Neural systems underlying opiate addiction.

Opiate addiction is a chronically relapsing disorder that is characterized by compulsive drug taking, an inability to limit intake, and bouts of intense drug craving that can be precipitated by the mere presence of people, places, or objects previously associated with drug use. Although knowledge of the neural mechanisms that underlie the transition from casual drug use to addiction is still incomplete, the development of animal models that enable differentiation of the various stages of the addiction process have provided new insights regarding the neural substrates on which opiates act to affect and subsequently control behavior. Data derived from these models are consistent with the hypothesis that opiates, like psychostimulants, are initially abused by virtue of their rewarding or hedonic effects. However, as will be discussed in this review, the repeated use of opiates induces alterations in neurotransmitter and neuropeptide systems that regulate incentive–motivation and stress–responsiveness. Increasing evidence indicates that the dysregulation of these systems underlies the compulsive use and loss of control of drug-taking that characterizes opiate and other addictions. Studies examining the neural basis of drug addiction have been guided by the premise that the motivation of an addict to take drugs results from the desire to experience the hedonic (e.g., rewarding) effects of the drug as well as from the desire to avoid the anhedonia and aversive consequences of drug withdrawal (Wikler, 1948; Koob et al., 1989). More recently, it has been posited that repeated drug use induces long-lasting adaptations in neural systems that mediate a subcomponent of drug reward, termed incentive salience (Robinson and Berridge, 1993). Hypersensitivity (e.g., sensitization) of these systems is hypothesized to lead to an enhanced incentive value of drug-related stimuli, compulsive patterns of drug seeking, and the vulnerability to relapse that persists long after the cessation of drug use. In view of the documented involvement of the mesoaccumbens dopamine (DA) system in incentive motivation and psychostimulant-induced reward (Koob et al., 1998; Schultz et al., 1998), studies examining the neural basis of opiate addiction have focused on the mesolimbic DA projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), and to a lesser extent on its afferent and efferent projection areas such as medial prefrontal cortex (mPFC), amygdala, and ventral pallidum. In contrast to the study of psychostimulants, a systematic examination of the neuroanatomical and neurochemical substrates underlying the various stages of opiate addiction is only just beginning.