Efforts to understand the causes of opiate abuse commonly focus on two prominent motivational effects of opiates: (i) the pleasurable consequences of drug intake and (ii) the strongly unpleasant withdrawal symptoms that occur with cessation of chronic drug use. Considerable evidence indicates that the rewarding effects of opiates result from the indirect stimulation of dopamine (DA) release within the nucleus accumbens (NAc) and from direct actions on non-DA cells within this region, whereas the aversive withdrawal symptoms are thought to be initiated at multiple sites throughout the central and peripheral nervous system. However, recent findings by the Co-PI on this proposal indicate that the mesolimbic DA-NAc system plays an unexpected but critical role in the opiate withdrawal response as well. In particular, he found that stimulation of D2-type DA receptors in the NAc prevented withdrawal responses, whereas blockade of D2 receptors produced severe withdrawal signs in opiate- dependent rats. This application proposes behavioral, neurochemical and anatomical experiments to extend these recent results and more precisely delineate the role of DA and other NAc processes in the development of opiate dependence and addiction. Initial studies will determine whether the development of behavioral withdrawal responses to a D2 antagonist follow the same time course as those elicited by naloxone. These experiments will test the hypothesis that the development of D2 receptor dependency occurs in parallel with the development of dependence as assessed by naloxone challenge. The effects of D2 or opiate antagonists on DA release and immediate early gene expression within the NAc also will be measured at different stages of opiate dependence. Subsequent studies will assess whether excitatory amino acid (EAA) transmitters within the NAc participate in the development of dependence. This will be accomplished by determining whether competitive BAA receptor antagonists, given coincident with morphine pre-exposures, can prevent the development of the behavioral, neurochemical and genomic withdrawal responses described above. A final set of experiments will employ drug discrimination, self-administration and place conditioning procedures to determine whether withdrawal states elicited by D2 antagonists are qualitatively similar to those precipitated by naloxone, and whether they produce motivational effects in morphine-dependent rats.
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