Positron emission tomography imaging studies of dopamine receptors in primate models of addiction (2008)

Michael A Nader,^* Paul W Czoty, Robert W Gould, and Natallia V Riddick

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Animal models have provided valuable information related to trait and state variables associated with vulnerability to drug addiction. Our brain imaging studies in monkeys have implicated D₂ receptors in cocaine addiction. For example, an inverse relationship between D₂ receptor availability and rates of cocaine self-administration has been documented. Moreover, environmental variables, such as those associated with formation of the social hierarchy, can impact receptor availability and sensitivity to the abuse-related effects of cocaine. Similarly, both D₂ receptor availability and cocaine self-administration can be altered by chronic drug administration and fluctuations in hormone levels. In addition, cocaine self-administration can be altered in an orderly fashion by presentation of an acute stressor, such as acting as an intruder into an unfamiliar social group, which can shift the cocaine dose–response curve to the left in subordinate monkeys and to the right in dominant animals, suggesting an interaction between social variables and acute stressors. Conversely, irrespective of social rank, acute environmental enrichment, such as increasing the size of the living space, shifts the cocaine dose–response curve to the right. These findings highlight a pervasive influence of the environment in modifying the reinforcing effects of cocaine and strongly implicate brain D₂ receptors.

(a) The agent

Cocaine is an indirect-acting monoamine agonist, which binds with approximately equal affinity at the dopamine (DA), serotonin (5-HT) and noradrenaline transporters (Ritz et al. 1987; Woolverton & Johnson 1992). The vast majority of studies on the mechanisms of action mediating the high abuse liability of cocaine focus on the DA system. Briefly, DA cells from the ventral tegmental area project to structures within the striatum, including the nucleus accumbens, and project to the cortex (Haber & McFarland 1999); these pathways have been implicated in all rewarding behaviours (Di Chiara & Imperato 1988). DA released into the synapse is primarily removed by active uptake by the DA transporter. Cocaine acts by blocking the transporter and elevating the levels of extracellular DA, which produces its downstream effects by binding to two superfamilies of DA receptors, D₁– and D₂-like receptors (Sibley et al. 1993). The imaging work described in this review will focus on D₂-like receptors and imaging tools, [¹¹C]raclopride and [¹⁸F]fluoroclebopride (FCP), that do not differentiate among the subtypes of the D₂ superfamily (Mach et al. 1993). Also of relevance is whether the D₂ positron emission tomography (PET) ligands are assessing pre- or postsynaptic D₂-like receptors. Based on lesioning work (Chalon et al. 1999), we hypothesize that changes in D₂ receptor availability are primarily due to changes in postsynaptic D₂ receptor function (see Nader & Czoty 2005).

Research into the pharmacodynamics and pharmacokinetics of cocaine that leads to its high abuse potential has enhanced our understanding of the DA system and reward mechanisms. Using techniques such as in vivo microdialysis in animals surgically implanted with cannulae targeting various brain structures, cocaine has been shown to elevate levels of extracellular DA in areas of the brain that are believed to mediate reinforcement (see Bradberry 2000; Czoty et al. 2002; Howell & Wilcox 2002). In humans, using non-invasive brain imaging techniques such as PET, the relationship between elevating DA and subjective drug effects was examined (Volkow et al. 1999). In that study, investigators administered [¹¹C]raclopride, which binds to postsynaptic DA-D₂ receptors, and measured the displacement of that radiotracer by DA in non-drug abusing individuals. Because cocaine could not be administered to these individuals for ethical reasons, the investigators used another indirect-acting DA agonist, methylphenidate, that has reinforcing effects in animals and humans (e.g. Johanson & Schuster 1975; Volkow et al. 1999). There was an orderly relationship between the ability of methylphenidate to elevate DA and displace [¹¹C]raclopride from D₂-like receptors and the intensity of the subjective reports of ‘high’. Importantly, in the subjects that did not report a high, methylphenidate did not elevate DA.

Finally, despite the clear relevance of specific actions of cocaine at neurobiological target sites, it is important to point out that it is our premise that the prominent abuse-related effects of cocaine are not simply explained by pharmacological interactions between drug and receptor. There are clearly profound differences in the behavioural effects of cocaine when administered non-contingently by the investigator versus self-administered by the animal (Dworkin et al. 1995; Stefanski et al. 1999; Bradberry 2000). Moreover, as described in detail below, the schedule of cocaine availability can have profound effects on the CNS consequences of cocaine exposure.

(b) The host

The studies described below used non-human primates, specifically, rhesus monkeys (Macaca mulatta) or cynomolgus monkeys (Macaca fascicularis). Along with baboons, these Old World monkeys are the most closely phylogenetically related species to humans that can be used in biomedical research. Thus, our ability to accurately generalize from laboratory animal models to human drug abuse is enhanced by using monkeys as subjects; this is particularly important for imaging studies (Nader & Czoty 2008). There are documented differences between monkey and rodent dopaminergic systems (Berger et al. 1991; Joel & Weiner 2000), including differences in DA affinity at D₁– and D₂-like receptors (Weed et al. 1998), as well as evidence of species differences in cocaine-induced changes in brain function (e.g. Lyons et al. 1996) and in the behavioural effects of indirect-acting DA agonists including cocaine (e.g. Roberts et al. 1999; Lile et al. 2003). There are also data indicating that many drugs, including drugs of abuse, have similar pharmacokinetic profiles in monkeys and humans, which differ in rodents (e.g. Banks et al. 2007; see Weerts et al. 2007 for review).

Monkeys also allow for the investigation of social variables in cocaine abuse (Morgan et al. 2002; Czoty et al. 2005); these studies provide a unique translational component to our research. The social hierarchy (i.e. the social ranks of each of the four monkeys in a group) is determined by recording winners of fights between the monkeys (Kaplan et al. 1982). The first-ranking (‘dominant’) monkey is defined as the monkey that wins fights against the other three monkeys. The second-ranking monkey wins all fights except against the first-ranking monkey, and so on. The monkey that loses fights with all others in the pen is designated the lowest-ranking (‘subordinate’) monkey.

