The functional DRD3 Ser9Gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement.
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.
Laureate Institute for Brain Research, and Department of Psychiatry, University of Oklahoma College of Medicine, Tulsa, Oklahoma, United States of America. jonathansavitz@hotmail.com
Jonathan
J
Savitz
Colin A
CA
Hodgkinson
Chantal
C
Martin-Soelch
Pei-Hong
PH
Shen
Joanna
J
Szczepanik
Allison
A
Nugent
Peter
P
Herscovitch
Anthony A
AA
Grace
David
D
Goldman
Wayne C
WC
Drevets
D000328:Adult; D000367:Age Factors; D000483:Alleles; D059445:Anhedonia; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D005715:Gambling / Q000523:psychology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009042:Motivation; D011110:Polymorphism, Genetic; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012201:Reward; D012737:Sex Factors
C493593:DRD3 protein, human; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D020891:Raclopride