A behavioral/systems approach to the neuroscience of drug addiction.

Drug addiction is likely to affect all of our lives, with any luck not through our own actions but probably because of one or more of our family and friends. Now firmly entrenched as a brain disease (Leshner, 1999; Wise, 2000), drug addiction is among the most costly such diseases in modern society. Drug addiction is most often defined as a chronically relapsing disorder in which the addict experiences uncontrollable compulsion to take drugs, while simultaneously the repertoire of behaviors not related to drug seeking, taking, and recovery, declines dramatically. What transpires to lead the drug user into this cyclical, self-destructive pattern of behavior? Through a rapid escalation of basic neuro-science research, we have begun to answer this critical question at both the cellular/molecular and behavioral/systems levels of analysis. There have been many excellent recent reviews regarding the molecular mechanism of drug addiction (see references below). Such has not been the case from a systems neuroscience perspective. The present set of mini-reviews has been solicited to address issues concerning the brain systems responsible for specific immediate behavioral consequences of drug intake, how such systems are altered during the process of repeated drug administration , and whether additional systems become engaged during the process of drug dependence, withdrawal, and relapse to drug-taking. The aim of these reviews is to provide the nonspecialist neuroscientist with a contemporary yet comprehensible overview of exciting recent developments in our understanding of brain circuits related to specific aspects of drug addiction. Drug addiction is presently viewed as a complex neuroadaptive process through which drugs of abuse alter cellular and molecular aspects of neural function in such a way as to render the brain circuits mediating various behavioral effects of these drugs more, or less, responsive to those effects. This process guides behavior in maladaptive directions during which severe physical and social consequences engulf and disable the addict. Cellular and molecular mechanisms of tolerance, sensitization (reverse tolerance), and dependence are rapidly being identified for almost all classes of abused drugs, and both established and new molecules are being investigated intensively using the most modern and advanced technologies available to neuroscience (Nestler, 2001b,d). As the neurobiology of drug addiction has advanced, the discovery of precise cellular and molecular adaptations related to the addictive process has been substantial. Alterations in many molecules have been newly implicated. From long-suspected involvement of the cAMP pathway in tolerance to and dependence on …