J Genet Syndr Gene Ther. 2013 February 10; 4(121): 1000121. doi: 10.4172/2157-7412.1000121
Abstract
Having entered the genomics era with confidence in the future of medicine, including psychiatry, identifying the role of DNA and polymorphic associations with brain reward circuitry has led to a new understanding of all addictive behaviors. It is noteworthy that this strategy may provide treatment for the millions who are the victims of “Reward Deficiency Syndrome” (RDS) a genetic disorder of brain reward circuitry. This article will focus on drugs and food being mutuality addictive, and the role of dopamine genetics and function in addictions, including the interaction of the dopamine transporter, and sodium food. We will briefly review our concept that concerns the genetic antecedents of multiple–addictions (RDS). Studies have also shown that evaluating a panel of established reward genes and polymorphisms enables the stratification of genetic risk to RDS. The panel is called the “Genetic Addiction Risk Score (GARS)”, and is a tool for the diagnosis of a genetic predisposition for RDS. The use of this test, as pointed out by others, would benefit the medical community by identifying at risk individuals at a very early age. We encourage, in depth work in both animal and human models of addiction. We encourage further exploration of the neurogenetic correlates of the commonalities between food and drug addiction and endorse forward thinking hypotheses like “The Salted Food Addiction Hypothesis”.
Introduction
Dopamine (DA) is a neurotransmitter in the brain, which controls feelings of wellbeing. This sense of wellbeing results from the interaction of DA and neurotransmitters such as serotonin, the opioids, and other brain chemicals. Low serotonin levels are associated with depression. High levels of the opioids (the brain’s opium) are also associated with a sense of wellbeing [1]. Moreover, DA receptors, a class of G-protein coupled receptors (GPCRs), have been targeted for drug development for the treatment of neurological, psychiatric and ocular disorders [2]. DA has been called the “anti-stress” and/or “pleasure” molecule, but this has been recently debated by Salamone and Correa [3] and Sinha [4].
Accordingly, we have argued [5–8] that Nucleus accumbens (NAc) DA has a role in motivational processes, and that mesolimbic DA dysfunction may contribute to motivational symptoms of depression, features of substance abuse and other disorders [3]. Although it has become traditional to label DA neurons as reward neurons, this is an over generalization, and it is necessary to consider how different aspects of motivation are affected by dopaminergic manipulations. For example, NAc DA is involved in Pavlovian processes, and instrumental learning appetitive-approach behavior, aversive motivation, behavioral activation processes sustained task engagement and exertion of effort although it does not mediate initial hunger, motivation to eat or appetite [3,5–7].
While it is true that NAc DA is involved in appetitive and aversive motivational processes we argue that DA is also involved as an important mediator in primary food motivation or appetite similar to drugs of abuse. A review of the literature provides a number of papers that show the importance of DA in food craving behavior and appetite mediation [6,7]. Gold has pioneered the concept of food addiction [5–8]. Avena et al. [9] correctly argue that because addictive drugs avtivate the same neurological pathways that evolved to respond to natural rewards, addiction to food seems plausible. Moreover, sugar per se is noteworthy as a substance that releases opioids and DA and thus might be expected to have addictive potential. Specifically, neural adaptations include changes in DA and opioid receptor binding, enkephalin mRNA expression and DA and acetylcholine release in the NAc. The evidence supports the hypothesis that under certain circumstances rats can become sugar dependent.
