35 The µ-pioid receptor gene OPRM1 is the most extensively studied of the opioid receptor genes because of its important role in reward mediated by endogenous opioids. The functional

OPRM1 Asn40Asp variant of the µ-opioid receptor gene has been shown in some studies to be associated with opioid addiction.36-37-38 For example, association of this OPRM1 variant to polysubstance abuse including opioids, cocaine, and alcohol was reported by Kranzler et al.36 Berrettini and colleagues Inhibitors,research,lifescience,medical reported that the major opioid preference quantitative trait loci in mice mapped to the location of the murine µopioid receptor gene.39 OPRM1 Asn40Asp has also been variably linked to alcoholism,29,30 and perhaps most intriguingly, appears to alter opioid-mediated release of Cortisol, this effect on the hypothalamicpituitary-adrenal axis potentially revealing its action on stress activations important in addiction.40 A delta opioid receptor, OPRD1, variant has also been reported to be associated with substance dependence.41 The endogenous Inhibitors,research,lifescience,medical opioid systern is also critical to the reinforcing effects of nonopioid drugs including nicotine, alcohol, cocaine, and cannabinoids.37,42 Inhibitors,research,lifescience,medical Gene-environment interactions in addiction Addiction is a complex disease involving the interaction of genes and environment. The vulnerability to abuse of addictive

agents is in part determined by genetic variation and in part by environmental factors including exposure to EGFR activation addictive agents, but also such nonspecific factors as stress exposure early in life. Several of the interacting genes found so far are stressrelated, Inhibitors,research,lifescience,medical modulating resiliency and vulnerability. Early life stress exposures such as childhood sexual abuse play a powerful but apparently Inhibitors,research,lifescience,medical nonspecific role, because such stress also increases vulnerability to other psychiatric diseases. In the rat preferring/nonpreferring (P/NP) model of alcohol consumption, a major quantitative locus for ethanol preference is at the site of the gene for neuropeptide Y, an anxiolytic neuropeptide. In the human,

genetic variants of neuropeptide Y have sometimes, first but not always, been linked to alcoholism as well as other behaviors, including obesity.43-44 A catechol-O-methyltransf erase polymorphism that predicts anxiety and cognitive function has been associated with alcoholism and polysubstance abuse.45 Another stress-related gene is the serotonin transporter, which contains the functional HTTLPR locus. In the rhesus macaque monkey, the reduction of function allele of the orthologous rh-HTTLPR locus predicts enhanced alcohol consumption, but only in the context of early life stress exposure.46 In humans with cocaine addiction, the already high rate of suicide attempts is greatly increased in carriers of the reduction of function HTTLPR allele who had a history of childhood abuse or neglect.