Opioid neuropeptide genotypes in relation to heroin abuse: Dopamine tone contributes to reversed mesolimbic proenkephalin expression

Abstract

Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, relevant to addiction disorders. We examined polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone, critical for drug reward and striatal function. Heroin abuse was significantly associated with PENK polymorphic 3 UTR dinucleotide (CA) repeats; 79% of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Control Met/ Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH) mRNA expression in mesolimbic dopamine neurons. In contrast to PENK, no association was detected between PDYN genotype (68-bp repeat element containing one to four copies of AP-1 binding sites in the promoter region) and heroin abuse, although there was a clear functional association with striatal PDYN mRNA expression: an increased number of inducible repeats (three and four) correlated with higher PDYN levels than adult or fetal subjects with noninducible (one and two) alleles. Moreover, PDYN expression was not related to COMT genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and TH function.catecholamine-O-methyltransferase ͉ drug abuse ͉ mu opioid receptor ͉ nucleus accumbens ͉ prodynorphin

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

“…Nevertheless, future studies involving larger populations will help clarify these issues especially in relation to novelty-seeking traits and allow the possibility to examine other markers specifically enriched in VSM neurons. Moreover, although we focused on the 3′UTR based on our initial hypothesis, other polymorphisms of PDYN within the promoter region have also been shown to be relevant for gene expression (Zimprich et al, 2000;Nikoshkov et al, 2008) and in relation to substance abuse (Ray et al, 2005;Clarke et al, 2012;Saify et al, 2014). The contribution of different variants within the PDYN gene to discrete behaviors needs to be addressed in larger populations that would provide the statistical power to examine such questions.…”

Extensive Changes in the Expression of the Opioid Genes between Humans and Chimpanzees

“…Opioid gene signaling is a critical link in a number of human behavioral responses [reviewed in Sonetti et al, 2005;Bodnar, 2009;Stein and Zollner, 2009], as well as in many human disease susceptibilities [Kreek, 1996a;Ogden et al, 2004;Kreek et al, 2005;Drakenberg et al, 2006;Kennedy et al, 2006;Xuei et al, 2006Xuei et al, , 2007Huang et al, 2008;Nikoshkov et al, 2008;Bodnar, 2009]. Several studies have presented evidence of functional changes that have occurred in the coding sequences of these genes, both across vertebrate evolution [Dores et al, 2002;Stevens et al, 2007;Dreborg et al, 2008] and within human populations (e.g.…”

“…A further challenge will be to understand the polymorphisms in the regulatory regions that have become fixed between species that might be driving differences in expression. To date, several studies have investigated the functional impact of regulatory variants of the PDYN gene [Zimprich et al, 2000;Nikoshkov et al, 2005Nikoshkov et al, , 2008Yuferov et al, 2009;Babbitt et al, 2010b] and OPRM1 [Shabalina et al, 2009] within human populations. There are also OPRM1 coding and 5 UTR variants found in macaques that have similar effects on in vitro expression [Vallender et al, 2008] and in behavioral associations [Miller et al, 2004;Barr et al, 2008] as the well-studied A118G variant identified in humans.…”

“…The primary and secondary binding affinities of these ligands and receptors are illustrated in figure 1 [Chen et al, 1993a;Meng et al, 1996;Gong et al, 1998;Zaveri et al, 2001;Snook et al, 2008;Liu et al, 2009]. Most investigations surrounding this gene family have focused on the role its members play in pain and nocicep-155 tion [reviewed in Stein and Zollner, 2009], stress response [Sonetti et al, 2005], behavior [reviewed in Bodnar, 2009], substance abuse [Kreek, 1996;Kreek et al, 2005;Drakenberg et al, 2006;Xuei et al, 2006Xuei et al, , 2007Huang et al, 2008;Nikoshkov et al, 2008], and some psychiatric affective disorders [reviewed in Ogden et al, 2004;Kennedy et al, 2006;Bodnar, 2009].…”

A Randomized Blinded Trial of Nucleus Accumbens Ablation to Treat Opiate Dependence in Humans: Location Correlates with Outcome

“…It has long been implicated in substance abuse and addiction, including ethanol, cocaine, and heroin [16][17][25][26][27][28][29][30][31][32][33].…”