The work of Wang et al. [10] involving brain imaging studies in humans has implicated DA-modulated circuits in pathologic eating behavior(s). Their studies suggest that the DA in the extracellular space of the striatum is increased by food cues, this is evidence that DA is potentially involved in the non-hedonic motivational properties of food. They also found that orbitofrontal cortex metabolism is increased by food cues indicating that this region is associated with motivation for the mediation of food consumption. There is an observed reduction in striatal DA D2 receptor availability in obese subjects, similar to the reduction in drug-addicted subjects, thus obese subjects may be predisposed to use food to compensate temporarily for under stimulated reward circuits [11]. In essence, the powerful reinforcing effects of both food and drugs are in part mediated by abrupt DA increases in the mesolimbic brain reward centers. Volkow et al. [11] point out that abrupt DA increases can override homeostatic control mechanisms in the brain’s of vulnerable individuals. Brain imaging studies have deliniated the neurological dysfunction that generates the shared features of food and drug addictions. The cornerstone of the commonality, of the root causes of addiction are impairments in the dopaminergic pathways that regulate the neuronal systems associated also with self-control, conditioning, stress reactivity, reward sensitivity and incentive motivation [11]. Metabolism in prefrontal regions is involved in inhibitory control, in obese subjects the inability to limit food intake involves ghrelin and may be the result of decreased DA D2 receptors which are associated with decreased prefrontal metabolism [12]. The limbic and cortical regions involved with motivation, memory and self-control, are activated by gastric stimulation in obese subjects [10] and during drug craving in drug-addicted subjects. An enhanced sensitivity to the sensory properties of food is suggested by increased metabolism in the somatosensory cortex of obese subjects. This enhanced sensitivity to food palatability coupled with reduced DA D2 receptors could make food the salient reinforcer for compulsive eating and obesity risk [10]. These research results indicate that numerous brain circuits are disrupted in obesity and drug addiction and that the prevention and treatment of obesity may benefit from strategies that target improved DA function.
Lindblom et al. [13] reported that dieting as a strategy to reduce body weight often fails as it causes food cravings leading to binging and weight regain. They also agree that evidence from several lines of research suggests the presence of shared elements in the neural regulation of food and drug craving. Lindblom et al. [13] quantified the expression of eight genes involved in DA signaling in brain regions related to the mesolimbic and nigrostriatal DA system in male rats subjected to chronic food restriction using quantitative real-time polymerase chain reaction. They found that mRNA levels of tyrosine hydroxylase, and the dopamine transporter in the ventral tegmental area were strongly increased by food restriction and concurrent DAT up-regulation at the protein level in the shell of the NAc was also observed via quantitative autoradiography. That these effects were observed after chronic rather than acute food restriction suggests that sensitization of the mesolimbic dopamine pathway may have occurred. Thus, sensitization possibly due to increased clearance of extracellular dopamine from the NAc shell may be one of the underlying causes for the food cravings that hinder dietary compliance. These findings are in agreement with earlier findings by Patterson et al. [14]. They demonstrated that direct intracerebroventricular infusion of insulin results in an increase in mRNA levels for the DA reuptake transporter DAT. In a 24- to 36-hour food deprivation study hybridization was used in situ to assess DAT mRNA levels in food-deprived (hypoinsulinemic) rats. Levels were in the ventral tegmental area/substantia nigra pars compacta significantly decreased suggesting that moderation of striatal DAT function can be effected by nutritional status, fasting and insulin. Ifland et al. [15] advanced the hypothesis that processed foods with high concentrations of sugar and other refined sweeteners, refined carbohydrates, fat, salt, and caffeine are addictive substances. Other studies have evaluated salt as important factor in food seeking behavior. Roitman et al. [16] points out that increased DA transmission in the NAc is correlated with motivated behaviors, including Na appetite. DA transmission is modulated by DAT and may play a role in motivated behaviors. In their studies in vivo, robust decreases in DA uptake via DAT in the rat NAc were correlated with and Na appetite induced by Na depletion. Decreased DAT activity in the NAc was observed after in vitro Aldosterone treatment. Thus, a reduction in DAT activity, in the NAc, may be the consequence of a direct action of Aldosterone and may be a mechanism by which Na depletion induces generation of increased NAc DA transmission during Na appetite. Increased NAc DA may be the motivating property for the Na-depleted rat. Further support for the role of salted food as possible substance (food) of abuse has resulted in the “The Salted Food Addiction Hypothesis” as proposed by Cocores and Gold [17]. In a pilot study, to determine if salted foods act like a mild opiate agonist which drives overeating and weight gain, they found that an opiate dependent group developed a 6.6% increase in weight during opiate withdrawal showing a strong preference for salted food. Based on this and other literature [18] they suggest that Salted Food may be an addictive substance that stimulates opiate and DA receptors in the reward and pleasure center of the brain. Alternately, preference, hunger, urge, and craving for “tasty” salted food may be symptoms of opiate withdrawal and the opiate like effect of salty food. Both salty foods and opiate withdrawal stimulate the Na appetite, result in increased calorie intake, overeating and disease related to obesity.
