than females across most drug classes, including alcohol, psychostimulants and narcotics (NHSDUH 2007; Tetrault et al. 2008). However, women develop addiction more quickly, demonstrating a “telescoping” between initial use and dependence for most drugs including alcohol, psychostimulants and narcotics and experience a higher incidence of psychiatric disease, history of physical or sexual abuse (Ross et al. 1988; Brady et al. 1993; Brady and Randall 1999; Van Etten et al. 1999; Brecht et al. 2004; Diala et al. 2004). However, these differences are diminishing rapidly, as changing social and cultural factors strongly influence drug taking behavior. There is considerable debate but little concrete information about the role of biologic factors in either of these phenomena.
Sex Differences in Drug Self-Administration in Non-Human Primates
Sex differences in vulnerability to addiction have been characterized more extensively in animals. These have also been summarized in previous articles in this volume and so only the main issues which are relevant to adolescence will be mentioned here. We will cover the brief literature on non-human primates first, and then the more extensive literature which used rodent models.
The literature on sex differences in drug self-administration in non-human primates is sparse and reviewed elsewhere (Lynch et al. 2002; Carroll et al. 2004), but some highlights will be presented here. The findings vary by drug and by experimental paradigm. While many self-administration studies conducted in non-human primates include both males and females, few utilize subject numbers large enough to detect sex differences. Findings for ethanol are especially contradictory. Sex differences in acquisition of ethanol-self administration were not observed in non-human primates (Grant and Johanson 1988). Females have been reported to drink more ethanol under free-drinking conditions but less ethanol under operant conditions (Juarez and Barrios de Tomasi 1999; Vivian et al. 2001). Careful consideration of differences in self-administration of cocaine based on dose, sex and menstrual cycle phase has showed that female cynomolgous monkeys will work to higher break points on a progressive ratio during the follicular phase of the cycle, but that otherwise males and females respond similarly (Mello et al. 2007). Female monkeys were reported to consume more phencyclidine than males (Carroll et al. 2005). In general, the study of sex differences in drug self-administration in non-human primates is inadequate to provide any definitive characterization.
Sex Differences in Addiction Vulnerability in Rodent Models
The majority of studies exploring sex differences use rodents although there is a growing literature with non-human primates. Animal models of the reinforcing effects of addictive drugs include locomotor activation and its sensitization, conditioned place preference (CPP) and self-administration. Locomotor activation estimates sensitivity to the activation of dopaminergic neurons projecting to the forebrain by addictive drugs but does not provide a direct measure of the reinforcing effects. CPP provides a more direct assessment of the reinforcing effects of drugs, and self administration provides the current “gold standard’ of voluntary drug intake. All of these have provided some insight into the emergence of sex differences in the effects of addictive drugs that occur across adolescence because robust and consistent sex differences exist for all of these measures.
Locomotor stimulation, locomotor sensitization, CPP and acquisition of self administration of psychostimulants, narcotics, nicotine and ethanol occur faster, at lower doses and/or are greater in magnitude in females than males (Donny et al. 2000; Carroll et al. 2004; Hu et al. 2004; Chaudhri et al. 2005; Craft 2008; Yararbas et al. 2009). During short access, fixed ratio responding, females and males self-administer comparable amounts of cocaine (Caine et al. 2004). However, females will work harder for psychostimulants under a progressive ratio, escalate use faster and bar press more during extinction than males (Lynch et al. 2002; Carroll et al. 2004; Lynch 2006; Quinones-Jenab 2006; Becker and Hu 2008). The latter findings have been interpreted to indicate that motivation to take drugs is stronger in females. During relapse to cocaine self administration, females are comparable to males after cocaine while they exhibit less reinstatement during cue-induced relapse (Fuchs et al. 2005). These latter characteristics are thought to be a better model of drug-taking characteristics that are relevant for human addiction than simple self-administration (Vanderschuren and Everitt 2004). Sex differences in several nonpharmacological controls of self-administration also have been reported. Self-administration of nicotine is more affected by non-drug stimuli in females than males and responding during time-out periods and during extinction are greater in females than males (Chaudhri et al. 2005). These differences could reflect sex differences in regulation of operant behavior. The finding with nicotine may be particularly relevant to humans, as women are reported to be more sensitive to conditioned cues associated with smoking than men (Perkins et al. 1999). In general, females show behaviors that can be interpreted as transitioning into compulsive phases of addiction faster, much as has been noted in humans.
Gonadal Steroid Influences on Addiction
Gonadal Steroid Influences in Humans and Non-human primates
Ovarian steroids are thought to influence the effects of addictive drugs in women, but often in subtle ways. One method that has been used to demonstrate these effects is to measure drug effects or consumption across the menstrual cycle. Women experience greater subjective effects of many addictive drugs during the follicular phase of the menstrual cycle (Terner and de Wit 2006). However, there are some notable exceptions including ethanol, for which neither subjective effects nor consumption vary with the menstrual cycle (Sofuoglu et al. 1999; Holdstock and de Wit 2000; Evans et al. 2002). Suppression of subjective effects of cocaine by progesterone has been reported in several studies (Sofuoglu et al. 2002; Sofuoglu et al. 2004; Evans 2007). These observations have initiated studies of a possible therapeutic use for progesterone, which might mediate the decreased subjective effects during the luteal phase of the cycle. These findings are discussed at length elsewhere in this volume.
Gonadal Steroid Influences on Addictive Behaviors in Rodent Models
A more extensive literature from studies conducted in rodents supports a facilitatory role for estradiol in self-administration of several drugs, and a suppressive role for progesterone. Estrogen facilitates acquisition, increases responding under a progressive ratio, and enhances responding during drug-induced relapse although negative reports exist (Grimm and See 1997). In contrast, progesterone suppresses these same behaviors (Feltenstein and See 2007; Feltenstein et al. 2009). The role of testicular steroids is less convincing. Castrating male rats does not change psychostimulant-enhanced dopamine release or rotational behavior after amphetamine (Becker 1999) or change cocaine self administration (Hu and Becker 2003; Hu et al. 2004). However, other studies show that castration of male rats causes a delayed increase in cocaine-stimulated locomotion (Long et al. 1994; van Luijtelaar et al. 1996; Walker et al. 2001). In general, ovarian steroids modulate addiction-related behaviors significantly : estrogen consistently enhances behaviors in rats that are relevant to addiction, while progesterone suppresses the same behaviors. Testosterone is either inactive or slightly suppresses the same behaviors.
Gonadal Steroid Effects on Dopaminergic Functions Relevant to Addiction
Dopamine and Reinforcement
Gonadal steroid effects on drug self administration are mediated in part by effects on dopaminergic neurons. The dopaminergic neurons that project from the substantia nigra and ventral tegmental area to the caudate nucleus, nucleus accumbens (dorsal and ventral striatum) and frontal cortex play a prominent role in both normal reinforcement and the initiation of drug addiction in adult animals and perhaps the transition into habitual use (Le Moal and Simon 1991; Kalivas and O’Brien 2008; Carlezon and Thomas 2009; Dalley and Everitt 2009). All drugs that humans self-administer activate these dopaminergic neurons, including nicotine, alcohol, opiates and psychomotor stimulants like cocaine and amphetamine (Di Chiara et al. 2004). Developmental changes in and gonadal steroid hormone effects on the dopaminergic neurons which project from the substantia nigra and ventral tegmental area will be focus of the present review. Although gonadal steroids strongly modulate hypothalamic dopaminergic neurons which regulate hormone release and sexual behavior (Hull et al. 1999; Ben-Jonathan and Hnasko 2001; Dominguez and Hull 2005), the contribution of these neurons to drug addiction has not been studied extensively and it will not be discussed here.
Sex Differences in Dopaminergic Function in Humans and Non-Human Primates
Sex differences in dopaminergic function exist which likely contribute to sex differences in drug self-administration (reviewed by Jill Becker in this Volume, and see also (Becker 1999; Becker and Hu 2008; Morissette et al. 2008). The available literature about humans and non-human primates is discussed first, followed by information about rodents.
Although sex differences in the neurochemistry and neuroanatomy of forebrain dopaminergic neurons have not been thoroughly studied in humans and non-human primates, some evidence indicates sex differences do exist. Fundamental data derive from studies of disease risk: females are significantly less likely to develop Parkinson’s disease, and do so at a later age (Baldereschi et al. 2000; Wooten et al. 2004). These studies suggest that dopaminergic innervation of basal ganglia may be different in men and women. However there has been little anatomical study of this question. Imaging studies of dopamine release are mixed: some studies show that women exhibit greater dopamine release in response to psychostimulants, and others show that men do so (Munro et al. 2006; Riccardi et al. 2006). Therefore, the literature is inconclusive about the nature of sex differences in dopaminergic function in humans.
Sex Differences in Dopaminergic Function in Rodents
Sex differences in both presynaptic function (release of dopamine) and postsynaptic function (expression and regulation of dopamine receptors) have been extensively characterized. These have been studied most widely in rodents. It has been proposed that the integration of basal dopamine release, capacity to stimulate dopamine release and receptor sensitivity contribute to the enhanced dopamine response of females (Castner and Becker 1996) that translates into an enhanced behavioral reactivity (Becker and Hu 2008). Basal dopamine release does not differ in males and females: studies utilizing microdialysis or low frequency stimulation with fast scan cyclic voltammetry show that males and females have roughly comparable levels of extracellular dopamine when they are gonadally intact (Becker and Ramirez 1981b; Castner et al. 1993; Walker et al. 2000; Walker et al. 2006). Similarly, the numbers of D1 and D2 receptors in dorsal and ventral striatum are fairly similar in males and females, and one study even reports greater D1 receptor density in males (Becker and Ramirez 1981b; Festa et al. 2006). However, females show consistently higher dopamine release in response to electrical stimulation or psychostimulants in dorsal striatum. Our laboratory has shown that maximal, electrically stimulated dopamine release in dorsal striatum in females is almost double that observed in males (Walker et al. 2000). These findings are consistent with the report that amphetamine causes the greatest c-fos responses (an immediate early gene response that reflects the sum of both pre- and post-synaptic stimulation) in proestrous females (Castner and Becker 1996). It has been postulated that female rodents in a high estrogen state exhibit dopaminergic responses to pharmacologic stimuli that exceed males as well as females in other endocrine states.
An extensive literature supports an important role for estrogen in augmenting both pre- and postsynaptic dopaminergic function. Estrogen augments dopamine release, increases both D1 and D2 receptor number by slowing receptor degradation rates and enhances DAT production (Morissette et al. 1990; Levesque and Di Paolo 1991; Morissette and Di Paolo 1993; Morissette and Di Paolo 1993; Becker and Hu 2008; Morissette et al. 2008). Multiple hypotheses have been proposed to explain how estrogen augments dopaminergic function. One hypothesis is that estradiol reduces GABA-mediated inhibition of dopaminergic terminals (Hu et al. 2006). In contrast, most studies of adult males suggest that testosterone does not regulate dopaminergic function in dorsal or ventral striatum (Becker 1999; Becker 2009). However, frontal cortex dopaminergic circuits that are important for executive function and working memory are facilitated by androgen (Adler et al. 1999; Kritzer 2000; Kritzer et al. 2001; Kritzer 2003; Kritzer et al. 2007), and these processes may contribute significantly to addiction vulnerability. Androgen actions on these brain functions represent an important gap in our knowledge about gonadal steroid effects on addictive behaviors.
Gonadal Steroid Effects on the Anatomy of Dopamine Systems
Gonadal Steroid Hormone Effects on Anatomy of Dopamine Systems in Humans and Non-Human Primates
Gonadal steroids may influence the morphology of dopaminergic neurons as well as expression of key dopaminergic proteins and afferent regulation of dopamine release. Convincing evidence supporting this possibility was the report that ovariectomy of female primates caused a permanent decrease in dopamine cell number in the substantia nigra that could be prevented by estradiol replacement (Leranth et al. 2000). In primates, estradiol and progesterone both increase the density of terminal arborization of dopaminergic neurons in some areas including the dorsolateral (sensory association areas) of the dorsal striatum as well as the frontal cortex (Kritzer and Kohama 1998; Kritzer et al. 2003). Estradiol also has functional effects on dopamine release in monkeys: estradiol replacement of Parkinsonian monkeys can enhance dopamine release even after a prolonged period of estrogen deprivation (Morissette and Di Paolo 2009).
Gonadal Steroid Hormone Effects on Anatomy of Dopaminergic System in Rodents
Numerous studies suggest that estradiol has a trophic role in maintaining dopaminergic neurons, especially in response to neurotoxic injury (Morissette et al. 2008). Recent studies from our own laboratory have shown that female rodents have more dopaminergic neurons in both the substantia nigra and ventral tegmental area, and that estradiol maintains dopamine cell number in both rats and mice, primarily through actions on estrogen receptor beta (Johnson 2009a). Our studies have also suggested a role for testicular steroids in this phenomenon, as castration of male rats resulted in an unexpected increase in the number of dopaminergic neurons (Johnson 2009b). Although other studies have not reported such a difference (Dewing et al. 2006; McArthur et al. 2007), the latter studies did not employ unbiased stereologic counting, which is the most rigorous standard in the field. These differences in the number of dopaminergic neurons may contribute to reported differences in dopaminergic function after manipulation of gonadal steroid hormone levels. Surprisingly, sex differences in dopaminergic innervation of the dorsal and ventral striatum have not been reported. However, dopaminergic innervation of the frontal cortex has been studied, and androgen may contribute significantly in this region. Kritzer showed that androgen reduces terminal density in cortex of rodents (Adler et al. 1999; Kritzer 2000; Kritzer 2003).
The existence of strong regulation by estradiol and modest regulation by testosterone are concordant with the reported expression of gonadal steroid hormone receptors in dopaminergic neurons. A significant percentage of the dopaminergic neurons in the midbrain express androgen receptors, while only a small percentage express either of the two main estradiol receptors (ERα and ERβ) (Kritzer 1997; Creutz and Kritzer 2002; Creutz and Kritzer 2004; Kritzer and Creutz 2008). These anatomical differences represent an important potential mediator of hormonal effects on dopaminergic function. They could be especially relevant as mediators of developmental changes.
Estrogen as a Mediator of Sex Differences in Addiction
The enhancement of dopaminergic function in the forebrain by estradiol has generated the hypothesis that this effect contributes to sex differences in drug self-administration across mammalian species (Lynch et al. 2002; Carroll et al. 2004; Lynch 2006; Becker and Hu 2008). The commonality of this finding may reflect the fundamental organization of how motivation is tied to reproductive state in males and females. Regulation of dopaminergic neurons projecting to the forebrain by ovarian but not testicular steroids is speculated to allow males to seek out sexual partners (using this dopaminergic system) at any time, while females will only seek out sexual partners when they are fertile (Becker and Taylor 2008) although this may not reflect specificity for sexual behavior per se (Paredes and Agmo 2004).
