α_2A‐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 α -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.

Cognitive and neuroanatomical impairments associated with chronic exposure to levamisole-contaminated cocaine

“…Interestingly, specific impairments in attentional set-shifting were reported for noradrenergic but not cholinergic deafferentation of the medial prefrontal cortex—the homolog of the primate dorsolateral prefrontal cortex in rats 54 . Given that we previously proposed that CU might show neuroplastic adaptations in the noradrenaline system 55 , 56 one could speculate that not only cocaine but specifically a cocaine–aminorex combination can disrupt the noradrenaline transmission. Moreover, medically prescribed levamisole intake is supposed to cause multifocal inflammatory leukoencephalopathy 57 , 58 , a disease associated with white matter lesions.…”

Attention-Deficit/Hyperactivity Disorder and Monetary Delay Discounting: A Meta-Analysis of Case-Control Studies

“…These links to dopamine-related loci are consistent with preclinical studies that implicate dopamine neurotransmission with delay discounting. Of note, however, serotonin and norepinephrine also appear to play important roles (50; 51; 74) and two studies have found associations between polymorphisms in serotonin and noradrenergic genes and delay discounting preferences (75; 76). Although genetic studies are at an early stage, the current findings support the need for further attempts to examine whether delay discounting can be used to understand one pathway for genetic influences on ADHD.…”

Cognitive Dysfunctions in Chronic Cocaine Users

“…However, molecular imaging studies investigating alterations in the serotonin and noradrenaline system in cocaine users are lacking, with one exception: a single positron emission tomography study has shown that norepinephrine transporter density in the thalamus is upregulated in cocaine users (Ding et al, 2010). In line with a recent publication demonstrating that increased delay discounting in cocaine users might be explained by an interaction between a genetic variation of an alpha-adrenergic receptor and cocaine use (Havranek et al, 2016), this finding suggests that adaptations in the norepinephrine system might also account for some cognitive changes found in cocaine users. Another recent study indicates that genetic variation in serotonin transporters also plays an important role in the development of working memory deficits in chronic cocaine users (Havranek et al, 2015); thus, changes in the serotonin system might be involved in cocaine-related cognitive impairments.…”