Sex is a host factor that has been largely overlooked in drug abuse research. While the majority of our research has focused on male subjects, there is growing evidence for sex differences in behaviour, pharmacology and neurochemical actions of abused drugs (Lynch et al. 2002; Lynch 2006; Terner & de Wit 2006). Importantly, these reported sex differences extend beyond drug abuse to include most psychiatric disorders including schizophrenia, Parkinson’s disease and obsessive–compulsive disorder (e.g. Seeman 1996; Wieck et al. 2003). In female subjects, there is evidence that menstrual cycle phase can alter sensitivity to drugs of abuse (see Terner & de Wit 2006). Female macaques have an approximately 28-day menstrual cycle, with fluctuations in oestrogen and progesterone resembling those of women (e.g. Jewitt & Dukelow 1972; Appt 2004), making them ideal for studying conditions related to women’s health. Although not discussed in this paper, studies related to prenatal drug exposure would also benefit from the use of non-human primates. For example, the gestation period in macaques is approximately six months, which is close to human gestation and much longer than rodent models (Sandberg & Olsen 1991).

Of relevance to the topic of this review, we recently investigated how menstrual cycle phase influenced measures of DA-D₂ receptor availability in female cynomolgus monkeys (Czoty et al. 2008). As will be described below, there appears to be a relationship between D₂ receptor availability and reinforcing effects of cocaine. Thus, if menstrual cycle phase influences D₂ receptor levels, this may be a primary mechanism for differences in abuse-related effects of cocaine (or other abused drugs) in women tested at different times of the month (Sofuoglu et al. 1999). Three PET imaging studies in women have investigated D₂ receptor availability as a function of menstrual cycle; three different outcomes were reported. Wong et al. (1988) reported a trend towards lower radiotracer uptake in the striatum of women tested in the follicular versus luteal phase. In a more recent study, they found lower D₂ receptor measures in the putamen (but not caudate nucleus or ventral striatum) in women in the luteal versus follicular phase (Munro et al. 2006). Finally, Nordstrom et al. (1998) found no evidence of menstrual cycle-dependent variations in D₂ receptor availability in the putamen in five women. Several factors could account for these disparate results, including the stress level and the drug history of the women. Importantly, these factors can be controlled in animal studies. In seven experimentally naive, normally cycling female cynomolgus monkeys, we found that D₂ receptor availability was significantly (approx. 13%) lower in the follicular phase compared with the same monkeys studied during the luteal phase (Czoty et al. 2008). Such an outcome supports differences in sensitivity to drug effects at various stages of the menstrual cycle and underscores the importance of the hormonal milieu as a host factor that may influence the effects of abused drugs. Moreover, these data suggest that studies in female subjects should minimize the influence of menstrual cycle fluctuations by taking measurements in the same menstrual cycle phase when conducting longitudinal studies.

(c) The context

In our studies, we view the context as encompassing all environmental stimuli, experimental history and social status. For this paper, we will limit the context to a brief description of models used to assess cocaine reinforcement and to non-human primate social behaviour. When describing the models of drug self-administration with respect to the schedule of reinforcement, an important distinction should be made between reinforcing ‘effects’ and reinforcing ‘strength’. A reinforcing effect simply means that responding leading to drug presentation occurs at higher rates than responding leading to vehicle presentation. For every drug that has reinforcing effects, the shape of the dose–response curve approximates an inverted U-shape. That is, there is an ascending limb characterized by dose-dependent increases in responding, a dose that results in peak rates of responding and a descending limb in which increases in dose result in lower rates of responding (see Zernig et al. 2004). Because several factors influence the shape of the curve, it is impossible to compare dose–response curves from different drugs and make statements related to which drug is ‘more reinforcing’ (Woolverton & Nader 1990). However, other schedules can be used to make assessments related to reinforcing strength; these will be described in more detail below. The main point to highlight is that different schedules of reinforcement have features that render them suitable for answering different questions about the behavioural effects of cocaine. For example, questions related to the relative importance of drug seeking (i.e. simply self-administering cocaine) versus total cocaine intake in producing changes in the brain can be assessed by studying different schedules of cocaine self-administration. Such a distinction is of clear relevance when considering treatment options for drug abuse—does it matter how much drug a patient has taken or how long (s)he has been abusing the drug? Volkow et al. (1999) found that levels of DA-D₂ receptor availability as measured with PET were more dependent on the duration of cocaine use than on the amount of drug used prior to the study. This finding suggested that the behaviours leading to drug procurement, independent of the pharmacology of cocaine, could contribute to the reported changes in DA receptor availability in cocaine abusers and supported the hypothesis that the environment can have profound effects on the brain.

The use of non-human primates, PET imaging and different schedules of reinforcement provided an opportunity to directly assess the importance of drug seeking versus total cocaine intake (Czoty et al. 2007a,b). To directly test this hypothesis, 12 experimentally naive rhesus monkeys received baseline PET scans using the D₂ receptor ligand [¹⁸F]FCP. Six of these monkeys were then trained to self-administer cocaine under a second-order schedule, a very lean schedule of reinforcement in which drug seeking was maintained by the presentation of conditioned stimuli throughout the 60 min session until cocaine was finally administered (Katz 1980). Under the final schedule parameters, the first response after 3min (fixed interval; FI 3min) produced a stimulus change (S) associated with cocaine reinforcement and the tenth completed FI (i.e. fixed ratio 10) resulted in cocaine presentation (designated FR 10 [FI 3min:S]). Sessions ended after two cocaine injections (0.1mgkg⁻¹injection⁻¹). Thus, these animals had an extensive drug-seeking history, but very low levels of cocaine intake. The second group of six monkeys was trained to respond under an FR 30 schedule of cocaine presentation. Conditions for this group were arranged to model ‘binge’ access—monkeys could receive up to 30 injections of 0.3mgkg⁻¹ cocaine twice per day, 2 days per week. Thus, relative to the other group of monkeys, this set of subjects received much more cocaine but drug seeking was only 2 days per week. We found that binge access to cocaine resulted in significant reductions in D₂ receptor availability at every time point, while ‘drug seeking’ under the second-order schedule did not significantly affect D₂ receptor availability over 1 year. These findings suggest that the reductions in D₂ availability seen in humans were primarily due to the direct effects of cocaine on DA receptor levels.

