Header

UZH-Logo

Maintenance Infos

Serotonin transporter and tryptophan hydroxylase gene variations mediate working memory deficits of cocaine users


Havranek, M M; Vonmoos, Matthias; Müller, C P; Büetiger, J R; Tasiudi, Eve; Hulka, Lea M; Preller, Katrin H; Mössner, R; Grünblatt, Edna; Seifritz, Erich; Quednow, Boris B (2015). Serotonin transporter and tryptophan hydroxylase gene variations mediate working memory deficits of cocaine users. Neuropsychopharmacology, 40:2929-2937.

Abstract

Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant naive controls. Two hundred twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial, and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single-nucleotide polymorphisms (rs4570625 and rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole-blood samples. Several significant gene × environment interactions between 5-HT genotypes and cocaine use on WM emerged: in cocaine users, the long/long (5-HTTLPR), 9+10/9+10 (VNTR In2) and C/C (TPH2 rs1386497) genotypes were risk alleles for WM impairments, whereas in healthy controls these polymorphisms were associated with improved WM performance. Analogously, high 5-HTT mRNA levels were associated with worse executive WM performance in cocaine users but with increased performance in controls. These gene × environment interactions suggest that the 5-HT system has an important role in the development of cognitive deficits in chronic cocaine users. Hence, pharmacological compounds targeting 5-HT neurotransmission might be promising for the treatment of cognitive deficits in cocaine dependence.

Abstract

Cocaine users consistently develop working memory (WM) impairments but the mediating molecular mechanisms are unknown so far. Recent evidence suggests that the serotonin (5-HT) system is altered by chronic cocaine use, while also being involved in WM processing. Thus, we investigated the effects of genetic variations impacting 5-HT activity and of peripheral 5-HT transporter (5-HTT) mRNA expression on WM performance in cocaine users and stimulant naive controls. Two hundred twenty participants (126 cocaine users, 94 controls) were assessed with visuospatial, spatial, and verbal WM tasks, genotyped for the length polymorphism in the promoter region of the 5-HTT (5-HTTLPR), the variable number of tandem repeats in the second intron of the 5-HTT (VNTR In2), two single-nucleotide polymorphisms (rs4570625 and rs1386497) in the tryptophan hydroxylase-2 (TPH2) gene and quantified for peripheral 5-HTT mRNA expression in whole-blood samples. Several significant gene × environment interactions between 5-HT genotypes and cocaine use on WM emerged: in cocaine users, the long/long (5-HTTLPR), 9+10/9+10 (VNTR In2) and C/C (TPH2 rs1386497) genotypes were risk alleles for WM impairments, whereas in healthy controls these polymorphisms were associated with improved WM performance. Analogously, high 5-HTT mRNA levels were associated with worse executive WM performance in cocaine users but with increased performance in controls. These gene × environment interactions suggest that the 5-HT system has an important role in the development of cognitive deficits in chronic cocaine users. Hence, pharmacological compounds targeting 5-HT neurotransmission might be promising for the treatment of cognitive deficits in cocaine dependence.

Statistics

Citations

4 citations in Web of Science®
2 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

48 downloads since deposited on 31 Dec 2015
11 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
04 Faculty of Medicine > Psychiatric University Hospital Zurich > Center for Child and Adolescent Psychiatry
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2015
Deposited On:31 Dec 2015 06:02
Last Modified:08 Oct 2017 05:36
Publisher:Nature Publishing Group
ISSN:0893-133X
Funders:SNF
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/npp.2015.146
PubMed ID:26013962

Download

Download PDF  'Serotonin transporter and tryptophan hydroxylase gene variations mediate working memory deficits of cocaine users'.
Preview
Content: Accepted Version
Filetype: PDF
Size: 1MB
View at publisher