The well-described decrease in sexual motivation (among other deficits) in Parkinson’s disease and the emergence of inappropriate sexual behavior during treatment with dopaminergic agonists suggests that dopamine contributes to these behaviors in humans (Meco et al. 2008). However, the relative contribution of specific gonadal steroids is notoriously species-specific and recent studies in humans showed that hypogonadism impaired sexual function in both men and women, but that testosterone restored function in men but estradiol did not do so in women (Czoty et al. 2009). Furthermore, studies of dopamine release in dorsal and ventral striatum of humans show inconsistent sex differences. Two studies of dopamine release have been published in humans which report opposite gender related findings: one reports that release was greater in males, and another that it was greater in females (Munro et al. 2006; Riccardi et al. 2006)
Gonadal steroids also regulate sexual motivation in primates although non-hormonal (social) cues play a significant role (Wallen and Zehr 2004). Female non-human primates coordinate sexual behavior with the time of menstrual cycle (mid cycle) that is associated with high fertility (Bonsall et al. 1978). Furthermore, dopamine release may be regulated by ovarian steroids in non-human primates, as a recent PET study showed that basal DA release may be lower during the luteal than follicular phase in non-human primates (Schmidt et al. 2009).
Part 2: Adolescence and Addiction
Adolescence as a Developmental Epoch Critical for Addiction in Humans
Adolescence is the final developmental epoch which marks the transition to adulthood (Spear 2000; Windle et al. 2008). For the purposes of this review, we will use the age ranges described in these two reviews. In humans, it spans roughly from years 10-25. This age range is larger than that typically given. However, recent brain imaging studies suggest that the brain is not fully mature until the mid-twenties (Lenroot and Giedd 2006).
The completion of brain and somatic development interact with the dramatic cultural and social changes occurring as children shift their sphere of influence from family to peers. Recent studies have shown that brain structure is undergoing final maturation during this period. Gray matter density falls, perhaps reflecting an offsetting increase in myelin although the trajectory for individual brain regions varies (Isralowitz and Rawson 2006; Paus et al. 2008; Giedd et al. 2009) and synaptic density falls slowly during late adolescence, at least in non-human primates (Bourgeois et al. 1994).
Brain function is also completing critical final stages of development during which executive functions like delayed gratification (Casey et al. 2000; Steinberg et al. 2008; Astle and Scerif 2009) and processing of reward and aversive stimuli finally mature at the end of adolescence (Ernst et al. 2006; Ernst and Mueller 2008; Ernst and Fudge 2009). The immaturity of reward processing by the dopaminergic system and of cortical circuits that inhibit behavior are particularly critical for addiction vulnerability in adolescence. Imaging studies in humans suggest that adolescents may be more sensitive to reward, less sensitive to aversive stimuli and less able to inhibit responses because frontal cortex circuits which regulate behavior are immature compared to adults (Crews and Boettiger 2009; Geier and Luna 2009). Impulsivity and sensation seeking are high during adolescence (Spear 2000; Steinberg et al. 2008). A substantial literature points to these behavioral traits or related psychological constructs like “neurobehavioral disinhibition” as significant risk factors for the development of drug dependence, especially in adolescence (Dawes et al. 2000; Crews et al. 2007; Everitt et al. 2008; Perry and Carroll 2008; Crews and Boettiger 2009; Volkow et al. 2009). In summary, the state of adolescent brain development may place adolescents at risk for substance abuse for several reasons: they may respond to rewarding stimuli more than aversive stimuli relative to adults, they relatively discount future outcomes, and they are sensation seeking and impulsive. There are several excellent reviews in this area (Crews et al. 2007; Brown et al. 2008; Windle et al. 2008).
Adolescence as a Developmental Epoch for Addiction in Rodents
In rodents, adolescence spans from postnatal day (PN) 25 to early adulthood on PN60 (Spear 2000). This time frame includes but is not restricted to pubertal development. As with humans, brain development continues until the end of the time frame, and PN60 should be viewed as the earliest time that adult brain function exists, and it is likely that the latest developing functions mature somewhat after this arbitrary cutoff (Rice and Barone 2000; McCutcheon and Marinelli 2009).
Although the literature on behavioral development is less abundant, when the appropriate postnatal age is considered, similar behavioral development occurs in rodents and humans during adolescence. Risk-taking and sensation seeking are high in rodents, as they are in humans (Spear 2000; Laviola et al. 2003). A smaller but emerging animal literature supports the same dominance of rewarding over aversive effects of addictive drugs during adolescence (Laviola et al. 2003; Schramm-Sapyta et al. 2009). The commonality of these processes suggest that rodent models can provide a useful tool for exploring brain mechanisms that are important for the development of addiction.
In summary, several behaviors that are critically involved in the development of drug addiction change rapidly during adolescence. Neural circuits involved in processing reward as well as those that control executive functions that inhibit behavior may be the most relevant to the adolescent vulnerability to addiction, as adolescents are possibly more sensitive to reinforcement, and show less ability to inhibit responses based on future outcomes.
Addiction-Related Behaviors during Adolescence
Animal models provide a crucial insight into how addiction-related behaviors change during adolescence, as experimental studies in humans are ethically impermissible, and naturalistic studies are seriously confounded by socioeconomic, environmental and genetic complexities that require an analysis that is beyond the scope of the present review. The majority of these studies have been conducted in rodents; these studies will be reviewed below.
The characteristic behavioral effects of many addictive drugs change as adolescents mature, and the changes generally tend to be consistent across drugs for a given behavior. The one exception may be locomotor activity, as the changes in locomotor response across adolescence are somewhat drug specific. These studies are reviewed by Schramm-Sapyta (Schramm-Sapyta et al. 2009). Amphetamine and methamphetamine stimulate locomotion less in early adolescents than adults, while locomotor stimulation by cocaine is greater during early adolescence than adulthood. Nicotine has been reported to decrease or increase locomotion in a developmentally specific way, depending upon the dose or species under study. Decreases in locomotion result from nicotine treatment of mice, and this decrease is less in adolescents (Lopez et al. 2003). In rats, nicotine is reported to increase locomotion, and adolescents are more rather than less sensitive to this effect (Faraday et al. 2001).
Locomotor sensitization, which is thought to reflect neuroplastic events during early addictive drug exposure, gradually increases across adolescence after treatment with amphetamine, cocaine or methylphenidate: sensitization is low when treatment is initiated during the perinatal period, becomes more robust during adolescence but is greater in adulthood than in adolescence (Kolta et al. 1990; McDougall et al. 1994; Ujike et al. 1995; Bowman et al. 1997; Laviola et al. 1999; Tirelli et al. 2003; Frantz et al. 2007). One exception may be sensitization following single drug exposures, as our laboratory has observed enhanced single-dose sensitization in adolescents compared to adults (Caster et al. 2007). Nicotine sensitization produced by treatment of adolescent rats is less than that observed after a comparable treatment of adult rats, although cross-sensitization to cocaine and amphetamine were both greater in adolescent males than adult males (Collins and Izenwasser 2004; Collins et al. 2004; Cruz et al. 2005; McQuown et al. 2009).
CPP for most addictive drugs including nicotine, cocaine and amphetamine is enhanced during adolescence (Vastola et al. 2002; Belluzzi et al. 2004; Badanich et al. 2006; Kota et al. 2007; Torres et al. 2008; Brenhouse and Andersen 2008a; Schramm-Sapyta et al. 2009; Shram and Le 2009; Zakharova et al. 2009) although conflicting findings have been reported for both cocaine and amphetamine (Adriani and Laviola 2003; Tirelli et al. 2003; Schramm-Sapyta et al. 2004). Conflicting data exist for ethanol CPP in rats and mice (Philpot et al. 2003; Dickinson et al. 2009) and the cannabinoid agonist WIN5512-2 causes CPP at lower doses in adult than adolescent rats (Pandolfo et al. 2009). In summary, CPP is enhanced in adolescents compared to adults while sensitization is less in animals treated repetitively with psychostimulants in adolescence than those treated as adults. These divergent results suggest that adolescents experience both the reinforcing and neuroplastic effects of addictive drugs, but that the latter may be diminished relative to adults while the former are exaggerated. The enhanced reinforcing effects of most addictive drugs in adolescent rodents is consistent with the increased response to reward reported above that has been observed both in humans and rodents.
The standard for evaluating the addiction liability of drugs of abuse is self-administration. Animal studies in which self-administration starting in adolescence and adulthood were compared have yielded consistent findings for some drugs, but contradictory findings for other drugs. In general, acquisition of self administration of ethanol is consistently faster in adolescents (Bell et al. 2003; Brunell and Spear 2005; Doremus et al. 2005; Bell et al. 2006; Vetter et al. 2007). Faster acquisition of nicotine self-administration has been reported in adolescents compared to animals that begin self-administration as adults (Chen et al. 2007; Levin et al. 2007) and adolescent but not adult mice will voluntarily drink nicotine-containing solutions (Adriani et al. 2002). However, adolescents self-administer less nicotine than adults on demanding reinforcement schedules, and show faster extinction and less relapse than adults (Shram et al. 2008; Shram et al. 2008). Some of these inconsistencies in reports of nicotine self -administration in adolescents and adults may reflect the relative importance of reward and withdrawal at different ages. While adolescents tend to be more sensitive to the rewarding effects of nicotine (see above), they tend to exhibit less pronounced dependence (O’Dell et al. 2004; O’Dell et al. 2006; Wilmouth and Spear 2006; O’Dell et al. 2007; Shram et al. 2008). Finally, findings with self-administration of cocaine have been the most equivocal. Although faster acquisition of self-administration has been observed at least for animals with low saccharin preference (Perry et al. 2007), several other studies have shown that stable self-administration does not differ based on whether self-administration begins during adolescence or adulthood (Frantz et al. 2007; Kantak et al. 2007; Kerstetter and Kantak 2007; Li and Frantz 2009). Most of these studies employ traditional fixed-ratio schedules which do not test for the key transitions to compulsivity and escalation that are tested by escalation regimens (Vanderschuren and Everitt 2004). In general, the literature suggests that adolescents may be more sensitive to the reinforcing effects of drugs of abuse, but no data exist yet to assess whether adolescents escalate use and progress to compulsive use faster than adults.
Maturation of Forebrain Dopaminergic Function during Adolescence
The important role of dopaminergic neurons in sexual and drug reinforcement and the important pubertal events which initiate sexual motivation suggest that the developmental changes in dopaminergic neurons during puberty may be a key event for drug abuse vulnerability. The studies cited above suggest that activation of dopaminergic neurons by reinforcers including drugs might be greater during adolescence compared to adults. In the next section, we will review what is known about the ontogeny of dopaminergic neurons and present new data about the emergence of sex differences in dopaminergic function.
Maturation of Forebrain Dopaminergic Function in Humans
Non-human primate and human dopaminergic systems develop similarly. Dopamine content, tyrosine hydroxylase and anatomic measures of dopaminergic innervation of frontal cortex rise to a peak just before adolescence and fall in non-human primates (Goldman-Rakic and Brown 1982; Rosenberg and Lewis 1994; Rosenberg and Lewis 1995; Erickson et al. 1998). Striatal dopamine content increases through adolescence in humans (Haycock et al. 2003) although other synaptic markers including tyrosine hydroxylase, the vesicular transporter (VMAT2) and the plasma membrane transporter (DAT) peak just at the beginning of adolescence (Meng et al. 1999; Haycock et al. 2003).
Although all of the neurochemical “machinery” for dopaminergic transmission is present soon after birth, a number of indices of dopaminergic function change markedly during adolescence. Many indices reach peak levels of expression during late adolescence or early adulthood followed by a fall to adult levels. Changes in postsynaptic receptors have been described most thoroughly. Overexpression of D1 and D2 receptors early in development and subsequent decreases during adolescence have been reported in several studies (Meng et al. 1999; Seeman 1999). A recent study in humans shows a similar loss of presynaptic markers during early adolescence (Haycock et al. 2003).
Maturation of Forebrain Dopaminergic Function in Rodents
The ontogeny of dopaminergic neurons innervating the forebrain in rodents is quite similar to that reported above for non-human primates and humans. Dopaminergic neurons which eventually innervate the dorsal and ventral striatum and frontal cortex in rats undergo their final division during mid-gestation (Lauder and Bloom 1974). All molecular markers of dopaminergic neurons are expressed at significant levels before birth, but the explosive growth of dopamine innervation of the forebrain occurs after birth in the rat. From PN5 to PN40, most markers including dopamine content, tyrosine hydroxylase, D1 and D2 receptors and dopamine transporter increase markedly in striatum, n. accumbens and frontal cortex (Coyle and Axelrod 1972; Porcher and Heller 1972; Nomura et al. 1976; Kirksey and Slotkin 1979; Giorgi et al. 1987; Gelbard et al. 1989; Broaddus and Bennett 1990; Broaddus and Bennett 1990; Rao et al. 1991; Coulter et al. 1997; Tarazi et al. 1999). A dramatic rise in all of these dopaminergic markers occurs between two to three weeks postnatally, just before adolescence, but maturation continues until at least PN60. Frontal cortex innervation in the rat lags slightly behind that of more caudal regions, with almost all dopaminergic innervation arriving postnatally and achieving adult levels by PN60 (Kalsbeek et al. 1988).
Dopamine receptors in rodents undergo a rise followed by adolescent pruning like that reported in humans (Huttenlocher 1979; Giorgi et al. 1987; Gelbard et al. 1989; Teicher et al. 1995; Montague et al. 1999; Tarazi et al. 1999; Andersen et al. 2000; Tarazi and Baldessarini 2000; Andersen et al. 2002). Although marked pruning of presynaptic markers was not observed in the one rat study that used narrow windows (Tarazi et al. 1998), the radioligand used in these studies (GBR12935) binds in a different way to the DAT than WIN 35,428, a radioligand which shows better correlation between binding and uptake inhibition (Xu et al. 1995). These studies suggest that pruning of critical connections from weaning to adulthood could play a role in behavioral changes.
Extracellular dopamine levels parallel the reported increases in innervation density that occurs throughout adolescence. Basal extracellular dopamine levels as measured by voltammetry or microdialysis are lower during adolescence than adulthood (Gazzara et al. 1986; Stamford 1989; Andersen and Gazzara 1993; Laviola et al. 2001).