(i) Organism×environment interactions: part 1

Acquisition of drug reinforcement is influenced by characteristics of the individual (i.e. trait variables) as well as by features of the environment (e.g. state variables). One of the first studies of the relationship of trait variables to sensitivity to drug reinforcement was provided by Piazza et al. (1989) in which two groups of rats were differentiated based on locomotor activity in an open-field apparatus as high responders (HR) or low responders (LR). Rats were implanted with indwelling intravenous catheters and given access to low doses of d-amphetamine under an FR schedule. HR rats acquired d-amphetamine self-administration at lower doses than LR rats. The use of this simple schedule allowed for characterization of vulnerability based on an inherent behavioural characteristic, namely, locomotor activity in an open field.

More recently, laboratory animal studies have examined behaviours related to ‘impulsivity’, a trait shown to be high in cocaine abusers (Moeller et al. 2002). Rats characterized as more impulsive acquired cocaine self-administration more rapidly than less impulsive rats (Dalley et al. 2007). Perry et al. (2005) addressed whether impulsivity precedes drug abuse. In that study, rats were trained on a delay discounting procedure in which responding on one lever under an FR 1 contingency resulted in the immediate delivery of one food pellet, while responding on another lever under an FR 1 contingency resulted in the delivery of three food pellets after a variable delay. If the rat chose the immediate option, the delay value decreased on the next trial for the alternative; if the delay option was chosen, the delay value increased on the next trial. A mean adjusted delay (MAD) value was calculated for each rat by averaging all delay values across trials. As described by Perry et al. (2005), the MAD served as a quantitative measure of the extent to which each rat discounted delayed food reinforcers. Higher MAD values, representing longer delays, were indicative of low impulsivity, while smaller MAD values indicated more impulsive behaviour. The rats were divided into two groups, high and low impulsiveness (HiI and LoI, respectively) based on MAD values. When cocaine acquisition was studied, HiI animals acquired self-administration more rapidly and at higher levels than LoI rats. Taken together, these findings support the hypothesis that there are behavioural traits that predispose individuals to drug abuse and these can be examined using animal models.

Our group has studied trait variables and gene–environment interactions in relation to drug abuse in non-human primates for over a decade. Much of our research has been conducted in cocaine-naive monkeys prior to being exposed to cocaine in order to address gaps in the clinical data—questions that cannot be answered in humans due to ethical concerns. For example, as described above, cocaine abusers have lower levels of D₂ receptor availability than control subjects (Volkow et al. 1990, 1993; Martinez et al. 2004) and non-drug abusers with lower basal levels of D₂ receptor availability found methylphenidate more reinforcing (Volkow et al. 1999). It is not known whether low D₂ levels were the result of cocaine use or a pre-existing feature that conferred vulnerability to the reinforcing effect of cocaine. The question is whether D₂ receptor availability is a trait marker for vulnerability to cocaine abuse. We have directly addressed this question in two ways. First, we correlated basal D₂ receptor availability in cocaine-naive monkeys with subsequent rates of cocaine self-administration. Second, we studied the changes in D₂ receptor availability in cocaine-naive monkeys over 1 year of access to determine whether cocaine reinforcement decreased these levels (Nader et al. 2006). A summary of the findings is shown in figure 1. Initially, cocaine-naive monkeys were scanned with the D₂ receptor ligand [¹⁸F]FCP and then trained to respond under an FI 3min schedule of food presentation. When responding was stable, each monkey was surgically implanted with an indwelling venous catheter, a dose of cocaine (0.2mgkg⁻¹injection⁻¹) was substituted for food and response rates were recorded. An important point is that there was no training under the cocaine self-administration paradigm—the monkeys were simply exposed to the drug and response rates were recorded. We found an inverse relationship between baseline D₂ receptor availability and the rates of cocaine self-administration (figure 1a). Monkeys with low D₂ receptor levels self-administered cocaine at higher rates compared with monkeys with high D₂ receptor availability. These findings are very similar to the observations by Volkow et al. (1999) using non-drug abusers and methylphenidate. We also found that, over a 1-year period in which cocaine intake increased steadily, D₂ receptor availability decreased irrespective of what the initial levels of D₂ receptor availability were for each monkey (figure 1b). Thus, it appears that low D₂ receptor availability makes an individual more vulnerable to cocaine reinforcement and continued exposure to cocaine further decreases those levels (Nader et al. 2002, 2006).

