Under Siege: The Brain on Opiates

and dependence, at least in in vivo systems. The recent cloning of these receptors has enabled more penetrating Laboratory of Molecular Psychiatry Yale University School of Medicine analyses (Mansour et al., 1995), which could yet reveal alterations related to opiate addiction. For example, ex-New Haven, Connecticut 06508 posure to agonist in vitro elicits receptor desensitization and down-regulation, which could be related to aspects Many of the terms used in the addiction field today were developed originally based on the opiates, one of the of tolerance in vivo (e.g., Harris and Williams, 1991; Von Zastrow et al., 1994). oldest and best characterized classes of abused drugs. Tolerance describes the need for an increasing dose of In contrast with the lack of evidence for a role of adaptations in opioid peptides and receptors in opiate opiate to achieve the same effect; this term was based originally on the tolerance that develops to many of addiction, considerable evidence has implicated a role for postreceptor, intracellular messenger pathways. the acute behavioral actions of opiates (e.g., analgesia, autonomic inhibition, and " high "). Dependence de-Chronic exposure to opiates has been shown to elicit adaptations in some of the same intracellular pathways scribes an altered physiological state caused by repeated opiate exposure such that cessation of drug that mediate the acute actions of the drugs. Moreover, such adaptations have been related to tolerance and administration leads to a withdrawal syndrome characterized by serious physiological disturbances. This term dependence phenomena that can be demonstrated at the level of individual neurons. was used originally to describe physical opiate dependence as characterized by classical opiate withdrawal Studies of the Locus Coeruleus The locus coeruleus (LC), the major noradrenergic nu-(i.e., " cold turkey "). More recently, it has become clear that opiates also result in a psychological form of depen-cleus in brain, is located in the brain stem and involved in control of autonomic function and attentional states. dence, which results in emotional or motivational symptoms upon drug withdrawal. This latter form of depen-Activation of this brain region, and the resulting increase in noradrenergic innervation of large regions of the brain dence is probably the strongest determinant of opiate addiction, which can be defined as compulsive drug and spinal cord, is one of the major determinants of physical opiate withdrawal (Koob et al., 1992; Nestler et craving and administration despite horrendous adverse consequences. al., 1993, 1994). Since LC neurons are …