Brain Dopaminergic Function
Dopamine D2 receptor gene (DRD2)
When synaptic, DA stimulates DA receptors (D1–D5), individuals experience stress reduction and feelings of wellbeing [19]. As mentioned earlier, the mesocorticolimbic dopaminergic pathway mediates reinforcement of both unnatural rewards and natural rewards. Natural drives are reinforced physiological drives such as hunger and reproduction while unnatural rewards involve satisfaction of acquired learned pleasures, hedonic sensations like those derived from drugs, alcohol, gambling and other risk-taking behaviors [8,20,21].
One notable DA gene is the DRD2 gene which is responsible for the synthesis of DA D2 receptors [22]. The allelic form of the DRD2 gene (A1 versus A2) dictates the number of receptors at post-junctional sites and hypodopaminergic function [23,24]. A paucity of DA receptors predisposes individuals to seek any substance or behavior that stimulates the dopaminergic system [25–27].
The DRD2 gene and DA have long been associated with reward [28] in spite of controversy [3,4]. Although the Taq1 A1 allele of the DRD2 gene, has been associated with many neuropsychiatric disorders and initially with severe alcoholism, it is also associated with other substance and process addictions, as well as, Tourette’s Syndrome, high novelty seeking behaviors, Attention Deficit Hyperactivity Disorder (ADHD), and in children and adults, with co-morbid antisocial personality disorder symptoms [28].
While this article will focus on drugs and food being mutuality addictive, and the role of DA genetics and function in addictions, for completeness, we will briefly review our concept that concerns the genetic antecedents of multiple–addictions. “Reward Deficiency Syndrome” (RDS) was first described in 1996 as a theoretical genetic predictor of compulsive, addictive and impulsive behaviors with the realization that the DRD2 A1 genetic variant is associated with these behaviors [29–32]. RDS involves the pleasure or reward mechanisms that rely on DA. Behaviors or conditions that are the consequence of DA resistance or depletion are manifestations of RDS [30]. An individual’s biochemical reward deficiency can be mild, the result of overindulgence or stress or more severe, the result of a DA deficiency based on genetic makeup. RDS or anti-reward pathways help to explain how certain genetic anomalies can give rise to complex aberrant behavior. There may be a common neurobiology, neuro-circuitry and neuroanatomy, for a number of psychiatric disorders and multiple addictions. It is well known that .drugs of abuse, alcohol, sex, food, gambling and aggressive thrills, indeed, most positive reinforcers, cause activation and neuronal release of brain DA and can decrease negative feelings. Abnormal cravings are linked to low DA function [33]. Here is an example of how complex behaviors can be produced by specific genetic antecedents. A deficiency of, for example, the D2 receptors a consequence of having the A1 variant of the DRD2 gene [34] may predispose individuals to a high risk for cravings that can be satisfied by multiple addictive, impulsive, and compulsive behaviors. This deficiency could be compounded if the individual had another polymorphism in for example the DAT gene that resulted in excessive removal of DA from the synapse. In addition, the use of substances and aborant behaviors also deplete DA. Thus, RDS can be manifest in severe or mild forms that are a consequence a biochemical inability to derive reward from ordinary, everyday activities. Although many genes and polymorphisms predispose individuals to abnormal DA function, carriers of the Taq1 A1 allele of the DRD2 gene lack enough DA receptor sites to achieve adequate DA sensitivity. This DA deficit in the reward site of the brain can results in unhealthy appetites and craving. In essence, they seek substances like alcohol, opiates, cocaine, nicotine, glucose and behaviors; even abnormally aggressive behaviors that are known to activate dopaminergic pathways and cause preferential release of DA at the NAc. There is now evidence that rather than the NAc, the anterior cingulate cortex may be involved in operant, effort-based decision making [35–37] and a site of relapse.