 

Figure 1

(a) Correlation between baseline D₂ receptor availability and rates of cocaine self-administration in male rhesus monkeys. (b) Representative data from one monkey (R-1241) showing cumulative cocaine intake and associated changes in D₂ receptor availability. …

The above findings clearly support the idea that there are biological trait variables, in this case D₂ receptor availability, that influence vulnerability to cocaine abuse. We have also examined the impact of environmental variables on D₂ receptor availability and whether these effects influenced vulnerability to cocaine reinforcement. Earlier work from our group demonstrated a relationship between D₂ receptor availability and social rank in female monkeys, such that subordinate monkeys had lower D₂ receptor levels than dominant monkeys (Grant et al. 1998). We next assessed whether D₂ receptor availability was a trait variable that predicted social rank. For these studies, we used 20 experimentally naive and individually housed male cynomolgus monkeys. After baseline PET scans using [¹⁸F]FCP were conducted, monkeys were placed in social groups of four monkeys per pen and after three months were rescanned with [¹⁸F]FCP (Morgan et al. 2002). D₂ receptor availability was not a trait marker for eventual social rank. After three months of social housing, we observed the same effect that was reported by Grant et al. (1998) in female monkeys that had been living together for over 3 years—subordinate monkeys had lower D₂ receptor availability compared with dominant monkeys. However, it came about in a manner opposite to what we had expected. We had hypothesized that the lower D₂ receptor levels in subordinate monkeys compared with dominant monkeys arose as the result of chronic social stress that is unequivocally experienced by subordinate monkeys (Kaplan et al. 1982; Shively & Kaplan 1984). However, the over 20% difference between dominant and subordinate monkeys in our study was due to a significant increase in D₂ receptor availability in dominant monkeys whereas subordinates, on average, did not change. These increases in D₂ measures were in the same direction as reported in rodent studies demonstrating the influence of environmental enrichment on DA function—including increased D₂ receptor densities (e.g. Bowling et al. 1993; Rilke et al. 1995; Hall et al. 1998). Based on these rodent studies and on our findings that there was an inverse relationship between D₂ receptor availability and cocaine self-administration, we hypothesized that the subordinate monkeys would self-administer more cocaine than the dominant monkeys. Our hypothesis was borne out (Morgan et al. 2002). In fact, cocaine was not a reinforcer in the dominant monkeys when assessed under an FR 50 schedule of reinforcement (see Nader & Czoty 2005 for additional discussion).

We also examined other behaviours that we hypothesized could be trait variables predictive of social rank. In our initial study (Morgan et al. 2000), locomotor activity predicted eventual social rank in that eventual subordinate monkeys had higher locomotor scores compared with eventual dominant monkeys; interestingly, this was not extended to female monkeys (Riddick et al. submitted). Most recently, we have extended our measures to include behaviours deemed to assess impulsivity in an effort to extend more recent work in rodents (e.g. Perry et al. 2005; Dalley et al. 2007). In a group of experimentally naive and individually housed female cynomolgus monkeys, we used a measure of novel object reactivity to assess impulsivity in each animal prior to being socially housed (Riddick et al. submitted). Monkeys that would eventually become subordinate had shorter latencies to approach the novel object compared with eventual dominant female monkeys. Shorter latency is hypothesized to represent greater impulsivity. Whether the more impulsive monkeys are also more vulnerable to self-administer cocaine as was reported in rodents by Perry et al. (2005) and Dalley et al. (2007) is currently being evaluated.

(ii) Organism×environment interactions: part 2

In our socially housed male monkeys, we have extended earlier work in an effort to further enhance our homologous model of the human condition. These experiments primarily focus on changing environmental conditions. For example, we found that the protective effect associated with being the dominant monkey can be attenuated by continual exposure to cocaine (Czoty et al. 2004). That is, while there were differences in rates of self-administration when initially exposed to the FR 50 schedule (Morgan et al. 2002), repeated exposure to cocaine over a 1-year period resulted in cocaine becoming a reinforcer in dominant monkeys (see e.g. figure 2a). After several months to years of cocaine self-administration, neither response rates nor D₂ receptor availability were different in dominant compared with subordinate monkeys (Czoty et al. 2004). As mentioned above, simple schedules do not provide information related to reinforcing strength. Thus, we examined whether there would be differences between social ranks under conditions in which cocaine was available in the context of an alternative, non-drug reinforcer (Czoty et al. 2005). We found that subordinate monkeys were significantly more sensitive to the reinforcing effects of cocaine using this procedure, such that they would choose a lower dose of cocaine over food compared with dominant monkeys (figure 2b). These findings highlight several important facets of organismal and environmental interactions. These data support the observations that measures of reinforcing strength provide different information related to cocaine self-administration than measures of reinforcing effects. In addition, these findings indicate that after years of living in these stable groups the influence of the social context was still apparent.

 

Figure 2

(a) Cocaine dose–response curve in a dominant male monkey (C-5386). Filled circles (initial) were taken shortly after social hierarchies became stable (adapted from Morgan et al. 2002); open circles are the re-determined cocaine dose–response …

A question that is frequently asked is ‘what if circumstances change and a dominant monkey becomes subordinate and a subordinate monkey becomes dominant?’ To address this question, we rearranged groups such that one pen consisted of four previously dominant (first-ranked) monkeys and another pen was made up of four previously subordinate (fourth-ranked) monkeys. Additional pens were composed of intermediate (second- and third-ranked) monkeys and experimentally naive monkeys (Czoty et al. in preparation). After three months of social housing under these new conditions, PET studies were conducted and cocaine self-administration was examined under the concurrent schedule of reinforcement with food as the alternative. The relationship between new social rank and D₂ receptor availability was not evident—that is, the newly dominant monkeys did not have significantly higher levels of D₂ receptor availability compared with newly subordinate monkeys. (Note, some of the dominant monkeys were previously subordinate and some of the subordinate monkeys were once dominant.) Also, there were no differences in cocaine choice between the monkeys. Additional studies using other measures, including novel object reactivity, noted that previous rank was more predictive of outcome than current rank. There is a long and extensive literature on behavioural and pharmacological history influencing behaviour and drug effects (e.g. Barrett et al. 1989) and these studies extend those findings to include a history of social interactions.

