This is a competing renewal application to continue to study the neural mechanisms of opiate reinforcement and dependence. Work during the previous funding period has established separate neural sites involved in the classic physical and motivational signs of opiate withdrawal. The region of the locus coeruleus and other brain sites such as the hypothalamus appear to have an important role in the expression of physical signs such as wet dog shakes, ptosis and jumping. However, the region of the nucleus accumbens and amygdala appear to be important sites for the motivational effects of opiate withdrawal as measured by lever response suppression and place aversions and are the sites least involved in the physical signs of withdrawal. These same sites are also responsible for the reinforcing effects of opiates in both the non-dependent and dependent state supporting the hypothesis that elements in this limbic- extrapyramidal interface are the critical determinants of the motivational components of opiate dependence. The purpose of the present proposal is to continue to test this hypothesis by further exploring the neural basis for both the positive and negative reinforcing effect of opiate dependence. Local intracerebral microinjections of the hydrophilic opiate antagonist methylnaloxonium will be used to explore the subregions of the extended amygdala in opiate reinforcement as measured by intravenous self- administration (Specific Aim 1) and the motivational effects of opiate withdrawal as measured by response suppression, place aversion and intracranial self-stimulation (Specific Aim 2). An animal model for the positive conditioned effects of opiates in non-dependent and dependent rats will -be developed using operant schedules of heroin self- administration (Specific Aim 3). The motivational effects of both the positive and negative conditioned reinforcing stimuli will be assessed in both non-dependent and dependent rats using intravenous self- administration of heroin (Specific Aim 4). Finally, the neural substrates for the positive and negative conditioned reinforcing stimuli established by pairings with opiates or opiate withdrawal, respectively, will be explored using cell body specific neurotoxic lesions with focus on amygdala- accumbens interactions (Specific Aim 5). These studies will go far towards elucidating the neural mechanisms mediating the brain changes critical for the development of opiate dependence and the neural- mechanisms responsible for the association of this dependence with previously neutral stimuli. Knowledge of these neural substrate will provide information critical for the prevention, treatment and medication of opiate abuse and drug abuse in general.
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