Activity of Forebrain Dopaminergic Neurons during Adolescence
The previous description provides the impression that dopaminergic innervation of forebrain targets is deficient in early adolescence, becomes fully functional during later adolescence, followed by some “pruning’ back as animals become fully adult. However, measures of dopaminergic neuron activity suggest that these neurons are extremely active during this time frame. Functional studies show that dopaminergic neurons achieve nearly adult levels of function during early adolescence, at about the time that stimulant-induced behavioral activation peaks. Dopaminergic neurons attain adult firing patterns including autoreceptor function and bursting pattern of firing just before or during adolescence (Pitts et al. 1990; Tepper et al. 1990; Lin and Walters 1994; Wang and Pitts 1995; Marinelli et al. 2006; McCutcheon and Marinelli 2009). Microdialysis and neurotransmitter turnover studies have shown that axonal transection, gamma hydroxybutyrate, and psychomotor stimulants can activate dopaminergic neurons well before weaning (Erinoff and Heller 1978; Cheronis et al. 1979). Single unit studies of dopamine cell firing show that the firing rate is higher during adolescence, perhaps because it is less restrained by autoreceptor inhibition (Marinelli et al. 2006). Our laboratory has shown that cocaine-induced dopamine overflow is greater in dorsal striatum in adolescent than adult rats even though maximal dopamine release (which reflects terminal stores) is significantly less (Walker and Kuhn 2008). The traditional turnover measure of HVA/DA ratio also is significantly higher in adolescent than adult rats (see Figure 1). Similar findings have been reported in a study that compared 18, 30 and 110 day old rats (Teicher et al. 1993). These data all suggest that dopaminergic neurons that project to forebrain targets relevant to addiction may not have complete, adult levels of innervation, but if anything are more responsive to neuronal inputs.
Enhanced activation of dopaminergic neurons in early adolescence may not extend to the dopaminergic neurons that innervate the cerebral cortex. An elegant series of studies in rat brain slices showed that both D1 excitatory and D2 inhibitory influences on interneuron function were absent in cortex during the same phase of development that is described above (Tseng and O’Donnell 2005; Tseng and O’Donnell 2007). However, these studies employed a different model system, and comparable end points have not been assessed in dorsal or ventral striatum during adolescence. It is possible that cortical dopaminergic inputs may mature at a slightly different pace than the striatal inputs.
Part 3: Sex, Gonadal Steroids and Addiction in Adolescence
Emergence of Sex Differences in the Use of Addictive Drugs by Humans
Sex differences in drug use by humans appear during adolescence. However, generational cohort effects influenced by changing social roles for women and other factors highly influence these findings. Initiation in drug use has almost equalized in boys and girls (Johnston et al. 2007; NHSDUH 2007). Young adolescent females are as likely to drink alcohol, use marijuana and other illicit drugs and to use multiple drugs as young adolescent males (Johnston et al. 2007; NHSDUH 2007; Palmer et al. 2009). Use of tobacco, alcohol, marijuana and other illicit drugs increases linearly across adolescence in a parallel way in males and females. The significant differences emerge later in adolescence, when males are slightly more likely to be alcohol dependent and females to smoke (Young et al. 2002; Cropsey et al. 2008). Other studies that include older teenagers show that males’ use of marijuana and other illicit drugs exceeds that of females (Terry-McElrath et al. 2008) although cohorts vary and in some studies, use of even “hard” drugs like heroin and cocaine are comparable in adolescent males and females (Gerra et al. 2004). In general, the two major sex differences in drug use (more frequent drug use by males and the “telescoping” of progression from use to abuse in females) appear by the end of adolescence (Nolen-Hoeksema 2004; Ridenour et al. 2006).
Puberty as an Influence on Vulnerability to Addiction in Adolescence?
Puberty as a Critical Aspect of Adolescent Brain Development
Puberty is superimposed upon and contributes to adolescent brain development. The animal models are so concordant with studies in humans, that these will be discussed together in this section. In humans, pubertal development occurs over a wide age range depending on ethnic background, culture and health of the individual, but in the developed world, girls generally attain adult estradiol and progesterone levels by age 14-15 (when they are menstruating) and boys attain adult testosterone levels a year later, by age 16-17 (Styne and Grumbach 2008). Similarly, in rodents, females have adult cyclic gonadal steroid hormone levels by about postnatal day PN35 when they experience their first estrus, while males experience a liner increase in testosterone from PN25 until about PN60. At this age, puberty is generally complete in both sexes and animals are reproductively mature (Lee et al. 1975; Korenbrot et al. 1977; Ojeda et al. 1980; Ojeda et al. 1986).
Both activational and organizational effects of gonadal steroids contribute significantly to changes in brain structure and function during puberty. During puberty, both males and females attain adult levels of reproductive hormones, which then regulate their targets on an ongoing basis: this process provides the activational effects of gonadal steroids which regulate brain function in an ongoing and reversible fashion. However, there is a growing appreciation that the rise of gonadal steroids during puberty in both males and females contribute to the completion of sexual differentiation of the brain by triggering irreversible processes – the organizational effects of gonadal steroids (Cooke et al. 1998; Becker et al. 2005; Schulz et al. 2009).
Sexual dimorphisms in brain structure that emerge during puberty are also influenced by gonadal steroids. In fact, human brain structure is sexually dimorphic even at birth (Gilmore et al. 2007) and the trajectory of change in brain structure across adolescence varies in girls and boys well before puberty. Girls attain peak gray matter density 1-2 years before boys (Giedd et al. 2006). This trajectory is further influenced by pubertal stage (De Bellis et al. 2001). The changes in some brain structures including amygdala and hippocampus reflect the stage of pubertal development and gray matter changes depend on circulating estradiol in girls and testosterone in boys (Peper et al. 2009). The sexual dimorphisms in brain structures in rodents have been well described and are well beyond the scope of the present review. Several excellent reviews exist (MacLusky and Naftolin 1981; Cooke et al. 1998; Morris et al. 2004; Ahmed et al. 2008).
Puberty and Behavioral Change during Adolescence
The increased secretion of gonadal hormones during puberty contribute to maturation of behavior as well as brain structure and function. In females, pubertal increases in both estradiol and progesterone are necessary for the appearance of the full complement of female behaviors and in males, both testosterone and estradiol formed from aromatization of testosterone contribute to activational and organizational effects. Several recent reviews of how gonadal steroids contribute to the development of reproductive function and sexual behaviors during puberty have been published (Romeo et al. 2002; Romeo 2003; Sisk et al. 2003; Sisk and Zehr 2005; Schulz and Sisk 2006). Testicular and ovarian steroids permit the onset of sex- appropriate social behavior, aggression, and parental behavior as well as reproductive behaviors. While the majority of these data have been collected in mice, rats and hamsters, similar findings have been reported in humans who experience precocious puberty (reviewed in (Sisk and Zehr 2005).
Gender differences in behavior which are relevant to addiction also emerge during puberty (Windle et al. 2008). Sensation seeking is expressed at higher rates and often more strongly associated with drug abuse in men than women (Butkovic and Bratko 2003; Nolen-Hoeksema 2004). Sensation seeking is highest during mid/late puberty in both boys and girls compared to similarly-aged children at an earlier pubertal stage (Quevedo et al. 2009). Furthermore, pubertal hormone levels contribute to these events. Testosterone has been positively correlated with sensation-seeking in both adult males (Coccaro et al. 2007) and adolescent males (Martin et al. 2004) while high estradiol has been associated with lower levels of sensation seeking (Balada et al. 1993) although pubertal changes have not been reported. Finally, testosterone levels during puberty are positively correlated with sensation seeking and concurrent drug use (Martin et al. 2002) Although it is likely that hormonal events in both males and females contribute to the emergence of sex differences in addiction-critical behaviors, the study of pubertal influences on these critical developmental events is in its infancy
Emergence of Sex Differences in the Action of Addictive Drugs
The well-established stimulation of dopaminergic function by estradiol reviewed above suggests the rise in estradiol that occurs with the onset of estrous cyclicity should trigger an increase of dopamine release and in the behavioral response to addictive drugs. In fact, sex differences in multiple addiction-related behaviors do appear during adolescence in rodents, and in the very small number of primate studies that exist. However, emerging evidence indicates that both ovarian and testicular steroids might contribute to these changes.
Our laboratory has shown that young adolescent male rats exhibited greater cocaine-stimulated locomotion, more activation of downstream signaling pathways in the dorsal striatum (as measured by c-fos activation), and greater single-dose sensitization of locomotor behavior than adult (Caster et al. 2005; Caster et al. 2007). Comparison of cocaine-stimulated locomotion in adolescent and adult males and females has shown that adolescent males and females respond similarly to cocaine, and that the sex difference in cocaine-stimulated locomotion appears during adolescence. The sex difference reflects in part the decline in cocaine-stimulated activity in males as well as an increase in cocaine-stimulated locomotion in females (Parylak et al. 2008). A similar developmental change in the locomotor response to methylphenidate has been reported: while male and female adolescents exhibited comparable locomotor stimulation, methylphenidate stimulated significantly more locomotor activity in adult females than in males (Wooters et al. 2006). Morphine-induced locomotor stimulation showed a somewhat different pattern: adolescent males exhibited more locomotor stimulation than adult males, but adolescent and adult females were equivalent to adult males – there was a sex difference during adolescence but not adulthood (White et al. 2008). The greater sensitivity of male mice to inhibition of locomotion by nicotine relative to females appears after adolescence (Lopez et al. 2003) Finally, locomotor stimulation associated with low doses of ethanol increases as adolescent monkeys become adult (Schwandt et al. 2007).
Sex differences in sensitization also emerge during adolescence. Cross-sensitization between nicotine and the psychostimulants cocaine and amphetamine are greater in male than female adolescent rats (Collins and Izenwasser 2004; Collins et al. 2004). Sex differences in ethanol sensitization in mice similarly have been reported in adult but not adolescent mice, suggesting that these differences emerge during puberty (Itzhak and Anderson 2008). Ethanol-induced locomotor sensitization in female but not male non-human primates has been reported during adolescence (Schwandt et al. 2008).
Sex differences in the reinforcing effects of addictive drugs also appear during adolescence. The greater sensitivity of females to cocaine CPP emerges during adolescence (Zakharova et al. 2009). Adult but not adolescent female mice experience greater CPP to cocaine than age-matched males (Balda et al. 2009). One study reported no sex difference in either morphine or cocaine CPP when adolescent and adult rats were compared, but the number of experimental subjects was small enough that it would be been unlikely to detect such a difference unless it had been extremely large (Campbell et al. 2000).
Sex differences in self-administration of many addictive drugs appear during adolescence. We have shown that adult but not prepubertal female rats ingest more cocaine and two laboratories have reported the appearance of faster acquisition of cocaine self administration during adolescence (Perry et al. 2007; Carroll et al. 2008; Lynch 2008; Walker et al. 2009). While both adolescent male and female rats acquire nicotine self administration faster than adults, levels of self-administration actually fall in males as they enter adulthood, while females maintain levels of intake (Levin et al. 2003; Levin et al. 2007). Females and males exhibit comparable nicotine self administration under a progressive ratio schedule early in adolescence but by the end of adolescence, females take more nicotine than males (Lynch 2009). Finally, adolescent mice self-administered fewer doses of oxycodone than adults, but this result was interpreted as greater sensitivity to the effects of oxycodone on dopaminergic neurotransmitter because they demonstrated an exaggerated increase in dopamine in the ventral striatum at the end of self administration (Zhang et al. 2009).
Emergence of sex differences in alcohol ingestion have been reported in both rodents and non-human primates, although the specific sex differences depend upon species. Female rats ingest more alcohol than male rats, and this sex difference appears during adolescence (Lancaster and Spiegel 1992; Lancaster et al. 1996). The one primate study that exists shows that males and females ingested equal amounts of ethanol in these studies (Schwandt et al. 2008).
Developmental changes in responses to amphetamine differ from the other drugs that have been studied and so these are described separately. Both male and female adolescent rats acquired amphetamine self administration faster than adults in a study by Shabazi (Shahbazi et al. 2008). Adolescent males in this study took less amphetamine under a progressive ratio schedule than adult males, while young adult females took more than older adult females. In another study, adolescent females exhibited greater sensitization to amphetamine than adult females or males of either age, but no sex differences were observed in either amphetamine-induced locomotion or CPP in this study, which diverges from the literature (Mathews and McCormick 2007). One important caveat in interpreting sex differences in amphetamine self- administration is that amphetamine metabolism is enhanced by testosterone, and thus likely changes across adolescence (Meyer and Lytle 1978; Becker et al. 1982; Milesi-Halle et al. 2005).
There are some notable gaps in our information about sex differences in the effects of addictive drugs in adolescent animals. There is little information about the reinforcing effects of cannabinoids. Higuera-Matas investigated the adult consequences of treating male and female rats with the CB1 agonist CP55,940 from PN28-38 and showed that females showed enhanced cocaine self-administration (Higuera-Matas et al. 2008; Higuera-Matas et al. 2009). Wiley and colleagues have compared the acute effects of THC on the cannabinoid tetrad: of catalepsy, hypolocomotion, analgesia and hypothermia as well as tolerance and sensitization following repeated THC. They found that female adolescents were less sensitive than female adults to catalepsy, antinociception and hypothermia and tended to show less tolerance, while adolescent males were more sensitive to the inhibition of locomotion than adult males (Wiley et al. 2007). Most importantly, there are no studies of changes in the actions of addictive drugs during adolescence in non-human primates excluding the two reported for ethanol.
Gonadal Steroid Role in the Emergence of Sex Differences in the Effects of Addictive Drugs in Adolescence
Studies of the sexual differentiation of reproductive as well as non reproductive behaviors have shown that puberty represents a second “critical period” in which organizational effects of gonadal steroids produce irreversible effects on sexually dimorphic brain structures and function (see above). Activational effects of gonadal steroids also begin during puberty, and so both processes can contribute to the emergence of sexual dimorphisms in vulnerability to addiction during adolescence. These studies indicate that an early developmental window just before and after birth contributes to the organizational effects of gonadal steroids on the actions of addictive drugs.
Behavioral studies support a role for ovarian and testicular steroids in sexual differentiation of the behavioral response to addictive drugs, but the relative contribution of organizational and activational effects is far from clear. Several studies support a role for organizational effects of gonadal steroids on the effects of addictive drugs. Ovariectomy or masculinization of female rat pups by androgen treatment right after birth prevented the appearance of the enhanced responses of females to the locomotor stimulant effects of amphetamine (Forgie and Stewart 1993; Forgie and Stewart 1994). A single study of the weak estrogen bisphenol showed that even gestational exposure could influence the ontogeny of dopaminergic neurons, as bisphenol exposure during prenatal days 11-18 suppressed amphetamine-induced CPP in female offspring (Laviola et al. 2005).