Another example of organism×environment interaction involves the use of socially housed monkeys to examine drug-induced changes in social behaviour and the consequence of those effects on subsequent cocaine self-administration. There is an extensive literature on the interaction of social rank with drug effects in non-human primates (e.g. Smith & Byrd 1985; Martin et al. 1990; reviewed by Miczek et al. 2004). For example, Miczek and colleagues (e.g. Miczek & Yoshimura 1982; Miczek & Gold 1983a) have shown that the effects of alcohol, amphetamine or cocaine can be influenced by social rank and environmental context. In one study (Winslow & Miczek 1985), low to intermediate doses of alcohol produced increases in aggression by dominant monkeys, but no effect on aggression by subordinate animals. However, co-administration of alcohol and testosterone to subordinate monkeys resulted in increases in aggression. Crowley et al. (1974, 1992) examined the effects of a number of abused drugs on the social behaviour of macaques. Methamphetamine produced pronounced increases in locomotion and stereotypes, and declines in food-foraging behaviour and aggression. In a low-ranking monkey, high doses of methamphetamine produced such profound increases in submissive behaviours that the amount of aggression directed from the (untreated) dominant monkeys towards the drug-treated animal increased. Of all the studies examining the effects of drugs on social behaviour, this result is one of the few descriptions of the behaviour of the untreated monkeys. In our socially housed monkeys, we tested the hypothesis that if reinforcing doses of cocaine resulted in increased aggression and changes in social rank, then the frequency of cocaine self-administration in that monkey would increase in subsequent experimental sessions.

Monkeys lived in stable social groups of three and social rank was determined in each pen as described above. For these studies, only one monkey in the social group was given access to cocaine (saline, 0.01–0.1mgkg⁻¹injection⁻¹) under an FR 50 schedule of reinforcement, while the remaining monkeys in the pen had access to food presentation under an FR 50 schedule; conditions remained in effect for five consecutive sessions. When the session was completed, monkeys were returned to their social groups and agonistic and submissive behaviours were recorded over a 15min period. All monkeys (dominant, intermediate and subordinate) were studied at all cocaine doses. Social interactions did not affect response rates or cocaine intake for any monkey. However, cocaine-induced changes in social behaviour were dependent on the rank of the monkey. Irrespective of which animal in the pen self-administered cocaine, the first- and second-ranked monkeys showed increases in aggression; the subordinate monkey never demonstrated any aggression during the course of the study. These data indicate that social rank is the most important determinant of cocaine-induced changes in social behaviour. One possible reason that self-administration was insensitive to the consequences of social behaviour is that cocaine access was not scheduled until approximately 24 hours after the social interaction. Current studies are examining the consequences of cocaine-induced changes in social behaviour on cocaine self-administration that are more closely associated in time.

All experimental manipulations described in this review were performed in accordance with the National Research Council Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research and were approved by the Animal Care and Use Committee of Wake Forest University. Environmental enrichment was provided as outlined in the Animal Care and Use Committee of Wake Forest University Non-Human Primate Environmental Enrichment Plan.

We thank K. A. Grant, L. J. Porrino, R. H. Mach, J. R. Kaplan and H. D. Gage for their long-standing collaborations and contributions to this research and to Susan Nader, Tonya Calhoun, Mikki Sandridge, Michelle Icenhower and Nicholas Garrett for their excellent technical assistance throughout these research projects. Research from our laboratory and preparation of this manuscript was supported in part by NIDA grants DA 10584, DA 017763, DA 14637 and DA 06634.

One contribution of 17 to a Discussion Meeting Issue ‘The neurobiology of addiction: new vistas’.

