title: Serotonin Transporter and Tryptophan Hydroxylase Gene Variations Mediate Working Memory Deficits of Cocaine Users.
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.
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Havranek
authors.affiliation: Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Vonmoos
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.affiliation: Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Büetiger
authors.affiliation: University Clinic for Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.
authors.forename: Eve
authors.initials: E
authors.lastname: Tasiudi
authors.affiliation: Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.
authors.forename: Lea M
authors.initials: LM
authors.lastname: Hulka
authors.affiliation: Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.
authors.forename: Katrin H
authors.initials: KH
authors.lastname: Preller
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany.
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.affiliation: University Clinic for Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.
authors.forename: Edna
authors.initials: E
authors.lastname: Grünblatt
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.
authors.forename: Boris B
authors.identifier: http://orcid.org/0000-0001-7933-2865
authors.initials: BB
authors.lastname: Quednow
mesh_terms: D000328:Adult; D019970:Cocaine-Related Disorders / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D042622:DNA Repeat Expansion; D056344:Executive Function / Q000502:physiology; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D008297:Male; D008569:Memory Disorders / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase