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

Savitz, J and Hodgkinson, CA and Martin-Soelch, C and Shen, PH and Szczepanik, J and Nugent, A and Herscovitch, P and Grace, AA and Goldman, D and Drevets, WC (2013) The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement. PLoS ONE, 8 (1).

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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 [11C]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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Savitz, J
Hodgkinson, CA
Martin-Soelch, C
Shen, PH
Szczepanik, J
Nugent, A
Herscovitch, P
Grace, AAgraceaa@pitt.eduGRACEAA
Goldman, D
Drevets, WC
Date: 30 January 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 1
DOI or Unique Handle: 10.1371/journal.pone.0054108
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Dietrich School of Arts and Sciences > Psychology
School of Medicine > Psychiatry
Refereed: Yes
Other ID: NLM PMC3554713
PubMed Central ID: PMC3554713
PubMed ID: 23365649
Date Deposited: 14 Mar 2013 14:40
Last Modified: 22 Jun 2021 12:55


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