1. Appt S.E. Usefulness of the monkey model to investigate the role of soy in postmenopausal women’s health. ILAR J. 2004;45:200–211. [PubMed]
2. Banks M.L, Sprague J.E, Kisor D.F, Czoty P.W, Nichols D.E, Nader M.A. Ambient temperature effects on 3,4-methylenedioxymethamphetamine (MDMA)-induced thermodysregulation and pharmacokinetics in male monkeys. Drug Dispos. Metab. 2007;35:1840–1845. doi:10.1124/dmd.107.016261 [PubMed]
3. Barrett J.E, Glowa J.R, Nader M.A. Behavioral and pharmacological history as determinants of tolerance and sensitization-like phenomena in drug action. In: Goudie A.J, Emmett-Oglesby M.W, editors. Psychoactive drugs. Humana Press; Clifton, NJ: 1989. pp. 181–219.
4. Berger B, Gaspar P, Verney C. Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci. 1991;14:21–27. doi:10.1016/0166-2236(91)90179-X [PubMed]
5. Bowling S.L, Rowlett J.K, Bardo M.T. The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release. Neuropsychopharmacology. 1993;32:885–893. [PubMed]
6. Bradberry C.W. Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine use. J. Neurosci. 2000;20:7109–7115. [PubMed]
7. Carroll M.E, Lac S.T, Nygaard S.L. A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior. Psychopharmacology. 1989;97:23–29. doi:10.1007/BF00443407 [PubMed]
8. Chalon S, Edmond P, Bodard S, Vilar M.P, Thiercelin C, Besnard J.C, Builloteau D. Time course of changes in striatal dopamine transporters and D₂ receptors with specific iodinated markers in a rat model of Parkinson’s disease. Synapse. 1999;31:134–139. doi:10.1002/(SICI)1098-2396(199902)31:2<134::AID-SYN6>3.0.CO;2-V [PubMed]
9. Crowley T.J, Stynes A.J, Hydinger M, Kaufman I.C. Ethanol, methamphetamine, pentobarbital, morphine, and monkey social behavior. Arch. Gen. Psychiatry. 1974;31:829–838. [PubMed]
10. Crowley T.J, Mikulich S.K, Williams E.A, Zerbe G.O, Ingersoll N.C. Cocaine, social behavior, and alcohol-solution drinking in monkeys. Drug Alcohol Depend. 1992;29:205–223. doi:10.1016/0376-8716(92)90094-S [PubMed]
11. Czoty P.W, Ginsburg B.C, Howell L.L. Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys. J. Pharmacol. Exp. Ther. 2002;300:831–837. doi:10.1124/jpet.300.3.831 [PubMed]
12. Czoty P.W, Morgan D, Shannon E.E, Gage H.D, Nader M.A. Characterization of dopamine D₁ and D₂ receptor function in socially housed cynomolgus monkeys self-administering cocaine. Psychopharmacology. 2004;174:381–388. doi:10.1007/s00213-003-1752-z [PubMed]
13. Czoty P.W, McCabe C, Nader M.A. Assessment of the reinforcing strength of cocaine in socially housed monkeys using a choice procedure. J. Pharmacol. Exp. Ther. 2005;312:96–102. doi:10.1124/jpet.104.073411 [PubMed]
14. Czoty P.W, Gage H.D, Nader S.H, Reboussin B.A, Bounds M, Nader M.A. Acquisition of cocaine self-administration does not alter dopamine D₂ receptor or transporter availability in rhesus monkeys. J. Addict. Med. 2007a;1:33–39. doi:10.1097/ADM.0b013e318045c038 [PubMed]
15. Czoty P.W, Reboussin B.A, Calhoun T.L, Nader S.H, Nader M.A. Long-term cocaine self-administration under fixed-ratio and second-order schedules in monkeys. Psychopharmacology. 2007b;131:287–295. doi:10.1007/s00213-006-0665-z [PubMed]
16. Czoty, P. W., Riddick, N. V., Gage, H. D., Sandridge, M., Nader, S. H., Garg, S., Bounds, M., Garg, P. K. & Nader, M. A. 2008 Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys. Neuropsychopharmacology (doi:10.1038/npp.2008.3) [PubMed]
17. Czoty, P. W., Nader, S. H., Gage, H. D. & Nader, M. A. In preparation. The effect of social reorganization on dopamine D₂ receptor availability and cocaine self-administration in socially housed male cynomolgus monkeys.
18. Dalley J.W, et al. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science. 2007;315:1267–1270. doi:10.1126/science.1137073 [PMC free article] [PubMed]
19. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl Acad. Sci. USA. 1988;85:5274–5278. doi:10.1073/pnas.85.14.5274 [PMC free article] [PubMed]
20. Dworkin S.I, Mirkis S, Smith J.E. Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug. Psychopharmacology. 1995;117:262–266. doi:10.1007/BF02246100 [PubMed]
21. Elkashef A, Biswas J, Acri J.B, Vocci F. Biotechnology and the treatment of addictive disorders. BioDrugs. 2007;21:259–267. doi:10.2165/00063030-200721040-00006 [PubMed]
22. Grant K.A, Shively C.A, Nader M.A, Ehrenkaufer R.L, Line S.W, Morton T.E, Gage H.D, Mach R.H. Effect of social status on striatal dopamine D₂ receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse. 1998;29:80–83. doi:10.1002/(SICI)1098-2396(199805)29:1<80::AID-SYN7>3.0.CO;2-7 [PubMed]
23. Griffiths, R. R., Bigelow, G. E. & Henningfield, J. E. 1980 Similarities in animal and human drug-taking behavior. In Advances in substance abuse, vol. 1 (ed. N. K. Mello), pp. 1–90. Greenwich, CN: JAI Press.
24. Haber S.N, McFarland N.R. The concept of the ventral striatum in nonhuman primates. Ann. N. Y. Acad. Sci. 1999;877:33–48. doi:10.1111/j.1749-6632.1999.tb09259.x [PubMed]
25. Hall F.S, Wilkinson L.S, Humby T, Inglis W, Kendall D.A, Marsden C.A, Robbins T.W. Isolation rearing in rats: pre- and postsynaptic changes in striatal dopaminergic systems. Pharmacol. Biochem. Behav. 1998;58:859–872. doi:10.1016/S0091-3057(97)00510-8 [PubMed]
26. Higgins S.T. The influence of alternative reinforcers on cocaine use and abuse: a brief review. Pharmacol. Biochem. Behav. 1997;57:419–427. doi:10.1016/S0091-3057(96)00446-7 [PubMed]
27. Howell L.L, Wilcox K.M. Functional imaging and neurochemical correlates of stimulant self-administration in primates. Psychopharmacology. 2002;163:352–361. doi:10.1007/s00213-002-1207-y [PubMed]
