alpha(2A)-Adrenergic receptor polymorphisms and mRNA expression levels are associated with delay discounting in cocaine users

作者：Havranek Michael M^*; Hulka Lea M; Tasiudi Eve; Eisenegger Christoph; Vonmoos Matthias; Preller Katrin H; Moessner Rainald; Baumgartner Markus R; Seifritz Erich; Grunblatt Edna; Quednow Boris B^*

来源：ADDICTION BIOLOGY, 2017, 22(2): 561-569.

DOI：10.1111/adb.12324

• delay of gratification
• drug dependence
• environment
• impulsivity
• intertemporal choice
• mutation
• noradrenaline
• self-control

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 alpha 2A-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-naive controls. Two hundred and twenty-three participants (129 cocaine users and 94 stimulant-naive 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 ADRA2Avariants 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 systemis involved in DD deficits observed in cocaine using individuals. Consequently, pharmacological compounds targeting ADRA2Asmight be considered for the symptom-specific treatment of delay aversion in stimulant addiction.

• 出版日期2017-3