Recent studies from our laboratory suggest that puberty may represent an additional window during which the organizational effect of gonadal steroids influences the effects of addictive drugs. In a series of studies we have compared the effects of pre- and post-pubertal ovariectomy or castration. Ovariectomy either in adulthood or before puberty suppressed cocaine-stimulated locomotion. However, pre- but not postpubertal castration significantly increased cocaine-stimulated locomotion in males (Kuhn et al. 2001; Walker et al. 2001; Parylak et al. 2008). The pre-pubertal surgery was conducted on PN25, after the well described perinatal sensitive period of steroid hormone effects on brain organization. These data both supported a role for ovarian hormones in females, but also suggested that a previously unrecognized organizational effect of androgen contributed to the normal developmental fall in cocaine-stimulated behavior in males. These findings suggest that gonadal steroids augment addiction-related behaviors in females and suppress them in males during adolescence.
Emergence of Sex Differences in Dopaminergic Function during Adolescence
The behavioral studies reviewed above demonstrate that locomotor activation, drug-related reinforcement and drug self administration become sexually dimorphic in rodents during adolescence. Given the demonstrated importance of drug-induced activation of dopaminergic neurons in these sex differences, it is logical to propose that sexual differentiation of dopaminergic function mediates these effects.
Sex differences in the anatomy of dopaminergic projections to the forebrain emerge prenatally in rodents. Ovtsharoff (Ovtscharoff et al. 1992) showed that females have higher density of dopaminergic fiber innervation in the caudate prenatally. It has further been suggested that genetic sex rather than circulating hormone levels influences dopaminergic neurons in female rodent brain (Beyer et al. 1991; Kolbinger et al. 1991). The demonstration that the testis-determining gene sry is expressed in dopaminergic neurons where it may regulate tyrosine hydroxylase expression independent of hormone levels further supports the likelihood that sex-specific regulation of dopaminergic neurons exists (Dewing et al. 2006), although this is an emerging area with little data.
There is little evidence yet about the effect of gonadal steroids on dopaminergic function during the critical periods during early postnatal and pubertal development. However, behavioral data suggest that exposure of males to androgen perinatally or during puberty and exposure of females to estrogen during puberty provide the critical hormonal cues (see recent review by Becker (Becker 2009)). The only existing study is the demonstration that gonadal steroids do not contribute to the adolescent pruning of D2 receptors (Andersen et al. 2002).
Gonadal Steroid Contribution to Changes on Dopaminergic Function during Adolescence
Our laboratory has begun to characterize the emergence of sex differences in dopaminergic cell bodies in the substantia nigra and ventral tegmental area and their terminal projections in order to understand the potential contribution of dopaminergic function to changing addiction vulnerability during puberty. Our previous findings showed that cocaine enhanced dopamine overflow in the dorsal striatum is 3 fold higher in young adolescent than adult male rats. This developmental difference is regionally selective, as it does not occur in the core of the nucleus accumbens (Walker and Kuhn 2008). Our behavioral studies predicted that the onset of estrous cyclicity in females during adolescence might prevent a similar developmental decrease in cocaine-stimulated dopamine overflow in females.
To investigate this possibility, we measured stimulated dopamine overflow at various times after cocaine administration (10 mg/kg) in adolescent (day 28) and adult (day 65) male and female rats using fast-scan cyclic voltammetry as previously described in both adolescents and adults (Walker et al. 2000; Walker et al. 2006; Walker and Kuhn 2008). Figure 2 shows the percent increase in dopamine relative to baseline stimulation at 20 Hz. Cocaine-stimulated dopamine overflow was greater in adolescent rats of both sexes compared to adults, and adolescent males and females were comparable to each other. Although cocaine-stimulated dopamine overflow was less in adulthood than in adolescents of both sexes, the decline from adolescence to adulthood in females was less than that observed in males (Walker et al. 2000; Walker et al. 2006). These findings suggest that dopaminergic function falls during adolescence in a sex-specific way. However, this study could not determine the contribution of organizational or activational effects of gonadal steroids to these changes in dopamine release.
The literature in adults suggests that activational effects of estradiol are the primary gonadal steroid influence on dopaminergic function in adult rats. However, our behavioral data (Parylak et al. 2008) indicated that important organizational effects of ovarian or testicular steroids might contribute to adolescent changes in endocrine function. To investigate this possibility, we conducted prepubertal castration or ovariectomy on PN25, and evaluated cocaine-stimulated dopamine overflow 30 days later, to match our previous behavioral studies. The results of these experiments are shown in Figures 3 and and4.4. As expected, prepubertal ovariectomy decreased cocaine-stimulated overflow (Figure 3). Surprisingly, prepubertal castration caused a significant increase in cocaine-stimulated dopamine overflow (Figure 4). Given the well-described effects of estradiol on dopaminergic function, it is difficult to discriminate the relative contribution of activational and organizational effects to the results in females. However, the weight of literature demonstrating the lack of androgen effects on dorsal striatal dopamine release in adult animals suggests that androgen may have a previously undescribed organizational effect on dopaminergic functions during puberty. This result matches the behavioral findings that we described above, which demonstrated a significant augmentation of cocaine-stimulated behavior after prepubertal but not adult castration.
The mechanisms by which both ovarian and testicular steroids influence dopaminergic function across adolescence are not known. Since we have recently shown that estradiol augments dopaminergic responses to psychostimulants in part by maintaining dopaminergic neuron number, we conducted a pilot study to determine whether sex differences in dopaminergic neuron number emerged during puberty. To investigate this possibility, we killed matched cohorts of male and female rats on PN21, 28, 42 and 65 and counted dopaminergic neuron number in the substantia nigra and ventral tegmental area, the nuclei from which dopamine projections to the forebrain arise, using unbiased stereology.
Animals were deeply anesthetized and transcardially perfused with 10% neutral buffered formalin. After perfusion, the brains were extracted and post-fixed overnight in 10% formalin, equilibrated in a 30% sucrose cryoprotectant solution and stored at 4°C. Serial coronal sections (30 μm) were cut on a cryostat, thaw-mounted onto slides and dried overnight at 37°C. Sections were rinsed in PBS and incubated in 0.3% hydrogen peroxide-methanol for 30 minutes, rinsed and blocked in 0.5% BSA + 0.3% Triton X-100 for 15 minutes at room temperature. After blocking, sections were incubated in primary antibody diluted in blocking buffer (1:10000, Immunostar, Inc., Hudson, WI) overnight at 4°C. The next day, sections were rinsed and incubated in a biotinylated horse anti-mouse secondary antibody (1:1000, Vector Labs, Burlingame, CA) for 1 hour at room temperature. The sections were then rinsed and incubated in avidin-biotin complex for 1 hour at room temperature, rinsed and stained with DAB (Vector Labs). Sections were rinsed, dehydrated through graded alcohols, counterstained with cresyl violet, mounted and coverslipped. Unbiased stereological estimation of the total number of TH-IR and TH-IN cell bodies in the SNpc and VTA was performed using the optical fractionator method (West et al. 1991). A computerized counting system containing a Nikon Optiphot-2 microscope, a camera (Dage) and motorized stage (Ludl) was used to estimate the total number of cells. Individual cell bodies were visualized with a 100× oil immersion lens (numerical aperture = 1.3). Enough cells were counted to achieve a coefficient of error that was ≤ 0.10. This study was conducted without heat-mediated antigen retrieval, and cell numbers were lower than can be detected with the latter technique. However, a clear and unexpected pattern emerged from this experiment. As shown in Figure 5, a dramatic fall in DA cell number occurred during adolescence. This fall seemed to plateau in females by day 65, when the characteristic sex difference emerged.
These findings suggest that a significant wave of dopaminergic cell death occurs during adolescence in rats, in both males and females. Two earlier waves of apoptotic cell death occur right after birth and on about PN14 (Jackson-Lewis et al. 2000; Burke 2003; Burke 2004). The relevance of the fall during adolescence to dopaminergic function is not clear, as it occurs during the same time that innervation density in the terminal areas is increasing (see above). It has been suggested that the cells that undergo apoptosis were those which did not reach their target appropriately and so did not receive trophic input from target neurons (Oo et al. 2003; Burke 2004). The emergence of the sex difference in the number of dopamine neurons only after puberty supports our initial hypothesis that trophic effects of estradiol might contribute to maintenance of dopaminergic neurons in adult life. It is intriguing that the changes in the number of dopaminergic neurons parallel the changes in cocaine’s effects on dopamine release that we saw: a dramatic decline across adolescence, only part of which was sexually dimorphic. We are currently investigating whether anatomic changes in cell body and/or terminal areas contributes to gonadal steroid regulation of addiction-related behaviors.
Significance of Adolescent Changes in Forebrain Dopaminergic Function for Addiction
The studies reviewed above show that dopaminergic function in the dorsal striatum undergoes its final maturation followed by a “pruning back” to adult function as adolescents develop. Sex differences in dopaminergic function and in behaviors regulated by dopamine appear during this time frame. These effects seem to reflect both the onset of activational effects of estradiol to augment dopaminergic function in females and possibly an organizational effect of androgen which suppresses dopaminergic function in males. Figure 6 summarizes one potential scheme that could explain the present findings. From left to right, the figure demonstrates three phases of dopaminergic neuron development. The leftmost panel shows dopamine neurogenesis. The middle panel depicts the period of axon outgrowth and innervation of targets that occurs during postnatal life and through adolescence. The final phase of dopaminergic neuron development is depicted on the right panel, as receptors “prune” back. Dopaminergic neurons are lost at every stage of the process, based on data in the present study and that published previously (Burke 2003; Burke 2004). We hypothesize that during adolescence, the final phase of apoptotic cell death of dopaminergic neurons in the midbrain is augmented by androgen and offset by trophic effects of estradiol. This is indicated by fewer cells in the middle and right panel for males, and a gray neuron in the bottom panel indicating population of neurons maintained by estradiol in females. A gray neuron is also included in the leftmost panel, as studies in culture have suggested that females may have more neurons at early phases of development, although we did not detect such differences by the beginning of adolescence (Beyer et al. 1991). By the end of adolescence/puberty, females have more dopaminergic neurons, which we hypothesize contributes to the sex enhanced dopamine function observed in females. However, additional effects beyond those on the number of dopaminergic cell bodies likely contribute to the emergence of sex differences in dopaminergic function. Potential candidates include the appearance of cyclic effects of estradiol on DAT and receptors as well as activational effects of androgen on cortical neural circuits involved in executive function. In addition, afferent input (perhaps GABAergic feedback on dopaminergic neurons, indicated in the bottom right panel) may also contribute to additional regulation of dopaminergic functions in females.
There is one caveat in interpreting the relevance of these findings for addiction. The main adolescence-related changes in dopaminergic function we have observed occurred in dorsal striatum. The dopaminergic neurons that project from the VTA to the nucleus accumbens may be more important for the initial phases of drug reinforcement (Koob 1996; McBride et al. 1999; Di Chiara 2002). However, dopamine increases in the dorsal striatum are thought to be critical for the transition from voluntary drug taking to habit learning, a crucial phase in the development of addiction (Vanderschuren and Everitt 2004; Volkow et al. 2006; See et al. 2007; Dalley and Everitt 2009). One implication of these findings is that while the reinforcing effects of drugs may not be uniformly greater during adolescence, the transition to addictive patterns of behavior may occur more quickly in people who use drugs in early adolescence.
The emergence of sex differences in dopaminergic function was superimposed on normal developmental influences. These data are again consistent with the epidemiologic literature showing that adolescents of both genders are at greater risk to experiment with and become dependent upon addictive drugs but that gender-specific issues also emerge as adolescents mature. The behavioral significance of the attenuated dopaminergic function that develops across adolescence in males remains an important question. Is it associated with increased or decreased vulnerability to addiction? Epidemiologic studies do indicate that the earlier drug use starts (in early adolescence, at the beginning of pubertal development in males), the greater the risk of future drug dependence. How does rising testosterone influence drug taking behaviors? Intriguing studies that testosterone itself is self-administered through actions that involve both androgens and estrogens suggests an important role for androgen that has not yet been characterized (Wood 2004; Sato et al. 2008; Wood 2008). Animal studies which explore drug self-administration in males that have received prepubertal castration may help to answer these questions.
Endocrine Influences on Non-Dopaminergic Systems
This review has focused on one aspect of addiction that has proven relevance to addiction: the maturation of dopaminergic neurons involved in regulation of reinforcement. However, other elements of neural function critical to adolescence also change during adolescence. Maturation of executive function in the frontal cortex including the noradrenergic and serotonergic influences that are critically involved in attention and inhibition of behavior are key events of adolescent brain development (Chambers et al. 2003). We reviewed above evidence that androgen regulates frontal cortex dopaminergic circuits. Rising testosterone levels during puberty could influence frontal cortex functions like response inhibition, but the contribution of pubertal hormonal changes to these critical brain functions have not been studied either in humans or animal models.
Summary
Addiction vulnerability is high in adolescence. A significant component of this vulnerability reflects developmental stage not sex. Human studies show that both males and females who use addictive drugs early in adolescence have higher risk of addiction than those who start as adults. The dramatic fall in cocaine-induced dopamine release that we observed as adolescent males and females matured into adulthood suggests that important developmental changes in forebrain dopaminergic systems occur during adolescence in a sex-independent way. However, we also showed that well described sex differences in dopaminergic function emerge during adolescence, and could likely contribute to the sex differences in drug use patterns that emerge during late adolescence in humans.
Acknowledgments
Support by NIDA grant DA019114 and 009079 is gratefully acknowledged. All animal experiments were conducted in accordance with animal protocols approved by the Duke University IACUC.
