Molecular genetics of addiction vulnerability

Abstract

Summary:Classical genetic studies document strong complex genetic contributions to abuse of multiple addictive substances, to mnemonic processes that are likely to include those involved in substance dependence, and to the volumes of brain gray matter in regions that are likely to contribute to mnemonic/ cognitive and to addictive processes. The working idea that these three heritable phenotypes are likely to share some of the same complex genetic underpinnings is presented. This review contains association-based molecular genetic studies of addiction that largely derive from my laboratory and their fit with linkage data from other laboratories. These combined results now identify many of the loci and genes that contain allelic variants that are likely to provide the heritable components of human addiction vulnerability. These data are also likely to have broad implications for neurotherapeutics. Drugs with potential abuse liabilities are widely used for indications that include pain, anxiety, sleep, seizure, and attentional disorders. There is increasing nonmedical use of these prescribed substances. Increasing information about addiction vulnerability gene variants should help to improve management of risks of dependence in individuals who receive such therapeutics. In addition, since mnemonic components that correlate well with individual differences in brain regional volumes are likely to play major roles in addiction processes, many addiction vulnerability genes are also good candidates to contribute to individual differences in mnemonic processes. Recently elucidation of addiction-associated haplotypes for the "cell adhesion" Nr-CAM gene illustrate several of these points.

Association of the Neuronal Cell Adhesion Molecule (NrCAM) Gene Variants with Personality Traits and Addictive Symptoms in Methamphetamine Use Disorder

“…In addition, some of these polymorphisms and haplotypes have been associated with altered NrCAM expression in human postmortem brain samples 9. Although potentially important neurobiological roles of NrCAM have been reported in animal studies,9,10 few studies have focused on human subjects.…”

Genetic Factors Modulating the Response to Stimulant Drugs in Humans

“…Twin studies estimate the heritability of traits, whereas association studies examine specific polymorphisms in relation to a phenotype. We will not include family-based linkage studies of drug abuse or animal studies on genetic determinants of stimulant effects, both which have been carefully reviewed elsewhere (Phillips et al 2008; Kreek et al 2005; Uhl 2006). We will also not discuss the stimulant caffeine, because it acts by distinct neurochemical mechanisms and because we have recently reviewed the genetics of caffeine elsewhere (Yang et al 2010).…”

Alcohol-preferring (P) rats are more sensitive than Wistar rats to the reinforcing effects of cocaine self-administered directly into the nucleus accumbens shell

“…The majority of cocaine users (up to 90%) report co-administering EtOH during cocaine binges (Brookoff et al, 1996; Magura and Rosenblum, 2000). The high prevalence of co-abuse of alcohol with cocaine in humans has been postulated to be predicated upon both a common genetic factor that predispose an organism to abuse multiple substances, including alcohol, and the interaction of the drugs within the organism (Uhl 2004, 2006; Uhl et al, 2008). Individuals predisposed to abuse alcohol and other drugs of abuse are disproportionally reactive to alcohol and other drugs of abuse when given alone, and co-administration of alcohol and other drugs of abuse result in further divergence (Schuckit 1994a,b; Kareken et al, 2010; Uhl 2008; Piazza and LeMoal 1996).…”