28. Jewitt D.A, Dukelow W.R. Cyclicity and gestation length of Macaca fascicularis. Primates. 1972;13:327–330. doi:10.1007/BF01730578
29. Joel D, Weiner I. The connections of dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience. 2000;96:451–474. doi:10.1016/S0306-4522(99)00575-8 [PubMed]
30. Johanson C.E, Schuster C.R. A choice procedure for drug reinforcers: cocaine and methylphenidate in the rhesus monkey. J. Pharmacol. Exp. Ther. 1975;193:676–688. [PubMed]
31. Kaplan J.R, Manuck S.B, Clarkson T.B, Lusso F.M, Taub D.M. Social status, environment, and atherosclerosis in cynomolgus monkeys. Arterosclerosis. 1982;2:359–368. [PubMed]
32. Katz J.L. Second-order schedules of intramuscular cocaine injection in the squirrel monkey: comparisons with food presentation and effects of d-amphetamine and promazine. J. Pharmacol. Exp. Ther. 1980;212:405–411. [PubMed]
33. Lile J.A, Wang Z, Woolverton W.L, France J.E, Gregg T.C, Davies H.M.L, Nader M.A. The reinforcing efficacy of psychostimulants in rhesus monkeys: the role of pharmacokinetics and pharmacodynamics. J. Pharmacol. Exp. Ther. 2003;307:356–366. doi:10.1124/jpet.103.049825 [PubMed]
34. Lynch W.J. Sex differences in vulnerability to drug self-administration. Exp. Clin. Psychopharmacol. 2006;14:34–41. doi:10.1037/1064-1297.14.1.34 [PubMed]
35. Lynch W.J, Roth M.E, Carroll M.E. Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology. 2002;164:121–137. doi:10.1007/s00213-002-1183-2 [PubMed]
36. Lyons D, Friedman D.P, Nader M.A, Porrino L.J. Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J. Neurosci. 1996;16:1230–1238. [PubMed]
37. Mach R.H, et al. ¹⁸F-Labeled radioligands for studying the dopamine D₂ receptor with positron emission tomography. J. Med. Chem. 1993;36:3707–3720. doi:10.1021/jm00075a028 [PubMed]
38. Martin S.P, Smith E.O, Byrd L.D. Effects of dominance rank on d-amphetamine-induced increases in aggression. Pharmacol. Biochem. Behav. 1990;37:493–496. doi:10.1016/0091-3057(90)90018-D [PubMed]
39. Martinez D, et al. Cocaine dependence and D₂ receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior. Neuropsychopharmacology. 2004;29:1190–1202. doi:10.1038/sj.npp.1300420 [PubMed]
40. Miczek K.A, Gold L.H. d-Amphetamine in squirrel monkeys of different social status: effects on social and agonistic behavior, locomotion, and stereotypies. Psychopharmacology. 1983a;81:183–190. doi:10.1007/BF00427259 [PubMed]
41. Miczek K.A, Gold L.H. Ethological analysis of amphetamine action on social behavior in squirrel monkeys (Saimiri sciureus) In: Miczek K.A, editor. Ethopharmacology: primate models of neuropsychiatric disorders. Alan R. Liss; New York, NY: 1983b. pp. 137–155. [PubMed]
42. Miczek, K. A. & Tidey, J. W. 1989 Amphetamines: aggressive and social behavior. In Pharmacology and toxicology of amphetamine and related designer drugs (eds K. Asghar & E. De Souza). NIDA Research Monograph, no. 94, pp. 68–100. Washington, DC: U.S. Government Printing Office.
43. Miczek K.A, Yoshimura H. Disruption of primate social behavior by d-amphetamine and cocaine: differential antagonism by antipsychotics. Psychopharmacology. 1982;76:163–171. doi:10.1007/BF00435272 [PubMed]
44. Miczek K.A, Covington H.E, Nikulina E, Hammer R.P. Aggression and defeat: persistant effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits. Neurosci. Biobehav. Rev. 2004;27:787–802. doi:10.1016/j.neubiorev.2003.11.005 [PubMed]
45. Mills, J. 1965 Needle park. Life Magazine, 5 March.
46. Moeller F.G, Dougherty D.M, Barratt E.S, Oderinde V, Mathias C.W, Harper R.A, Swann A.C. Increased impulsivity in cocaine dependent subjects independent of antisocial personality disorder and aggression. Drug Alcohol Depend. 2002;68:105–111. doi:10.1016/S0376-8716(02)00106-0 [PubMed]
47. Morgan D, Grant K.A, Prioleau O.A, Nader S.H, Kaplan J.R, Nader M.A. Predictors of social status in cynomolgus monkeys (Macaca fascicularis) after group formation. Am. J. Primatol. 2000;52:115–131. doi:10.1002/1098-2345(200011)52:3<115::AID-AJP1>3.0.CO;2-Z [PubMed]
48. Morgan D, et al. Social dominance in monkeys: dopamine D₂ receptors and cocaine self-administration. Nat. Neurosci. 2002;5:169–174. doi:10.1038/nn798 [PubMed]
49. Munro C.A, et al. Sex differences in striatal dopamine release in healthy adults. Biol. Psychiatry. 2006;59:966–974. doi:10.1016/j.biopsych.2006.01.008 [PubMed]
50. Nader M.A, Czoty P.W. PET imaging of dopamine D₂ receptors in monkeys: genetic predisposition vs. environmental modulation. Am. J. Psychiatry. 2005;162:1473–1482. doi:10.1176/appi.ajp.162.8.1473 [PubMed]
51. Nader M.A, Czoty P.W. Brain imaging in nonhuman primates: insights into drug addiction. ILAR. 2008;49:89–102. [PubMed]
52. Nader M.A, Woolverton W.L. Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure. Psychopharmacology. 1991;105:169–174. doi:10.1007/BF02244304 [PubMed]
53. Nader M.A, Woolverton W.L. Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys. Psychopharmacology. 1992;108:295–300. doi:10.1007/BF02245115 [PubMed]
54. Nader M.A, Daunais J.B, Moore T, Nader S.H, Moore R.J, Smith H.R, Friedman D.P, Porrino L.J. Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology. 2002;27:35–46. doi:10.1016/S0893-133X(01)00427-4 [PubMed]
55. Nader M.A, Morgan D, Gage H.D, Nader S.H, Calhoun T, Buchheimer N, Ehrenkaufer R, Mach R.H. PET imaging of dopamine D₂ receptors during chronic cocaine self-administration in monkeys. Nat. Neurosci. 2006;9:1050–1056. doi:10.1038/nn1737 [PubMed]