Footnotes
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References
- Adler A, Vescovo P, Robinson JK, Kritzer MF. Gonadectomy in adult life increases tyrosine hydroxylase immunoreactivity in the prefrontal cortex and decreases open field activity in male rats. Neuroscience. 1999;89(3):939–54. [PubMed]
- Adriani W, Laviola G. Elevated levels of impulsivity and reduced place conditioning with d-amphetamine: two behavioral features of adolescence in mice. Behav Neurosci. 2003;117(4):695–703. [PubMed]
- Adriani W, Macri S, Pacifici R, Laviola G. Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology. 2002;27(2):212–24. [PubMed]
- Ahmed EI, Zehr JL, Schulz KM, Lorenz BH, DonCarlos LL, Sisk CL. Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions. Nat Neurosci. 2008;11(9):995–7. [PMC free article] [PubMed]
- Andersen SL, Gazzara RA. The ontogeny of apomorphine-induced alterations of neostriatal dopamine release: effects on spontaneous release. J Neurochem. 1993;61(6):2247–55. [PubMed]
- Andersen SL, Thompson AP, Krenzel E, Teicher MH. Pubertal changes in gonadal hormones do not underlie adolescent dopamine receptor overproduction. Psychoneuroendocrinology. 2002;27(6):683–91. [PubMed]
- Andersen SL, Thompson AT, Rutstein M, Hostetter JC, Teicher MH. Dopamine receptor pruning in prefrontal cortex during the periadolescent period in rats. Synapse. 2000;37(2):167–9. [PubMed]
- Astle DE, Scerif G. Using developmental cognitive neuroscience to study behavioral and attentional control. Dev Psychobiol. 2009;51(2):107–18. [PubMed]
- Badanich KA, Adler KJ, Kirstein CL. Adolescents differ from adults in cocaine conditioned place preference and cocaine-induced dopamine in the nucleus accumbens septi. Eur J Pharmacol. 2006;550(1-3):95–106. [PubMed]
- Balada F, Torrubia R, Arque JM. Gonadal hormone correlates of sensation seeking and anxiety in healthy human females. Neuropsychobiology. 1993;27(2):91–6. [PubMed]
- Balda MA, Anderson KL, Itzhak Y. Development and persistence of long-lasting behavioral sensitization to cocaine in female mice: role of the nNOS gene. Neuropharmacology. 2009;56(3):709–15. [PubMed]
- Baldereschi M, Di Carlo A, Rocca WA, Vanni P, Maggi S, Perissinotto E, Grigoletto F, Amaducci L, Inzitari D. Parkinson’s disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging. Neurology. 2000;55(9):1358–63. [PubMed]
- Becker JB. Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav. 1999;64(4):803–12. [PubMed]
- Becker JB. Sexual differentiation of motivation: a novel mechanism? Horm Behav. 2009;55(5):646–54. [PMC free article] [PubMed]
- Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, Herman JP, Marts S, Sadee W, Steiner M, Taylor J, Young E. Strategies and methods for research on sex differences in brain and behavior. Endocrinology. 2005;146(4):1650–73. [PubMed]
- Becker JB, Hu M. Sex differences in drug abuse. Front Neuroendocrinol. 2008;29(1):36–47. [PMC free article] [PubMed]
- Becker JB, Ramirez VD. Sex differences in the amphetamine stimulated release of catecholamines from rat striatal tissue in vitro. Brain Res. 1981b;204(2):361–72. [PubMed]
- Becker JB, Robinson TE, Lorenz KA. Sex differences and estrous cycle variations in amphetamine-elicited rotational behavior. Eur J Pharmacol. 1982;80(1):65–72. [PubMed]
- Becker JB, Taylor J. Sex Differences in motivation. Oxford, UK: Oxford University Press; 2008.
- Bell RL, Rodd-Henricks ZA, Kuc KA, Lumeng L, Li TK, Murphy JM, McBride WJ. Effects of concurrent access to a single concentration or multiple concentrations of ethanol on the intake of ethanol by male and female periadolescent alcohol-preferring (P) rats. Alcohol. 2003;29(3):137–48. [PubMed]
- Bell RL, Rodd ZA, Sable HJ, Schultz JA, Hsu CC, Lumeng L, Murphy JM, McBride WJ. Daily patterns of ethanol drinking in peri-adolescent and adult alcohol-preferring (P) rats. Pharmacol Biochem Behav. 2006;83(1):35–46. [PubMed]
- Belluzzi JD, Lee AG, Oliff HS, Leslie FM. Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats. Psychopharmacology (Berl) 2004;174(3):389–95. [PubMed]
- Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22(6):724–63. [PubMed]
- Beyer C, Pilgrim C, Reisert I. Dopamine content and metabolism in mesencephalic and diencephalic cell cultures: sex differences and effects of sex steroids. J Neurosci. 1991;11(5):1325–33. [PubMed]
- Bonsall RW, Zumpe D, Michael RP. Menstrual cycle influences on operant behavior of female rhesus monkeys. J Comp Physiol Psychol. 1978;92(5):846–55. [PubMed]
- Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;4(1):78–96. [PubMed]
- Bowman BP, Blatt B, Kuhn CM. Ontogeny of the behavioral response to dopamine agonists after chronic cocaine. Psychopharmacology (Berl) 1997;129(2):121–7. [PubMed]
- Brady KT, Grice DE, Dustan L, Randall C. Gender differences in substance use disorders. Am J Psychiatry. 1993;150(11):1707–11. [PubMed]
- Brady KT, Randall CL. Gender differences in substance use disorders. Psychiatr Clin North Am. 1999;22(2):241–52. [PubMed]
- Brecht ML, O’Brien A, von Mayrhauser C, Anglin MD. Methamphetamine use behaviors and gender differences. Addict Behav. 2004;29(1):89–106. [PubMed]
- Brenhouse HC, Andersen SL. Delayed extinction and stronger reinstatement of cocaine conditioned place preference in adolescent rats, compared to adults. Behav Neurosci. 2008a;122(2):460–5. [PubMed]
- Broaddus WC, Bennett JP., Jr Postnatal development of striatal dopamine function. I. An examination of D1 and D2 receptors, adenylate cyclase regulation and presynaptic dopamine markers. Brain Res Dev Brain Res. 1990;52(1-2):265–71.
- Broaddus WC, Bennett JP., Jr Postnatal development of striatal dopamine function. II. Effects of neonatal 6-hydroxydopamine treatments on D1 and D2 receptors, adenylate cyclase activity and presynaptic dopamine function. Brain Res Dev Brain Res. 1990;52(1-2):273–7.
- Brown SA, McGue M, Maggs J, Schulenberg J, Hingson R, Swartzwelder S, Martin C, Chung T, Tapert SF, Sher K, Winters KC, Lowman C, Murphy S. A developmental perspective on alcohol and youths 16 to 20 years of age. Pediatrics. 2008;121 4:S290–310. [PMC free article] [PubMed]
- Brunell SC, Spear LP. Effect of stress on the voluntary intake of a sweetened ethanol solution in pair-housed adolescent and adult rats. Alcohol Clin Exp Res. 2005;29(9):1641–53. [PubMed]
- Burke RE. Postnatal developmental programmed cell death in dopamine neurons. Ann N Y Acad Sci. 2003;991:69–79. [PubMed]
- Burke RE. Ontogenic cell death in the nigrostriatal system. Cell Tissue Res. 2004;318(1):63–72. [PubMed]
- Butkovic A, Bratko D. Generation and sex differences in sensation seeking: results of the family study. Percept Mot Skills. 2003;97(3 Pt 1):965–70. [PubMed]
- Caine SB, Bowen CA, Yu G, Zuzga D, Negus SS, Mello NK. Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats. Neuropsychopharmacology. 2004;29(5):929–42. [PubMed]
- Campbell JO, Wood RD, Spear LP. Cocaine and morphine-induced place conditioning in adolescent and adult rats. Physiol Behav. 2000;68(4):487–93. [PubMed]
- Carlezon WA, Jr, Thomas MJ. Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacology. 2009;56 1:122–32. [PMC free article] [PubMed]
- Carroll ME, Batulis DK, Landry KL, Morgan AD. Sex differences in the escalation of oral phencyclidine (PCP) self-administration under FR and PR schedules in rhesus monkeys. Psychopharmacology (Berl) 2005;180(3):414–26. [PubMed]
- Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP. Sex and estrogen influence drug abuse. Trends Pharmacol Sci. 2004;25(5):273–9. [PubMed]
- Carroll ME, Morgan AD, Anker JJ, Perry JL, Dess NK. Selective breeding for differential saccharin intake as an animal model of drug abuse. Behav Pharmacol. 2008;19(5-6):435–60. [PubMed]
- Casey BJ, Giedd JN, Thomas KM. Structural and functional brain development and its relation to cognitive development. Biol Psychol. 2000;54(1-3):241–57. [PubMed]
- Caster JM, Walker QD, Kuhn CM. Enhanced behavioral response to repeated-dose cocaine in adolescent rats. Psychopharmacology (Berl) 2005;183(2):218–25. [PubMed]
- Caster JM, Walker QD, Kuhn CM. A single high dose of cocaine induces differential sensitization to specific behaviors across adolescence. Psychopharmacology (Berl) 2007;193(2):247–60. [PubMed]
- Castner SA, Becker JB. Sex differences in the effect of amphetamine on immediate early gene expression in the rat dorsal striatum. Brain Res. 1996;712(2):245–57. [PubMed]
- Castner SA, Xiao L, Becker JB. Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies. Brain Res. 1993;610(1):127–34. [PubMed]
- Chambers RA, Taylor JR, Potenza MN. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry. 2003;160(6):1041–52. [PMC free article] [PubMed]
- Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib MA, Craven LA, Allen SS, Sved AF, Perkins KA. Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats. Psychopharmacology (Berl) 2005;180(2):258–66. [PubMed]
- Chen H, Matta SG, Sharp BM. Acquisition of nicotine self-administration in adolescent rats given prolonged access to the drug. Neuropsychopharmacology. 2007;32(3):700–9. [PubMed]
- Cheronis JC, Erinoff L, Heller A, Hoffmann PC. Pharmacological analysis of the functional ontogeny of the nigrostriatal dopaminergic neurons. Brain Res. 1979;169(3):545–60. [PubMed]
- Clark DB, Kirisci L, Tarter RE. Adolescent versus adult onset and the development of substance use disorders in males. Drug Alcohol Depend. 1998;49(2):115–21. [PubMed]
- Coccaro EF, Beresford B, Minar P, Kaskow J, Geracioti T. CSF testosterone: relationship to aggression, impulsivity, and venturesomeness in adult males with personality disorder. J Psychiatr Res. 2007;41(6):488–92. [PubMed]
- Collins SL, Izenwasser S. Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs. adult male and female rats. Neuropharmacology. 2004;46(3):349–62. [PubMed]
- Collins SL, Montano R, Izenwasser S. Nicotine treatment produces persistent increases in amphetamine-stimulated locomotor activity in periadolescent male but not female or adult male rats. Brain Res Dev Brain Res. 2004;153(2):175–87.
- Cooke B, Hegstrom CD, Villeneuve LS, Breedlove SM. Sexual differentiation of the vertebrate brain: principles and mechanisms. Front Neuroendocrinol. 1998;19(4):323–62. [PubMed]
- Coulter CL, Happe HK, Murrin LC. Dopamine transporter development in postnatal rat striatum: an autoradiographic study with [3H]WIN 35,428. Brain Res Dev Brain Res. 1997;104(1-2):55–62.
- Coyle JT, Axelrod J. Tyrosine hydroxylase in rat brain: developmental characteristics. J Neurochem. 1972;19(4):1117–23. [PubMed]
- Craft RM. Sex differences in analgesic, reinforcing, discriminative, and motoric effects of opioids. Exp Clin Psychopharmacol. 2008;16(5):376–85. [PubMed]
- Creutz LM, Kritzer MF. Estrogen receptor-beta immunoreactivity in the midbrain of adult rats: regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups. J Comp Neurol. 2002;446(3):288–300. [PubMed]
- Creutz LM, Kritzer MF. Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats. J Comp Neurol. 2004;476(4):348–62. [PubMed]
- Crews F, He J, Hodge C. Adolescent cortical development: a critical period of vulnerability for addiction. Pharmacol Biochem Behav. 2007;86(2):189–99. [PubMed]
- Crews FT, Boettiger CA. Impulsivity, frontal lobes and risk for addiction. Pharmacol Biochem Behav. 2009;93(3):237–47. [PMC free article] [PubMed]
- Cropsey KL, Linker JA, Waite DE. An analysis of racial and sex differences for smoking among adolescents in a juvenile correctional center. Drug Alcohol Depend. 2008;92(1-3):156–63. [PubMed]
- Cruz FC, Delucia R, Planeta CS. Differential behavioral and neuroendocrine effects of repeated nicotine in adolescent and adult rats. Pharmacol Biochem Behav. 2005;80(3):411–7. [PubMed]
- Czoty PW, Riddick NV, Gage HD, Sandridge M, Nader SH, Garg S, Bounds M, Garg PK, Nader MA. Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys. Neuropsychopharmacology. 2009;34(3):548–54. [PubMed]
- Dakof GA. Understanding gender differences in adolescent drug abuse: issues of comorbidity and family functioning. J Psychoactive Drugs. 2000;32(1):25–32. [PubMed]
- Dalley JW, Everitt BJ. Dopamine receptors in the learning, memory and drug reward circuitry. Semin Cell Dev Biol. 2009;20(4):403–10. [PubMed]
- Dawes MA, Antelman SM, Vanyukov MM, Giancola P, Tarter RE, Susman EJ, Mezzich A, Clark DB. Developmental sources of variation in liability to adolescent substance use disorders. Drug Alcohol Depend. 2000;61(1):3–14. [PubMed]
- De Bellis MD, Keshavan MS, Beers SR, Hall J, Frustaci K, Masalehdan A, Noll J, Boring AM. Sex differences in brain maturation during childhood and adolescence. Cereb Cortex. 2001;11(6):552–7. [PubMed]
- Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol. 2006;16(4):415–20. [PubMed]
- Di Chiara G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res. 2002;137(1-2):75–114. [PubMed]
- Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology. 2004;47 1:227–41. [PubMed]
- Diala CC, Muntaner C, Walrath C. Gender, occupational, and socioeconomic correlates of alcohol and drug abuse among U.S. rural, metropolitan, and urban residents. Am J Drug Alcohol Abuse. 2004;30(2):409–28. [PubMed]
- Dickinson SD, Kashawny SK, Thiebes KP, Charles DY. Decreased sensitivity to ethanol reward in adolescent mice as measured by conditioned place preference. Alcohol Clin Exp Res. 2009;33(7):1246–51. [PubMed]
- Dominguez JM, Hull EM. Dopamine, the medial preoptic area, and male sexual behavior. Physiol Behav. 2005;86(3):356–68. [PubMed]
- Donny EC, Caggiula AR, Rowell PP, Gharib MA, Maldovan V, Booth S, Mielke MM, Hoffman A, McCallum S. Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology (Berl) 2000;151(4):392–405. [PubMed]
- Doremus TL, Brunell SC, Rajendran P, Spear LP. Factors influencing elevated ethanol consumption in adolescent relative to adult rats. Alcohol Clin Exp Res. 2005;29(10):1796–808. [PubMed]
- Erickson SL, Akil M, Levey AI, Lewis DA. Postnatal development of tyrosine hydroxylase- and dopamine transporter-immunoreactive axons in monkey rostral entorhinal cortex. Cereb Cortex. 1998;8(5):415–27. [PubMed]
- Erinoff L, Heller A. Functional ontogeny of nigrostriatal neurons. Brain Res. 1978;142(3):566–9. [PubMed]
- Ernst M, Fudge JL. A developmental neurobiological model of motivated behavior: anatomy, connectivity and ontogeny of the triadic nodes. Neurosci Biobehav Rev. 2009;33(3):367–82. [PMC free article] [PubMed]
- Ernst M, Mueller SC. The adolescent brain: insights from functional neuroimaging research. Dev Neurobiol. 2008;68(6):729–43. [PMC free article] [PubMed]
- Ernst M, Pine DS, Hardin M. Triadic model of the neurobiology of motivated behavior in adolescence. Psychol Med. 2006;36(3):299–312. [PMC free article] [PubMed]
- Estroff TW, Schwartz RH, Hoffmann NG. Adolescent cocaine abuse. Addictive potential, behavioral and psychiatric effects. Clin Pediatr (Phila) 1989;28(12):550–5. [PubMed]
- Evans SM. The role of estradiol and progesterone in modulating the subjective effects of stimulants in humans. Exp Clin Psychopharmacol. 2007;15(5):418–26. [PubMed]
- Evans SM, Haney M, Foltin RW. The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology (Berl) 2002;159(4):397–406. [PubMed]
- Everitt BJ, Belin D, Economidou D, Pelloux Y, Dalley JW, Robbins TW. Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Philos Trans R Soc Lond B Biol Sci. 2008;363(1507):3125–35. [PMC free article] [PubMed]
- Faraday MM, Elliott BM, Grunberg NE. Adult vs. adolescent rats differ in biobehavioral responses to chronic nicotine administration. Pharmacol Biochem Behav. 2001;70(4):475–89. [PubMed]
- Feltenstein MW, Byrd EA, Henderson AR, See RE. Attenuation of cocaine-seeking by progesterone treatment in female rats. Psychoneuroendocrinology. 2009;34(3):343–52. [PMC free article] [PubMed]
- Feltenstein MW, See RE. Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle. Drug Alcohol Depend. 2007;89(2-3):183–9. [PMC free article] [PubMed]
- Festa ED, Jenab S, Weiner J, Nazarian A, Niyomchai T, Russo SJ, Kemen LM, Akhavan A, Wu HB, Quinones-Jenab V. Cocaine-induced sex differences in D1 receptor activation and binding levels after acute cocaine administration. Brain Res Bull. 2006;68(4):277–84. [PubMed]
- Forgie ML, Stewart J. Sex differences in amphetamine-induced locomotor activity in adult rats: role of testosterone exposure in the neonatal period. Pharmacol Biochem Behav. 1993;46(3):637–45. [PubMed]
- Forgie ML, Stewart J. Effect of prepubertal ovariectomy on amphetamine-induced locomotor activity in adult female rats. Horm Behav. 1994;28(3):241–60. [PubMed]
- Frantz KJ, O’Dell LE, Parsons LH. Behavioral and neurochemical responses to cocaine in periadolescent and adult rats. Neuropsychopharmacology. 2007;32(3):625–37. [PubMed]
- Fuchs RA, Evans KA, Mehta RH, Case JM, See RE. Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology (Berl) 2005;179(3):662–72. [PubMed]
- Gazzara RA, Fisher RS, Howard SG. The ontogeny of amphetamine-induced dopamine release in the caudate-putamen of the rat. Brain Res. 1986;393(2):213–20. [PubMed]
- Geier C, Luna B. The maturation of incentive processing and cognitive control. Pharmacol Biochem Behav. 2009;93(3):212–21. [PMC free article] [PubMed]
- Gelbard HA, Teicher MH, Faedda G, Baldessarini RJ. Postnatal development of dopamine D1 and D2 receptor sites in rat striatum. Brain Res Dev Brain Res. 1989;49(1):123–30.