Impairment of the DRD2 gene or in other DA receptor genes, such as the DRD1 involved in homeostasis and so called normal brain function, could ultimately lead to neuropsychiatric disorders including aberrant drug and food seeking behavior. Prenatal drug abuse in the pregnant female has been shown to have profound effects of the neurochemical state of offspring. These include ethanol [38]; cannabis [39]; heroin [40]; cocaine [41]; and drug abuse in general [42]. Most recently Novak et al. [43] provided strong evidence showing that abnormal development of striatal neurons are part of the pathology underlying major psychiatric illnesses. The authors identified an underdeveloped gene network (early) in rat that lacks important striatal receptor pathways (signaling). At two postnatal weeks the network is down regulated and replaced by a network of mature genes expressing striatal-specific genes including the DA D1 and D2 receptors and providing these neurons with their functional identity and phenotypic characteristics. Thus, this developmental switch in both the rat and human, has the potential to be a point of susceptibility to disruption of growth by enviromental factors such as an overindulgence in foods, like salt, and drug abuse.
Dopamine transporter (DAT)
The DA transporter (also DA active transporter, DAT, SLC6A3) is a membrane–spanning protein that pumps the neurotransmitter DA out of the synapse back into cytosol from which other known transporters sequester DA and norepinephrine into neuronal vesicles for later storage and subsequent release [44].
The DAT protein is encoded by a gene located on human chromosome 5 it is about 64 kbp long and consists of 15 coding exon. Specifically, the DAT gene (SLC6A3 or DAT1) is localized to chromosome 5p15.3. Moreover, there is a VNTR polymorphism within the 3′ non-coding region of DAT1. A genetic polymorphism in the DAT gene which effects the amount of protein expressed is evidence for an association between and DA related disorders and DAT [45]. It is well established that DAT is the primary mechanism which clears DA from synapses, except in the prefrontal cortex where DA reuptake involves norepinephrine [46,47]. DAT terminates the DA signal by removing the DA from the synaptic cleft and depositing it into surrounding cells. Importantly, several aspects of reward and cognition are functions of DA and DAT facilitates regulation of DA signaling [48].
It is noteworthy that DAT is an integral membrane protein and is considered a symporter and a co-transporter moving DA from the synaptic cleft across the phospholipid cell membrane by coupling its movement to the movement of Na ions down the electrochemical gradient (facilitated diffusion) and into the cell.
Moreover, DAT function requires the sequential binding and co-transport of two Na ions and one chloride ion with the DA substrate. The driving force for DAT-mediated DA reuptake is the ion concentration gradient generated by the plasma membrane Na+/K+ ATPase [49].
Sonders et al. [50] evaluated the role of the widely–accepted model for monoamine transporter function. They found that normal monoamine transporter function requires set rules. For example, Na ions must bind to the extracellular domain of the transporter before DA can bind. Once DA binds, the protein undergoes a conformational change, which allows both Na and DA to unbind on the intracellular side of the membrane. A number of electrophysiological studies have confirmed that DAT transports one molecule of neurotransmitter across the membrane with one or two Na ions like other monoamine transporters. Negatively charged chloride ions are required to prevent a buildup of positive charge. These studies used radioactive-labeled DA and have also shown that the transport rate and direction are totally dependent on the Na gradient [51].
