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 animal models of heroin self-administration in dependent animals and animal models of conditioned withdrawal in dependent animals. Studies have begun to elucidate the neurobiological substrates for these effects with a focus on a basal forebrain continuum from the shell of the nucleus accumbens to the central nucleus of the amygdala termed the """"""""extended amygdala."""""""" Sites in the shell of the nucleus accumbens, bed nucleus of the stria terminalis and central nucleus of the amygdala appear particularly important for processing the aversive stimulus effects of opiate dependence independent of somatic effects. Preliminary neuropharmacological studies also suggest a potential role for corticotropin-releasing factor in mediating such aversive stimulus effects. The purpose of the present proposal is to test the hypothesis that specific neuropharmacological elements in the extended amygdala contribute to the motivational effects associated with the development and maintenance of opiate dependence. To test this hypothesis, systematic neuropharmacological studies will be employed to examine the role of CRF, serotonin, glutamate, and dopamine in the reinforcing effects of heroin using intravenous self-administration in dependent rats (Specific Aim 1). In addition, the neuropharmacological basis for the aversive stimulus effects of opiate withdrawal in dependent rats will be explored using place conditioning (place aversion-- Specific Aim 2). An attempt will be made to determine the neural substrates for the expression of opiate withdrawal-induced place aversion by cell body-selective neurotoxin lesions of the regions projecting to the extended amygdala and with lesions of the extended amygdala itself (Specific Aim 3). Finally, the neuropharmacological basis within the extended amygdala itself for heroin self-administration in dependent rats and opiate withdrawal-induced place aversion will be explored using microinjections of neurotransmitter agonists and antagonists directly into sites within the extended amygdala continuum (Specific Aim 4). These studies will go far towards elucidating the neural mechanisms mediating the brain changes critical for the development of opiate dependence and as such will provide basic information important for establishing vulnerability to opiate addiction and for establishing novel prevention and treatment interventions.
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