- Gerra G, Angioni L, Zaimovic A, Moi G, Bussandri M, Bertacca S, Santoro G, Gardini S, Caccavari R, Nicoli MA. Substance use among high-school students: relationships with temperament, personality traits, and parental care perception. Subst Use Misuse. 2004;39(2):345–67. [PubMed]
- Giedd JN, Clasen LS, Lenroot R, Greenstein D, Wallace GL, Ordaz S, Molloy EA, Blumenthal JD, Tossell JW, Stayer C, Samango-Sprouse CA, Shen D, Davatzikos C, Merke D, Chrousos GP. Puberty-related influences on brain development. Mol Cell Endocrinol. 2006;254-255:154–62. [PubMed]
- Giedd JN, Lalonde FM, Celano MJ, White SL, Wallace GL, Lee NR, Lenroot RK. Anatomical brain magnetic resonance imaging of typically developing children and adolescents. J Am Acad Child Adolesc Psychiatry. 2009;48(5):465–70. [PMC free article] [PubMed]
- Gilmore JH, Lin W, Prastawa MW, Looney CB, Vetsa YS, Knickmeyer RC, Evans DD, Smith JK, Hamer RM, Lieberman JA, Gerig G. Regional gray matter growth, sexual dimorphism, and cerebral asymmetry in the neonatal brain. J Neurosci. 2007;27(6):1255–60. [PMC free article] [PubMed]
- Giorgi O, De Montis G, Porceddu ML, Mele S, Calderini G, Toffano G, Biggio G. Developmental and age-related changes in D1-dopamine receptors and dopamine content in the rat striatum. Brain Res. 1987;432(2):283–90. [PubMed]
- Goldman-Rakic PS, Brown RM. Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys. Brain Res. 1982;256(3):339–49. [PubMed]
- Grant KA, Johanson CE. Oral ethanol self-administration in free-feeding rhesus monkeys. Alcohol Clin Exp Res. 1988;12(6):780–4. [PubMed]
- Grimm JW, See RE. Cocaine self-administration in ovariectomized rats is predicted by response to novelty, attenuated by 17-beta estradiol, and associated with abnormal vaginal cytology. Physiol Behav. 1997;61(5):755–61. [PubMed]
- Haycock JW, Becker L, Ang L, Furukawa Y, Hornykiewicz O, Kish SJ. Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum. J Neurochem. 2003;87(3):574–85. [PubMed]
- Higuera-Matas A, Botreau F, Miguens M, Del Olmo N, Borcel E, Perez-Alvarez L, Garcia-Lecumberri C, Ambrosio E. Chronic periadolescent cannabinoid treatment enhances adult hippocampal PSA-NCAM expression in male Wistar rats but only has marginal effects on anxiety, learning and memory. Pharmacol Biochem Behav. 2009;93(4):482–90. [PubMed]
- Higuera-Matas A, Soto-Montenegro ML, del Olmo N, Miguens M, Torres I, Vaquero JJ, Sanchez J, Garcia-Lecumberri C, Desco M, Ambrosio E. Augmented acquisition of cocaine self-administration and altered brain glucose metabolism in adult female but not male rats exposed to a cannabinoid agonist during adolescence. Neuropsychopharmacology. 2008;33(4):806–13. [PubMed]
- Holdstock L, de Wit H. Effects of ethanol at four phases of the menstrual cycle. Psychopharmacology (Berl) 2000;150(4):374–82. [PubMed]
- Hu M, Becker JB. Effects of sex and estrogen on behavioral sensitization to cocaine in rats. J Neurosci. 2003;23(2):693–9. [PubMed]
- Hu M, Crombag HS, Robinson TE, Becker JB. Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology. 2004;29(1):81–5. [PubMed]
- Hu M, Watson CJ, Kennedy RT, Becker JB. Estradiol attenuates the K+-induced increase in extracellular GABA in rat striatum. Synapse. 2006;59(2):122–4. [PubMed]
- Hull EM, Lorrain DS, Du J, Matuszewich L, Lumley LA, Putnam SK, Moses J. Hormone-neurotransmitter interactions in the control of sexual behavior. Behav Brain Res. 1999;105(1):105–16. [PubMed]
- Huttenlocher PR. Synaptic density in human frontal cortex – developmental changes and effects of aging. Brain Res. 1979;163(2):195–205. [PubMed]
- Isralowitz R, Rawson R. Gender differences in prevalence of drug use among high risk adolescents in Israel. Addict Behav. 2006;31(2):355–8. [PubMed]
- Itzhak Y, Anderson KL. Ethanol-induced behavioral sensitization in adolescent and adult mice: role of the nNOS gene. Alcohol Clin Exp Res. 2008;32(10):1839–48. [PubMed]
- Jackson-Lewis V, Vila M, Djaldetti R, Guegan C, Liberatore G, Liu J, O’Malley KL, Burke RE, Przedborski S. Developmental cell death in dopaminergic neurons of the substantia nigra of mice. J Comp Neurol. 2000;424(3):476–88. [PubMed]
- Johnson M, Day A, Ho C, Walker QD, Franics R, Kuhn CM. Androgen decreases dopamine neurone survival in rat midbrain. J Endocrinology. 2009b submitted.
- Johnson M, Ho C, Day A, Walker QD, Franics R, Kuhn CM. Oestrogen receptors enhance dopamine neurone survival in rat midbrain. J Endocrinology. 2009a submitted.
- Johnston LD, Bachman JG, O’Malley PM. Monitoring the Future: A continuing Study of the Lifestyles and Values of Youth 2007
- Juarez J, Barrios de Tomasi E. Sex differences in alcohol drinking patterns during forced and voluntary consumption in rats. Alcohol. 1999;19(1):15–22. [PubMed]
- Kalivas PW, O’Brien C. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology. 2008;33(1):166–80. [PubMed]
- Kalsbeek A, Voorn P, Buijs RM, Pool CW, Uylings HB. Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol. 1988;269(1):58–72. [PubMed]
- Kantak KM, Goodrich CM, Uribe V. Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus) Exp Clin Psychopharmacol. 2007;15(1):37–47. [PubMed]
- Kerstetter KA, Kantak KM. Differential effects of self-administered cocaine in adolescent and adult rats on stimulus-reward learning. Psychopharmacology (Berl) 2007;194(3):403–11. [PubMed]
- Kirksey DF, Slotkin TA. Concomitant development of [3H]-dopamine and [3H]-5-hydroxytryptamine uptake systems in rat brain regions. Br J Pharmacol. 1979;67(3):387–91. [PMC free article] [PubMed]
- Kolbinger W, Trepel M, Beyer C, Pilgrim C, Reisert I. The influence of genetic sex on sexual differentiation of diencephalic dopaminergic neurons in vitro and in vivo. Brain Res. 1991;544(2):349–52. [PubMed]
- Kolta MG, Scalzo FM, Ali SF, Holson RR. Ontogeny of the enhanced behavioral response to amphetamine in amphetamine-pretreated rats. Psychopharmacology (Berl) 1990;100(3):377–82. [PubMed]
- Koob GF. Hedonic valence, dopamine and motivation. Mol Psychiatry. 1996;1(3):186–9. [PubMed]
- Korenbrot CC, Huhtaniemi IT, Weiner RI. Preputial separation as an external sign of pubertal development in the male rat. Biol Reprod. 1977;17(2):298–303. [PubMed]
- Kota D, Martin BR, Robinson SE, Damaj MI. Nicotine dependence and reward differ between adolescent and adult male mice. J Pharmacol Exp Ther. 2007;322(1):399–407. [PubMed]
- Kritzer MF. Selective colocalization of immunoreactivity for intracellular gonadal hormone receptors and tyrosine hydroxylase in the ventral tegmental area, substantia nigra, and retrorubral fields in the rat. J Comp Neurol. 1997;379(2):247–60. [PubMed]
- Kritzer MF. Effects of acute and chronic gonadectomy on the catecholamine innervation of the cerebral cortex in adult male rats: insensitivity of axons immunoreactive for dopamine-beta-hydroxylase to gonadal steroids, and differential sensitivity of axons immunoreactive for tyrosine hydroxylase to ovarian and testicular hormones. J Comp Neurol. 2000;427(4):617–33. [PubMed]
- Kritzer MF. Long-term gonadectomy affects the density of tyrosine hydroxylase- but not dopamine-beta-hydroxylase-, choline acetyltransferase- or serotonin-immunoreactive axons in the medial prefrontal cortices of adult male rats. Cereb Cortex. 2003;13(3):282–96. [PubMed]
- Kritzer MF, Adler A, Bethea CL. Ovarian hormone influences on the density of immunoreactivity for tyrosine hydroxylase and serotonin in the primate corpus striatum. Neuroscience. 2003;122(3):757–72. [PubMed]
- Kritzer MF, Brewer A, Montalmant F, Davenport M, Robinson JK. Effects of gonadectomy on performance in operant tasks measuring prefrontal cortical function in adult male rats. Horm Behav. 2007;51(2):183–94. [PubMed]
- Kritzer MF, Creutz LM. Region and sex differences in constituent dopamine neurons and immunoreactivity for intracellular estrogen and androgen receptors in mesocortical projections in rats. J Neurosci. 2008;28(38):9525–35. [PMC free article] [PubMed]
- Kritzer MF, Kohama SG. Ovarian hormones influence the morphology, distribution, and density of tyrosine hydroxylase immunoreactive axons in the dorsolateral prefrontal cortex of adult rhesus monkeys. J Comp Neurol. 1998;395(1):1–17. [PubMed]
- Kritzer MF, McLaughlin PJ, Smirlis T, Robinson JK. Gonadectomy impairs T-maze acquisition in adult male rats. Horm Behav. 2001;39(2):167–74. [PubMed]
- Kuhn CM, Walker QD, Kaplan KA, Li ST. Sex, steroids, and stimulant sensitivity. Ann N Y Acad Sci. 2001;937:188–201. [PubMed]
- Lancaster FE, Brown TD, Coker KL, Elliott JA, Wren SB. Sex differences in alcohol preference and drinking patterns emerge during the early postpubertal period. Alcohol Clin Exp Res. 1996;20(6):1043–9. [PubMed]
- Lancaster FE, Spiegel KS. Sex differences in pattern of drinking. Alcohol. 1992;9(5):415–20. [PubMed]
- Lauder JM, Bloom FE. Ontogeny of monoamine neurons in the locus coeruleus, Raphe nuclei and substantia nigra of the rat. I. Cell differentiation. J Comp Neurol. 1974;155(4):469–81. [PubMed]
- Laviola G, Adriani W, Terranova ML, Gerra G. Psychobiological risk factors for vulnerability to psychostimulants in human adolescents and animal models. Neurosci Biobehav Rev. 1999;23(7):993–1010. [PubMed]
- Laviola G, Gioiosa L, Adriani W, Palanza P. D-amphetamine-related reinforcing effects are reduced in mice exposed prenatally to estrogenic endocrine disruptors. Brain Res Bull. 2005;65(3):235–40. [PubMed]
- Laviola G, Macri S, Morley-Fletcher S, Adriani W. Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev. 2003;27(1-2):19–31. [PubMed]
- Laviola G, Pascucci T, Pieretti S. Striatal dopamine sensitization to D-amphetamine in periadolescent but not in adult rats. Pharmacol Biochem Behav. 2001;68(1):115–24. [PubMed]
- Le Moal M, Simon H. Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiol Rev. 1991;71(1):155–234. [PubMed]
- Lee VW, de Kretser DM, Hudson B, Wang C. Variations in serum FSH, LH and testosterone levels in male rats from birth to sexual maturity. J Reprod Fertil. 1975;42(1):121–6. [PubMed]
- Lenroot RK, Giedd JN. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev. 2006;30(6):718–29. [PubMed]
- Leranth C, Roth RH, Elsworth JD, Naftolin F, Horvath TL, Redmond DE., Jr Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson’s disease and memory. J Neurosci. 2000;20(23):8604–9. [PubMed]
- Levesque D, Di Paolo T. Dopamine receptor reappearance after irreversible receptor blockade: effect of chronic estradiol treatment of ovariectomized rats. Mol Pharmacol. 1991;39(5):659–65. [PubMed]
