title: Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity.
abstract: Individual differences in traits such as impulsivity involve high reward sensitivity and are associated with risk for substance use disorders. The ventral striatum (VS) has been widely implicated in reward processing, and individual differences in its function are linked to these disorders. Dopamine (DA) plays a critical role in reward processing and is a potent neuromodulator of VS reactivity. Moreover, altered DA signaling has been associated with normal and pathological reward-related behaviors. Functional polymorphisms in DA-related genes represent an important source of variability in DA function that may subsequently impact VS reactivity and associated reward-related behaviors. Using an imaging genetics approach, we examined the modulatory effects of common, putatively functional DA-related polymorphisms on reward-related VS reactivity associated with self-reported impulsivity. Genetic variants associated with relatively increased striatal DA release (DRD2 -141C deletion) and availability (DAT1 9-repeat), as well as diminished inhibitory postsynaptic DA effects (DRD2 -141C deletion and DRD4 7-repeat), predicted 9-12% of the interindividual variability in reward-related VS reactivity. In contrast, genetic variation directly affecting DA signaling only in the prefrontal cortex (COMT Val158Met) was not associated with variability in VS reactivity. Our results highlight an important role for genetic polymorphisms affecting striatal DA neurotransmission in mediating interindividual differences in reward-related VS reactivity. They further suggest that altered VS reactivity may represent a key neurobiological pathway through which these polymorphisms contribute to variability in behavioral impulsivity and related risk for substance use disorders.
authors: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: E E
authors: EE
authors: Forbes
authors: S M
authors: SM
authors: Brown
authors: M
authors: M
authors: Kimak
authors: R E
authors: RE
authors: Ferrell
authors: S B
authors: SB
authors: Manuck
authors: A R
authors: AR
authors: Hariri
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001479:Basal Ganglia / Q000098:blood supply / Q000503:physiopathology*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D004298:Dopamine / Q000235:genetics* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007175:Impulsive Behavior / Q000235:genetics* / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D050637:Receptors, Dopamine D3 / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012201:Reward; D009435:Synaptic Transmission / Q000235:genetics*; D055815:Young Adult
chemical_list: C493593:DRD3 protein, human; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D050637:Receptors, Dopamine D3; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4; D002394:Catechol O-Methyltransferase; D010100:Oxygen; D004298:Dopamine