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Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders.

ABSTRACT: The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure.Non-treatment-seeking volunteers (n=66) with cocaine use disorders received a single bolus infusion of saline and cocaine (40?mg, intravenous) in a randomized order. Subjective effects were assessed with visual analog scales administered before (-15?min) and up to 20?min after infusion. Ratings of subjective effects were normalized to baseline, and saline infusion values were subtracted. Data were analyzed using repeated measures analysis of variance. DNA from the participants was genotyped for the DAT1 intron 8 (rs3836790) and 3'-untranslated region (rs28363170) variable number of tandem repeats.Participants were mostly male (?80%) and African American (?70%). No differences were found among drug use variables between groups for either polymorphism. Carriers of the 9-allele of the DAT1 3'-untranslated region (9,9 and 9,10) exhibited greater responses to cocaine for 'high', 'any drug effect', 'anxious', and 'stimulated' (all P-values<0.001) compared with individuals homozygous for the 10-allele. For the intron 8 polymorphism, individuals homozygous for the 6-allele exhibited greater responses for 'anxious' compared with carriers of the 5-allele (P<0.001). Individuals possessing the genotype pattern of 10,10 and at least one 5-allele reported lower responses to 'good effects', 'bad effects', 'depressed', and 'anxious' (all P-values<0.01).The data presented here show for the first time support for the hypothesis that genetic differences in DAT1 contribute to the variation in subjective responses to cocaine among participants with cocaine use disorders.

SUBMITTER: Brewer AJ

PROVIDER: S-EPMC4414865 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders.

Brewer Alex J AJ Nielsen David A DA Spellicy Catherine J CJ Hamon Sara C SC Gingrich Justin J Thompson-Lake Daisy G Y DG Nielsen Ellen M EM Mahoney James J JJ Kosten Thomas R TR Newton Thomas F TF De La Garza Richard R

Pharmacogenetics and genomics 20150601 6

<h4>Objective</h4>The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure.<h4>Methods</h4>Non-treatment-seeking volunteers (n=66) with cocaine use disorders received a single bolus infusion of saline and cocaine (40 mg, intravenous) in a randomized order. Subjective effects were assessed with visual analog scales administered before (-15 min) and up to 20 min after infusion. Ratings of subjective effects were normalized to ...[more]

PMID: 25850966

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Project description:The dopamine transporter (DAT), a member of the neurotransmitter:sodium symporter family, mediates the reuptake of dopamine at the synaptic cleft. DAT is the primary target for psychostimulants such as cocaine and amphetamine. We previously demonstrated that cocaine binding and dopamine transport alter the accessibility of Cys342 in the third intracellular loop (IL3). To study the conformational changes associated with the functional mechanism of the transporter, we made cysteine substitution mutants, one at a time, from Phe332 to Ser351 in IL3 of the background DAT construct, X7C, in which 7 endogenous cysteines were mutated. The accessibility of the 20 engineered cysteines to polar charged sulfhydryl reagents was studied in the absence and presence of cocaine or dopamine. Of the 11 positions that reacted with methanethiosulfonate ethyl ammonium, as evidenced by inhibition of ligand binding, 5 were protected against this inhibition by cocaine and dopamine (S333C, S334C, N336C, M342C and T349C), indicating that reagent accessibility is affected by conformational changes associated with inhibitor and substrate binding. In some of the cysteine mutants, transport activity is disrupted, but can be rescued by the presence of zinc, most likely because the distribution between inward- and outward-facing conformations is restored by zinc binding. The experimental data were interpreted in the context of molecular models of DAT in both the inward- and outward-facing conformations. Differences in the solvent accessible surface area for individual IL3 residues calculated for these states correlate well with the experimental accessibility data, and suggest that protection by ligand binding results from the stabilization of the outward-facing configuration. Changes in the residue interaction networks observed from the molecular dynamics simulations also revealed the critical roles of several positions during the conformational transitions. We conclude that the IL3 region of DAT undergoes significant conformational changes in transitions necessary for both cocaine binding and substrate transport.

Dataset Information

Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders.

Publications

Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders.

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