- Levin ED, Lawrence SS, Petro A, Horton K, Rezvani AH, Seidler FJ, Slotkin TA. Adolescent vs. adult-onset nicotine self-administration in male rats: duration of effect and differential nicotinic receptor correlates. Neurotoxicol Teratol. 2007;29(4):458–65. [PMC free article] [PubMed]
- Levin ED, Rezvani AH, Montoya D, Rose JE, Swartzwelder HS. Adolescent-onset nicotine self-administration modeled in female rats. Psychopharmacology (Berl) 2003;169(2):141–9. [PubMed]
- Li C, Frantz KJ. Attenuated incubation of cocaine seeking in male rats trained to self-administer cocaine during periadolescence. Psychopharmacology (Berl) 2009;204(4):725–33. [PubMed]
- Lin MY, Walters DE. Dopamine D2 autoreceptors in rats are behaviorally functional at 21 but not 10 days of age. Psychopharmacology (Berl) 1994;114(2):262–8. [PubMed]
- Long SF, Dennis LA, Russell RK, Benson KA, Wilson MC. Testosterone implantation reduces the motor effects of cocaine. Behav Pharmacol. 1994;5(1):103–106. [PubMed]
- Lopez M, Simpson D, White N, Randall C. Age- and sex-related differences in alcohol and nicotine effects in C57BL/6J mice. Addict Biol. 2003;8(4):419–27. [PubMed]
- Lynch WJ. Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol. 2006;14(1):34–41. [PubMed]
- Lynch WJ. Acquisition and maintenance of cocaine self-administration in adolescent rats: effects of sex and gonadal hormones. Psychopharmacology (Berl) 2008;197(2):237–46. [PubMed]
- Lynch WJ. Sex and ovarian hormones influence vulnerability and motivation for nicotine during adolescence in rats. Pharmacol Biochem Behav 2009
- Lynch WJ, Roth ME, Carroll ME. Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology (Berl) 2002;164(2):121–37. [PubMed]
- MacLusky NJ, Naftolin F. Sexual differentiation of the central nervous system. Science. 1981;211(4488):1294–302. [PubMed]
- Marinelli M, Rudick CN, Hu XT, White FJ. Excitability of dopamine neurons: modulation and physiological consequences. CNS Neurol Disord Drug Targets. 2006;5(1):79–97. [PubMed]
- Martin CA, Kelly TH, Rayens MK, Brogli B, Himelreich K, Brenzel A, Bingcang CM, Omar H. Sensation seeking and symptoms of disruptive disorder: association with nicotine, alcohol, and marijuana use in early and mid-adolescence. Psychol Rep. 2004;94(3 Pt 1):1075–82. [PubMed]
- Martin CA, Kelly TH, Rayens MK, Brogli BR, Brenzel A, Smith WJ, Omar HA. Sensation seeking, puberty, and nicotine, alcohol, and marijuana use in adolescence. J Am Acad Child Adolesc Psychiatry. 2002;41(12):1495–502. [PubMed]
- Mathews IZ, McCormick CM. Female and male rats in late adolescence differ from adults in amphetamine-induced locomotor activity, but not in conditioned place preference for amphetamine. Behav Pharmacol. 2007;18(7):641–50. [PubMed]
- McArthur S, McHale E, Gillies GE. The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner. Neuropsychopharmacology. 2007;32(7):1462–76. [PubMed]
- McBride WJ, Murphy JM, Ikemoto S. Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies. Behav Brain Res. 1999;101(2):129–52. [PubMed]
- McCutcheon JE, Marinelli M. Age matters. Eur J Neurosci. 2009;29(5):997–1014. [PMC free article] [PubMed]
- McDougall SA, Duke MA, Bolanos CA, Crawford CA. Ontogeny of behavioral sensitization in the rat: effects of direct and indirect dopamine agonists. Psychopharmacology (Berl) 1994;116(4):483–90. [PubMed]
- McQuown SC, Dao JM, Belluzzi JD, Leslie FM. Age-dependent effects of low-dose nicotine treatment on cocaine-induced behavioral plasticity in rats. Psychopharmacology (Berl) 2009
- Meco G, Rubino A, Caravona N, Valente M. Sexual dysfunction in Parkinson’s disease. Parkinsonism Relat Disord. 2008;14(6):451–6. [PubMed]
- Mello NK, Knudson IM, Mendelson JH. Sex and menstrual cycle effects on progressive ratio measures of cocaine self-administration in cynomolgus monkeys. Neuropsychopharmacology. 2007;32(9):1956–66. [PubMed]
- Meng SZ, Ozawa Y, Itoh M, Takashima S. Developmental and age-related changes of dopamine transporter, and dopamine D1 and D2 receptors in human basal ganglia. Brain Res. 1999;843(1-2):136–44. [PubMed]
- Meyer EM, Jr, Lytle LD. Sex related differences in the physiological disposition of amphetamine and its metabolites in the rat. Proc West Pharmacol Soc. 1978;21:313–6. [PubMed]
- Milesi-Halle A, Hendrickson HP, Laurenzana EM, Gentry WB, Owens SM. Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats. Toxicol Appl Pharmacol. 2005;209(3):203–13. [PubMed]
- Montague DM, Lawler CP, Mailman RB, Gilmore JH. Developmental regulation of the dopamine D1 receptor in human caudate and putamen. Neuropsychopharmacology. 1999;21(5):641–9. [PubMed]
- Morissette M, Biron D, Di Paolo T. Effect of estradiol and progesterone on rat striatal dopamine uptake sites. Brain Res Bull. 1990;25(3):419–22. [PubMed]
- Morissette M, Di Paolo T. Effect of chronic estradiol and progesterone treatments of ovariectomized rats on brain dopamine uptake sites. J Neurochem. 1993;60(5):1876–83. [PubMed]
- Morissette M, Di Paolo T. Sex and estrous cycle variations of rat striatal dopamine uptake sites. Neuroendocrinology. 1993;58(1):16–22. [PubMed]
- Morissette M, Di Paolo T. Effect of estradiol on striatal dopamine activity of female hemiparkinsonian monkeys. J Neurosci Res. 2009;87(7):1634–44. [PubMed]
- Morissette M, Le Saux M, D’Astous M, Jourdain S, Al Sweidi S, Morin N, Estrada-Camarena E, Mendez P, Garcia-Segura LM, Di Paolo T. Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Steroid Biochem Mol Biol. 2008;108(3-5):327–38. [PubMed]
- Morris JA, Jordan CL, Breedlove SM. Sexual differentiation of the vertebrate nervous system. Nat Neurosci. 2004;7(10):1034–9. [PubMed]
- Munro CA, McCaul ME, Oswald LM, Wong DF, Zhou Y, Brasic J, Kuwabara H, Kumar A, Alexander M, Ye W, Wand GS. Striatal dopamine release and family history of alcoholism. Alcohol Clin Exp Res. 2006;30(7):1143–51. [PubMed]
- Munro CA, McCaul ME, Wong DF, Oswald LM, Zhou Y, Brasic J, Kuwabara H, Kumar A, Alexander M, Ye W, Wand GS. Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry. 2006;59(10):966–74. [PubMed]
- Myers DP, Andersen AR. Adolescent addiction. Assessment and identification. J Pediatr Health Care. 1991;5(2):86–93. [PubMed]
- NHSDUH. United States Department of Health and Human Services. Substance Abuse and Mental Health Services Administration. Office of Applied Studies. National Survey on Drug Use and Health, 2007 2007
- Nolen-Hoeksema S. Gender differences in risk factors and consequences for alcohol use and problems. Clin Psychol Rev. 2004;24(8):981–1010. [PubMed]
- Nomura Y, Naitoh F, Segawa T. Regional changes in monoamine content and uptake of the rat brain during postnatal development. Brain Res. 1976;101(2):305–15. [PubMed]
- O’Dell LE, Bruijnzeel AW, Ghozland S, Markou A, Koob GF. Nicotine withdrawal in adolescent and adult rats. Ann N Y Acad Sci. 2004;1021:167–74. [PubMed]
- O’Dell LE, Bruijnzeel AW, Smith RT, Parsons LH, Merves ML, Goldberger BA, Richardson HN, Koob GF, Markou A. Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction. Psychopharmacology (Berl) 2006;186(4):612–9. [PubMed]
- O’Dell LE, Torres OV, Natividad LA, Tejeda HA. Adolescent nicotine exposure produces less affective measures of withdrawal relative to adult nicotine exposure in male rats. Neurotoxicol Teratol. 2007;29(1):17–22. [PMC free article] [PubMed]
- Ojeda SR, Andrews WW, Advis JP, White SS. Recent advances in the endocrinology of puberty. Endocr Rev. 1980;1(3):228–57. [PubMed]
- Ojeda SR, Urbanski HF, Ahmed CE. The onset of female puberty: studies in the rat. Recent Prog Horm Res. 1986;42:385–442. [PubMed]
- Oo TF, Kholodilov N, Burke RE. Regulation of natural cell death in dopaminergic neurons of the substantia nigra by striatal glial cell line-derived neurotrophic factor in vivo. J Neurosci. 2003;23(12):5141–8. [PubMed]
- Ovtscharoff W, Eusterschulte B, Zienecker R, Reisert I, Pilgrim C. Sex differences in densities of dopaminergic fibers and GABAergic neurons in the prenatal rat striatum. J Comp Neurol. 1992;323(2):299–304. [PubMed]
- Palmer RH, Young SE, Hopfer CJ, Corley RP, Stallings MC, Crowley TJ, Hewitt JK. Developmental epidemiology of drug use and abuse in adolescence and young adulthood: Evidence of generalized risk. Drug Alcohol Depend. 2009;102(1-3):78–87. [PMC free article] [PubMed]
- Pandolfo P, Vendruscolo LF, Sordi R, Takahashi RN. Cannabinoid-induced conditioned place preference in the spontaneously hypertensive rat-an animal model of attention deficit hyperactivity disorder. Psychopharmacology (Berl) 2009;205(2):319–26. [PubMed]
- Paredes RG, Agmo A. Has dopamine a physiological role in the control of sexual behavior? A critical review of the evidence. Prog Neurobiol. 2004;73(3):179–226. [PubMed]
- Parylak SL, Caster JM, Walker QD, Kuhn CM. Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats. Pharmacol Biochem Behav. 2008;89(3):314–23. [PMC free article] [PubMed]
- Paus T, Keshavan M, Giedd JN. Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci. 2008;9(12):947–57. [PMC free article] [PubMed]
- Peper JS, Brouwer RM, Schnack HG, van Baal GC, van Leeuwen M, van den Berg SM, Delemarre-Van de Waal HA, Boomsma DI, Kahn RS, Hulshoff Pol HE. Sex steroids and brain structure in pubertal boys and girls. Psychoneuroendocrinology. 2009;34(3):332–42. [PubMed]
- Perkins KA, Donny E, Caggiula AR. Sex differences in nicotine effects and self-administration: review of human and animal evidence. Nicotine Tob Res. 1999;1(4):301–15. [PubMed]
- Perry JL, Anderson MM, Nelson SE, Carroll ME. Acquisition of i.v. cocaine self-administration in adolescent and adult male rats selectively bred for high and low saccharin intake. Physiol Behav. 2007;91(1):126–33. [PubMed]
- Perry JL, Carroll ME. The role of impulsive behavior in drug abuse. Psychopharmacology (Berl) 2008;200(1):1–26. [PubMed]
- Philpot RM, Badanich KA, Kirstein CL. Place conditioning: age-related changes in the rewarding and aversive effects of alcohol. Alcohol Clin Exp Res. 2003;27(4):593–9. [PubMed]
- Pitts DK, Freeman AS, Chiodo LA. Dopamine neuron ontogeny: electrophysiological studies. Synapse. 1990;6(4):309–20. [PubMed]
- Porcher W, Heller A. Regional development of catecholamine biosynthesis in rat brain. J Neurochem. 1972;19(8):1917–30. [PubMed]
- Quevedo KM, Benning SD, Gunnar MR, Dahl RE. The onset of puberty: effects on the psychophysiology of defensive and appetitive motivation. Dev Psychopathol. 2009;21(1):27–45. [PMC free article] [PubMed]
- Quinones-Jenab V. Why are women from Venus and men from Mars when they abuse cocaine? Brain Res. 2006;1126(1):200–3. [PubMed]
- Rao PA, Molinoff PB, Joyce JN. Ontogeny of dopamine D1 and D2 receptor subtypes in rat basal ganglia: a quantitative autoradiographic study. Brain Res Dev Brain Res. 1991;60(2):161–77.
