Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds ␤-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, ␤-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.The mu opioid receptor is the primary site of action of several of the endogenous opioid peptides including ␤-endorphin, Met-enkephalin-Arg-Phe, and the recently identified endomorphins (1). This receptor is also the major target for clinically important opioid analgesic agents including morphine, methadone, fentanyl, and related drugs (2, 3). Activation of this receptor has diverse physiological effects (4, 5). Furthermore, it is the major molecular site of action for heroin (6, 7). Rapid activation of the mu opioid receptor, such as that which occurs in the setting of drug abuse, results in a euphoric effect, thus conferring the reinforcing or rewarding effects of the drug, contributing to the development of addiction. Clinical observations have suggested that individuals have varied sensitivity to opioids, suggesting potential variability in the receptor protein and gene. Naturally occurring polymorphisms are well known to exist in human genes; some have been shown to produce profound effects on the function of the corresponding proteins. Molecular cloning of the mu opioid receptor (8-11) has made it possible to determine potential sequence polymorphism, as shown by two recent studies (12, 13). The mu opioid receptor is a member of the G protein-coupled receptor family (8,14). There are a number of well documented cases where natural...

Genetic variation may partially underlie complex personality and physiological traits--such as impulsivity, risk taking and stress responsivity--as well as a substantial proportion of vulnerability to addictive diseases. Furthermore, personality and physiological traits themselves may differentially affect the various stages of addiction, defined chronologically as initiation of drug use, regular drug use, addiction/dependence and potentially relapse. Here we focus on recent approaches to the study of genetic variation in these personality and physiological traits, and their influence on and interaction with addictive diseases.

This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from limited access to drugs to long-term compulsive use of drugs. A dramatic escalation in drug intake with extended access to drug self-administration is characterized by a dysregulation of brain reward pathways. Hormonal studies using an experimenter-administered cocaine binge model and an escalation self-administration model have revealed large increases in ACTH and corticosterone in rats during an acute binge with attenuation during the chronic binge stage and a reactivation of the hypothalamic-pituitary-adrenal axis during acute withdrawal. The activation of the hypothalamicpituitary-adrenal axis with cocaine appears to depend on feed-forward activation of the mesolimbic dopamine system. At the same time, escalation in drug intake with either extended access or dependence-induction produces an activation of the brain stress system's corticotropin-releasing factor outside of the hypothalamus in the extended amygdala, which is particularly evident during acute withdrawal. A model of the role of different levels of hormonal/brain stress activation in addiction is presented that has heuristic value for understanding individual vulnerability to drug dependence and novel treatments for the disorder.Drug addiction has been conceptualized as a chronic relapsing disorder characterized by compulsive drug-taking behavior with impairment in social and occupational functioning. From a psychiatric perspective, drug addiction has aspects of both impulse control disorders and compulsive disorders (1). Impulse control disorders are characterized by an increasing sense of tension or arousal before the commission of an impulsive act; pleasure, gratification, or relief at the time of commission of the act; and following the act, there may or may not be regret, self-reproach, or guilt (2). In contrast, compulsive disorders are characterized by anxiety and stress before the commission of a compulsive repetitive behavior and relief from the stress by performing the compulsive behavior. As an individual moves from an impulsive disorder to a compulsive disorder, there is a shift from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior. Drug addiction has been conceptualized as a disorder that progresses from impulsivity to compulsivity in a collapsed cycle of addiction composed of three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect (3). Different theoretical perspectives ranging from Psychoneuroendocrinology ©2003; Address correspondence and reprint requests to Dr. Koob, Committee on the Neurobiology, of Addictive Disorders, SP30-2400, the Scripps Research, Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037; gkoob@scripps.edu. All authors report no competing interests. This is publication number 16873-NP from the Scripps Research I...