Since it is well known that many drugs of abuse cause the release of neuronal DA [52], DAT may have a role in this effect. Because of the tight coupling of the membrane potential and the Na gradient, activity-induced changes in membrane polarity can dramatically influence transport rates. In addition, the transporter may contribute to DA release when the neuron depolarizes [53]. In essence, as pointed out by Vandenbergh et al. [54] the DAT protein regulates DA -mediated neurotransmission by rapidly accumulating DA that has been released into the synapse.
The DAT membrane topology was initially theoretical, determined based on hydrophobic sequence analysis and similarity to the GABA transporter. The initial prediction of Kilty et al. [55] of a large extracellular loop between the third and fourth of twelve transmembrane domains was confirmed by Vaughan and Kuhar [56] when they used proteases, to digest proteins into smaller fragments, and glycosylation, which occurs only on extracellular loops, to verify most aspects of DAT structure.
DAT has been found in regions of the brain where there is dopaminergic circuitry, these areas include mesocortical, mesolimbic, and nigrostriatal pathways [57]. The nuclei that make up these pathways have distinct patterns of expression. DAT was not detected within any synaptic cleft which suggests that striatal DA reuptake occurs outside of the synaptic active zones after DA has diffused from the synaptic cleft.
Two alleles, the 9 repeat (9R) and 10 repeat (10R) VNTR can increase the risk for RDS behaviors. The presence of the 9R VNTR has associated with alcoholism and Substance Use Disorder. It has been shown to augment transcription of the DAT protein resulting in an enhanced clearance of synaptic DA, resulting in a reduction in DA, and DA activation of postsynaptic neurons [58]. The tandem repeats of the DAT have been associated with reward sensitivity and high risk for Attention Deficit Hyperactivity Disorder (ADHD) in both children and adults [59,60]. The 10-repeat allele has a small but significant association with hyperactivity-impulsivity (HI) symptoms [61].
Mapping Reward Genes and RDS
Support for the impulsive nature of individuals possessing dopaminergic gene variants and other neurotransmitters (e.g. DRD2, DRD3, DRD4, DAT1, COMT, MOA-A, SLC6A4, Mu, GABAB) is derived from a number of important studies illustrating the genetic risk for drug-seeking behaviors based on association and linkage studies implicating these alleles as risk antecedents that have an impact in the mesocorticolimbic system (Table 1). Our laboratory in conjunction with LifeGen, Inc. and Dominion Diagnostics, Inc. is carrying out research involving twelve select centers across the United States to validate the first ever patented genetic test to determine a patient’s genetic risk for RDS called Genetic Addiction risk Score™ (GARS).
Acknowledgments
The authors appreciate the expert editorial input from Margaret A. Madigan and Paula J. Edge. We appreciate the comments by Eric R. Braverman, Raquel Lohmann, Joan Borsten, B.W Downs, Roger L. Waite, Mary Hauser, John Femino, David E Smith, and Thomas Simpatico. Marlene Oscar-Berman is the recipient of grants from the National Institutes of Health, NIAAA RO1-AA07112 and K05-AA00219 and the Medical Research Service of the US Department of Veterans Affairs. We also acknowledge the case report input Karen Hurley, Executive Director of National Institute of Holistic Addiction studies, North Miami Beach Florida. In-part this article was supported by a grand awarded to Path foundation NY from Life Extension Foundation.
Footnotes
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Conflict of Interest Kenneth Blum, PhD., holds a number of US and foreign patents related to diagnosis and treatment of RDS, which has been exclusively licensed to LifeGen, Inc. Lederach, PA. Dominion Diagnostics, LLC, North Kingstown, Rhode Island along with LifeGen, Inc., are actively involved in the commercial development of GARS. John Giordano is also a partner in LifeGen, Inc. There are no other conflicts of interest and all authors read & approved the manuscript.
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