- Riccardi P, Zald D, Li R, Park S, Ansari MS, Dawant B, Anderson S, Woodward N, Schmidt D, Baldwin R, Kessler R. Sex differences in amphetamine-induced displacement of [(18)F]fallypride in striatal and extrastriatal regions: a PET study. Am J Psychiatry. 2006;163(9):1639–41. [PubMed]
- Rice D, Barone S., Jr Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108 3:511–33. [PMC free article] [PubMed]
- Ridenour TA, Lanza ST, Donny EC, Clark DB. Different lengths of times for progressions in adolescent substance involvement. Addict Behav. 2006;31(6):962–83. [PMC free article] [PubMed]
- Romeo RD. Puberty: a period of both organizational and activational effects of steroid hormones on neurobehavioural development. J Neuroendocrinol. 2003;15(12):1185–92. [PubMed]
- Romeo RD, Richardson HN, Sisk CL. Puberty and the maturation of the male brain and sexual behavior: recasting a behavioral potential. Neurosci Biobehav Rev. 2002;26(3):381–91. [PubMed]
- Rosenberg DR, Lewis DA. Changes in the dopaminergic innervation of monkey prefrontal cortex during late postnatal development: a tyrosine hydroxylase immunohistochemical study. Biol Psychiatry. 1994;36(4):272–7. [PubMed]
- Rosenberg DR, Lewis DA. Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol. 1995;358(3):383–400. [PubMed]
- Ross HE, Glasser FB, Stiasny S. Sex differences in the prevalence of psychiatric disorders in patients with alcohol and drug problems. Br J Addict. 1988;83(10):1179–92. [PubMed]
- Sato SM, Schulz KM, Sisk CL, Wood RI. Adolescents and androgens, receptors and rewards. Horm Behav. 2008;53(5):647–58. [PMC free article] [PubMed]
- Schmidt PJ, Steinberg EM, Negro PP, Haq N, Gibson C, Rubinow DR. Pharmacologically induced hypogonadism and sexual function in healthy young women and men. Neuropsychopharmacology. 2009;34(3):565–76. [PMC free article] [PubMed]
- Schramm-Sapyta NL, Pratt AR, Winder DG. Effects of periadolescent versus adult cocaine exposure on cocaine conditioned place preference and motor sensitization in mice. Psychopharmacology (Berl) 2004;173(1-2):41–8. [PubMed]
- Schramm-Sapyta NL, Walker QD, Caster JM, Levin ED, Kuhn CM. Are adolescents more vulnerable to drug addiction than adults? Evidence from animal models. Psychopharmacology (Berl) 2009
- Schulz KM, Molenda-Figueira HA, Sisk CL. Back to the future: The organizational-activational hypothesis adapted to puberty and adolescence. Horm Behav. 2009;55(5):597–604. [PMC free article] [PubMed]
- Schulz KM, Sisk CL. Pubertal hormones, the adolescent brain, and the maturation of social behaviors: Lessons from the Syrian hamster. Mol Cell Endocrinol. 2006;254-255:120–6. [PubMed]
- Schwandt ML, Barr CS, Suomi SJ, Higley JD. Age-dependent variation in behavior following acute ethanol administration in male and female adolescent rhesus macaques (Macaca mulatta) Alcohol Clin Exp Res. 2007;31(2):228–37. [PubMed]
- Schwandt ML, Higley JD, Suomi SJ, Heilig M, Barr CS. Rapid tolerance and locomotor sensitization in ethanol-naive adolescent rhesus macaques. Alcohol Clin Exp Res. 2008;32(7):1217–28. [PubMed]
- See RE, Elliott JC, Feltenstein MW. The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats. Psychopharmacology (Berl) 2007;194(3):321–31. [PubMed]
- Seeman P. Images in neuroscience. Brain development, X: pruning during development. Am J Psychiatry. 1999;156(2):168. [PubMed]
- Shahbazi M, Moffett AM, Williams BF, Frantz KJ. Age- and sex-dependent amphetamine self-administration in rats. Psychopharmacology (Berl) 2008;196(1):71–81. [PubMed]
- Shram MJ, Funk D, Li Z, Le AD. Nicotine self-administration, extinction responding and reinstatement in adolescent and adult male rats: evidence against a biological vulnerability to nicotine addiction during adolescence. Neuropsychopharmacology. 2008;33(4):739–48. [PubMed]
- Shram MJ, Le AD. Adolescent male Wistar rats are more responsive than adult rats to the conditioned rewarding effects of intravenously administered nicotine in the place conditioning procedure. Behav Brain Res 2009
- Shram MJ, Li Z, Le AD. Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long-Evans rats. Psychopharmacology (Berl) 2008;197(1):45–58. [PubMed]
- Shram MJ, Siu EC, Li Z, Tyndale RF, Le AD. Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats. Psychopharmacology (Berl) 2008;198(2):181–90. [PubMed]
- Sisk CL, Schulz KM, Zehr JL. Puberty: a finishing school for male social behavior. Ann N Y Acad Sci. 2003;1007:189–98. [PubMed]
- Sisk CL, Zehr JL. Pubertal hormones organize the adolescent brain and behavior. Front Neuroendocrinol. 2005;26(3-4):163–74. [PubMed]
- Sofuoglu M, Babb DA, Hatsukami DK. Effects of progesterone treatment on smoked cocaine response in women. Pharmacol Biochem Behav. 2002;72(1-2):431–5. [PubMed]
- Sofuoglu M, Dudish-Poulsen S, Nelson D, Pentel PR, Hatsukami DK. Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans. Exp Clin Psychopharmacol. 1999;7(3):274–83. [PubMed]
- Sofuoglu M, Mitchell E, Kosten TR. Effects of progesterone treatment on cocaine responses in male and female cocaine users. Pharmacol Biochem Behav. 2004;78(4):699–705. [PubMed]
- Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24(4):417–63. [PubMed]
- Stamford JA. Development and ageing of the rat nigrostriatal dopamine system studied with fast cyclic voltammetry. J Neurochem. 1989;52(5):1582–9. [PubMed]
- Steinberg L, Albert D, Cauffman E, Banich M, Graham S, Woolard J. Age differences in sensation seeking and impulsivity as indexed by behavior and self-report: evidence for a dual systems model. Dev Psychol. 2008;44(6):1764–78. [PubMed]
- Styne DM, Grumbach MM. Puberty: Ontogeny, Neuroendocrinology, Physiology and Disorders in Williams Textbook of Endocrinology. Saunders; 2008.
- Tarazi FI, Baldessarini RJ. Comparative postnatal development of dopamine D(1), D(2) and D(4) receptors in rat forebrain. Int J Dev Neurosci. 2000;18(1):29–37. [PubMed]
- Tarazi FI, Tomasini EC, Baldessarini RJ. Postnatal development of dopamine and serotonin transporters in rat caudate-putamen and nucleus accumbens septi. Neurosci Lett. 1998;254(1):21–4. [PubMed]
- Tarazi FI, Tomasini EC, Baldessarini RJ. Postnatal development of dopamine D1-like receptors in rat cortical and striatolimbic brain regions: An autoradiographic study. Dev Neurosci. 1999;21(1):43–9. [PubMed]
- Teicher MH, Andersen SL, Hostetter JC., Jr Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. Brain Res Dev Brain Res. 1995;89(2):167–72.
- Teicher MH, Barber NI, Gelbard HA, Gallitano AL, Campbell A, Marsh E, Baldessarini RJ. Developmental differences in acute nigrostriatal and mesocorticolimbic system response to haloperidol. Neuropsychopharmacology. 1993;9(2):147–56. [PubMed]
- Tepper JM, Trent F, Nakamura S. Postnatal development of the electrical activity of rat nigrostriatal dopaminergic neurons. Brain Res Dev Brain Res. 1990;54(1):21–33.
- Terner JM, de Wit H. Menstrual cycle phase and responses to drugs of abuse in humans. Drug Alcohol Depend. 2006;84(1):1–13. [PubMed]
- Terry-McElrath YM, O’Malley P M, Johnston LD. Saying no to marijuana: why American youth report quitting or abstaining. J Stud Alcohol Drugs. 2008;69(6):796–805. [PMC free article] [PubMed]
- Tetrault JM, Desai RA, Becker WC, Fiellin DA, Concato J, Sullivan LE. Gender and non-medical use of prescription opioids: results from a national US survey. Addiction. 2008;103(2):258–68. [PubMed]
- Tirelli E, Laviola G, Adriani W. Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev. 2003;27(1-2):163–78. [PubMed]
- Torres OV, Tejeda HA, Natividad LA, O’Dell LE. Enhanced vulnerability to the rewarding effects of nicotine during the adolescent period of development. Pharmacol Biochem Behav. 2008;90(4):658–63. [PMC free article] [PubMed]
- Tseng KY, O’Donnell P. Post-pubertal emergence of prefrontal cortical up states induced by D1-NMDA co-activation. Cereb Cortex. 2005;15(1):49–57. [PubMed]
- Tseng KY, O’Donnell P. Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex. 2007;17(5):1235–40. [PMC free article] [PubMed]
- Ujike H, Tsuchida K, Akiyama K, Fujiwara Y, Kuroda S. Ontogeny of behavioral sensitization to cocaine. Pharmacol Biochem Behav. 1995;50(4):613–7. [PubMed]
- Van Etten ML, Neumark YD, Anthony JC. Male-female differences in the earliest stages of drug involvement. Addiction. 1999;94(9):1413–9. [PubMed]
- van Luijtelaar EL, Dirksen R, Vree TB, van Haaren F. Effects of acute and chronic cocaine administration on EEG and behaviour in intact and castrated male and intact and ovariectomized female rats. Brain Res Bull. 1996;40(1):43–50. [PubMed]
- Vanderschuren LJ, Everitt BJ. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science. 2004;305(5686):1017–9. [PubMed]
- Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP. Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol Behav. 2002;77(1):107–14. [PubMed]
- Vetter CS, Doremus-Fitzwater TL, Spear LP. Time course of elevated ethanol intake in adolescent relative to adult rats under continuous, voluntary-access conditions. Alcohol Clin Exp Res. 2007;31(7):1159–68. [PMC free article] [PubMed]
- Vivian JA, Green HL, Young JE, Majerksy LS, Thomas BW, Shively CA, Tobin JR, Nader MA, Grant KA. Induction and maintenance of ethanol self-administration in cynomolgus monkeys (Macaca fascicularis): long-term characterization of sex and individual differences. Alcohol Clin Exp Res. 2001;25(8):1087–97. [PubMed]
- Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology. 2009;56 1:3–8. [PMC free article] [PubMed]
- Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, Jayne M, Ma Y, Wong C. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26(24):6583–8. [PubMed]
- Walker QD, Cabassa J, Kaplan KA, Li ST, Haroon J, Spohr HA, Kuhn CM. Sex differences in cocaine-stimulated motor behavior: disparate effects of gonadectomy. Neuropsychopharmacology. 2001;25(1):118–30. [PubMed]
- Walker QD, Kuhn CM. Cocaine increases stimulated dopamine release more in periadolescent than adult rats. Neurotoxicol Teratol. 2008;30(5):412–8. [PMC free article] [PubMed]
- Walker QD, Ray R, Kuhn CM. Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology. 2006;31(6):1193–202. [PubMed]
- Walker QD, Rooney MB, Wightman RM, Kuhn CM. Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience. 2000;95(4):1061–70. [PubMed]
- Walker QD, Schramm-Sapyta NL, Caster JM, Waller ST, Brooks MP, Kuhn CM. Novelty-induced locomotion is positively associated with cocaine ingestion in adolescent rats; anxiety is correlated in adults. Pharmacol Biochem Behav. 2009;91(3):398–408. [PMC free article] [PubMed]
- Wallen K, Zehr JL. Hormones and history: the evolution and development of primate female sexuality. J Sex Res. 2004;41(1):101–12. [PMC free article] [PubMed]
- Wang L, Pitts DK. Ontogeny of nigrostriatal dopamine neuron autoreceptors: iontophoretic studies. J Pharmacol Exp Ther. 1995;272(1):164–76. [PubMed]
- Waylen A, Wolke D. Sex ‘n’ drugs ‘n’ rock ‘n’ roll: the meaning and social consequences of pubertal timing. Eur J Endocrinol. 2004;151 3:U151–9. [PubMed]
- West MJ, Slomianka L, Gundersen HJ. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec. 1991;231(4):482–97. [PubMed]
- White DA, Michaels CC, Holtzman SG. Periadolescent male but not female rats have higher motor activity in response to morphine than do adult rats. Pharmacol Biochem Behav. 2008;89(2):188–99. [PMC free article] [PubMed]
- Wiley JL, O’Connell M M, Tokarz ME, Wright MJ., Jr Pharmacological effects of acute and repeated administration of Delta(9)-tetrahydrocannabinol in adolescent and adult rats. J Pharmacol Exp Ther. 2007;320(3):1097–105. [PMC free article] [PubMed]
- Wilmouth CE, Spear LP. Withdrawal from chronic nicotine in adolescent and adult rats. Pharmacol Biochem Behav. 2006;85(3):648–57. [PMC free article] [PubMed]
- Windle M, Spear LP, Fuligni AJ, Angold A, Brown JD, Pine D, Smith GT, Giedd J, Dahl RE. Transitions into underage and problem drinking: developmental processes and mechanisms between 10 and 15 years of age. Pediatrics. 2008;121 4:S273–89. [PMC free article] [PubMed]
- Wood RI. Reinforcing aspects of androgens. Physiol Behav. 2004;83(2):279–89. [PubMed]
- Wood RI. Anabolic-androgenic steroid dependence? Insights from animals and humans. Front Neuroendocrinol. 2008;29(4):490–506. [PMC free article] [PubMed]
- Wooten GF, Currie LJ, Bovbjerg VE, Lee JK, Patrie J. Are men at greater risk for Parkinson’s disease than women? J Neurol Neurosurg Psychiatry. 2004;75(4):637–9. [PMC free article] [PubMed]
- Wooters TE, Dwoskin LP, Bardo MT. Age and sex differences in the locomotor effect of repeated methylphenidate in rats classified as high or low novelty responders. Psychopharmacology (Berl) 2006;188(1):18–27. [PubMed]
- Xu C, Coffey LL, Reith ME. Translocation of dopamine and binding of 2 beta-carbomethoxy-3 beta-(4-fluorophenyl) tropane (WIN 35,428) measured under identical conditions in rat striatal synaptosomal preparations. Inhibition by various blockers. Biochem Pharmacol. 1995;49(3):339–50. [PubMed]
- Yararbas G, Keser A, Kanit L, Pogun S. Nicotine-induced conditioned place preference in rats: Sex differences and the role of mGluR5 receptors. Neuropharmacology 2009
- Young SE, Corley RP, Stallings MC, Rhee SH, Crowley TJ, Hewitt JK. Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates. Drug Alcohol Depend. 2002;68(3):309–22. [PubMed]
- Zakharova E, Wade D, Izenwasser S. Sensitivity to cocaine conditioned reward depends on sex and age. Pharmacol Biochem Behav. 2009;92(1):131–4. [PMC free article] [PubMed]
- Zhang Y, Picetti R, Butelman ER, Schlussman SD, Ho A, Kreek MJ. Behavioral and neurochemical changes induced by oxycodone differ between adolescent and adult mice. Neuropsychopharmacology. 2009;34(4):912–22. [PubMed]
;