title: α2A-Adrenergic receptor polymorphisms and mRNA expression levels are associated with delay discounting in cocaine users.
abstract: Cocaine users characteristically display preferences for smaller immediate rewards over larger delayed rewards, and this delay discounting (DD) has been proposed as an endophenotype of cocaine addiction. Recent evidence suggests that the norepinephrine system and more specifically the α2A-adrenergic receptor (ADRA2A) are impacted by chronic cocaine use while also being potentially involved in the neural mechanisms underlying DD. Hence, we investigated the effects of ADRA2A polymorphisms and ADRA2A mRNA expression levels on DD of cocaine users and stimulant-naïve controls. Two hundred and twenty-three participants (129 cocaine users and 94 stimulant-naïve healthy controls) completed a computerized DD paradigm and were genotyped for three single nucleotide polymorphisms (SNPs; rs1800544, rs521674 and rs602618) in the ADRA2A gene, while their peripheral ADRA2A mRNA expression was quantified in whole blood samples. The three SNPs were in near-perfect linkage disequilibrium. Accordingly, significant group*genotype interactions were found for all three ADRA2A variants revealing steeper DD in cocaine users (but not in controls) carrying the G-allele of SNP rs1800544, the T-allele of rs521674 and the C-allele of rs602618. Similarly, high ADRA2A mRNA expression levels were significantly associated with a reduced tendency to choose smaller more immediate rewards (over larger delayed rewards) in cocaine users but not in controls. As the relationship between DD and cocaine use was moderated by ADRA2A SNPs and by peripheral ADRA2A gene expression, we propose that the norepinephrine system is involved in DD deficits observed in cocaine using individuals. Consequently, pharmacological compounds targeting ADRA2As might be considered for the symptom-specific treatment of delay aversion in stimulant addiction.
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Havranek
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Lea M
authors.initials: LM
authors.lastname: Hulka
authors.affiliation: University Clinic for Child and Adolescent Psychiatry, University of Zurich, Switzerland.
authors.forename: Eve
authors.initials: E
authors.lastname: Tasiudi
authors.affiliation: Neuropsychopharmacology and Biopsychology Unit, Institute of Basic Psychological Research and Research Methods, University of Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisenegger
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Vonmoos
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Katrin H
authors.initials: KH
authors.lastname: Preller
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Tübingen, Germany.
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.affiliation: Center of Forensic Hairanalytics, Institute of Legal Medicine, University of Zurich, Switzerland.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: University Clinic for Child and Adolescent Psychiatry, University of Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Switzerland.
authors.forename: Edna
authors.initials: E
authors.lastname: Grünblatt
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.|Neuroscience Center Zurich, University and ETH Zurich, Switzerland.
authors.forename: Boris B
authors.initials: BB
authors.lastname: Quednow
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D065786:Delay Discounting / Q000502:physiology*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D055815:Young Adult
chemical_list: C547768:ADRA2A protein, human; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2
keywords: delay of gratification; drug dependence; environment; impulsivity; intertemporal choice; mutation; noradrenaline; self-control