56. Nordstrom A.L, Olsson H, Halldin C. A PET study of D₂ dopamine receptor density at different phases of the menstrual cycle. Psychiatry Res. 1998;83:1–6. doi:10.1016/S0925-4927(98)00021-3 [PubMed]
57. O’Brien C.P. Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am. J. Psychiatry. 2005;162:1423–1431. doi:10.1176/appi.ajp.162.8.1423 [PubMed]
58. O’Brien C.P. Drug addiction and drug abuse. In: Brunton L, Lazo J.S, Parker K.L, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw-Hill; New York, NY: 2006. pp. 607–627. ch. 23.
59. Perry J.L, Larson E.B, German J.P, Madden G.J, Carroll M.E. Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats. Psychopharmacology. 2005;178:193–201. doi:10.1007/s00213-004-1994-4 [PubMed]
60. Piazza P.V, Deminiere J.M, Le Moal M, Simon H. Factors that predict individual vulnerability to amphetamine self-administration. Science. 1989;245:1511–1513. doi:10.1126/science.2781295 [PubMed]
61. Riddick, N. R. et al Submitted. Behavioral and neurobiological characteristics influencing social hierarchy formation in female cynomolgus monkeys. [PMC free article] [PubMed]
62. Rilke O, May T, Oehler J, Wolffgramm J. Influences of housing conditions and ethanol intake on binding characteristics of D₂, 5-HT_1A, and benzodiazepine receptors of rats. Pharmacol. Biochem. Behav. 1995;52:23–28. doi:10.1016/0091-3057(95)00093-C [PubMed]
63. Ritz M.C, Lamb R.J, Goldberg S.R, Kuhar M.J. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987;237:1219–1223. doi:10.1126/science.2820058 [PubMed]
64. Roberts D.C.S, Phelan R, Hodges L.M, Hodges M.M, Bennett B.A, Childers S.R, Davies H. Self-administration of cocaine analogs by rats. Psychopharmacology. 1999;144:389–397. doi:10.1007/s002130051022 [PubMed]
65. SAMHSA: Substance Abuse and Mental Health Services Administration 2006 Results from the 2005 national survey on drug use and health: national findings NSDUH Series H-30, DHHS Publication no. SMA 06-4194. Rockville, MD: Office of Applied Studies, SAMHSA.
66. Sandberg J.A, Olsen G.D. Cocaine pharmacokinetics in the pregnant guinea pig. J. Pharmacol. Exp. Ther. 1991;258:447–482. [PubMed]
67. Seeman M.V. Schizophrenia, gender, and affect. Can. J. Psychiatry. 1996;41:263–264. [PubMed]
68. Shively C, Kaplan J.R. Effects of social factors on adrenal weight and related physiology in Macaca fascicularis. Physiol. Behav. 1984;33:777–782. doi:10.1016/0031-9384(84)90047-7 [PubMed]
69. Sibley D.R, Monsma F.J, Jr, Shen Y. Molecular neurobiology of dopaminergic receptors. Int. Rev. Neurobiol. 1993;35:391–415. [PubMed]
70. Smith E.O, Byrd L.D. d-Amphetamine induced changes in social interaction patterns. Pharmacol. Biochem. Behav. 1985;22:135–139. doi:10.1016/0091-3057(85)90496-4 [PubMed]
71. Sofuoglu M, Dudish-Poulsen S, Nelson D, Pentel P.R, Hatsukami D.K. Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans. Exp. Clin. Psychopharmacol. 1999;7:274–283. doi:10.1037/1064-1297.7.3.274 [PubMed]
72. Stefanski R, Ladenheim B, Lee S.H, Cadet J.L, Goldberg S.R. Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur. J. Pharmacol. 1999;371:123–135. doi:10.1016/S0014-2999(99)00094-1 [PubMed]
73. Terner J.M, de Wit H. Menstrual cucle phase and responses to drugs of abuse in humans. Drug Alcohol Depend. 2006;84:1–13. doi:10.1016/j.drugalcdep.2005.12.007 [PubMed]
74. Volkow N.D, et al. Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am. J. Psychiatry. 1990;147:719–724. [PubMed]
75. Volkow N.D, Fowler J.S, Wang G.J, Hitzemann R, Logan J, Schlyer D.J, Dewey S.L, Wolf A.P. Decreased dopamine D₂ receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse. 1993;14:169–177. doi:10.1002/syn.890140210 [PubMed]
76. Volkow N.D, et al. Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of “high” J. Pharmacol. Exp. Ther. 1999;288:14–20. [PubMed]
77. Weed M.R, Woolverton W.L, Paul I.A. Dopamine D₁ and D₂ receptor selectivities of phenyl-benzazepines in rhesus monkey striata. Eur. J. Pharmacol. 1998;361:129–142. [PubMed]
78. Weerts E.M, Fantegrossi W.E, Goodwin A.K. The value of nonhuman primates in drug abuse research. Exp. Clin. Psychopharmacol. 2007;15:309–327. doi:10.1037/1064-1297.15.4.309 [PubMed]
79. WHO. World Health Organization; Geneva, Switzerland: 2004. Neuroscience of psychoactive substance use and dependence.
80. Wieck A, Davies R.A, Hirst A.D, Brown N, Papadopoulos A, Marks M.N, Checkley S.A, Kumar R.C, Campbell I.C. Menstrual cycle effects on hypothalamic dopamine receptor function in women with a history of puerperal bipolar disorder. J. Psychopharmacol. 2003;17:204–209. doi:10.1177/0269881103017002009 [PubMed]
81. Winslow J.T, Miczek K.A. Social status as determinant of alcohol effects on aggressive behavior in squirrel monkeys (Saimiri sciureus) Psychopharmacology. 1985;85:167–172. doi:10.1007/BF00428408 [PubMed]
82. Wong D.F, et al. In vivo measurement of dopamine receptors in human brain by positron emission tomography. Age and sex differences. Ann. N. Y. Acad. Sci. 1988;515:203–214. doi:10.1111/j.1749-6632.1988.tb32986.x [PubMed]
83. Woolverton W.L, Johnson K.M. Neurobiology of cocaine abuse. Trends Pharmacol. Sci. 1992;13:193–200. doi:10.1016/0165-6147(92)90063-C [PubMed]
84. Woolverton W.L, Nader M.A. Experimental evaluation of the reinforcing effects of drugs. In: Adler M.W, Cowan A, editors. Testing and evaluation of drugs of abuse. Wiley-Liss; New York, NY: 1990. pp. 165–192.
85. Zernig G, Wakonigg G, Madlung E, Haring C, Saria A. Do vertical shifts in dose–response rate-relationships in operant conditioning procedures indicate “sensitization” to “drug wanting”? Psychopharmacology. 2004;171:352–363. doi:10.1007/s00213-003-1601-0 [PubMed]