The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

• Published in: PloS one Vol. 8; no. 1; p. e54108
• Main Authors: Savitz, Jonathan, Hodgkinson, Colin A., Martin-Soelch, Chantal, Shen, Pei-Hong, Szczepanik, Joanna, Nugent, Allison, Herscovitch, Peter, Grace, Anthony A., Goldman, David, Drevets, Wayne C.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.01.2013; Public Library of Science (PLoS)
• Subjects: Abnormalities; Addictions; Adult; Age Factors; Alcoholism; Alleles; Anhedonia; Anxiety; Basal Ganglia - diagnostic imaging; Basal Ganglia - metabolism; Basal Ganglia - physiopathology; Biology; Brain research; Case-Control Studies; Caudate Nucleus - diagnostic imaging; Caudate Nucleus - metabolism; Caudate Nucleus - physiopathology; Cell receptors; Cocaine; Depressive Disorder, Major - genetics; Depressive Disorder, Major - metabolism; Depressive Disorder, Major - physiopathology; Depressive Disorder, Major - psychology; Dopamine; Dopamine D2 Receptor Antagonists; Dopamine D2 receptors; Dopamine D3 receptors; Dopaminergic mechanisms; Female; Gambling; Gambling - psychology; Gene mutation; Genetic aspects; Genetics; Glycine; Health aspects; Hedonic response; Humans; Intracellular signalling; Laboratories; Male; Medical imaging; Medicine; Mental depression; Mental disorders; Middle Aged; Missense mutation; Mood; Motivation; Mutation; Neostriatum; Neurosciences; Polymorphism; Polymorphism, Genetic; Positron emission; Positron emission tomography; Psychiatry; Psychological aspects; Psychosis; Raclopride; Raclopride - pharmacology; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - antagonists & inhibitors; Receptors, Dopamine D3 - metabolism; Regression analysis; Reinforcement; Reward; Rewards (Psychology); Schizophrenia; Sensorimotor system; Sex Factors; Social and Behavioral Sciences; Studies; Tomography; United States > US; Maryland; Oklahoma
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054108

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [(11)C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.