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 the motivational effects of opiate withdrawal (place aversion), animal models of heroin self-administration in dependent rats and animal models of conditioned increases in responding to precipitated opiate withdrawal. Using these models, studies have identified critical elements in the brain stress systems in the basal forebrain (corticotropin releasing factor, neuropeptide Y and norepinephrine) in the motivational effects of opiate withdrawal. The purpose of the present proposal is to test the hypothesis that the brain stress neurotransmitter systems: corticotropin-releasing factor, norepinephrine and neuropeptide Y may have critical roles in mediating the aversive stimulus effects of opiate withdrawal, the development of motivational aspects of opiate dependence, and the motivational effects of conditioning associated with the aversive stimulus effects of opiate withdrawal. A sub-hypothesis is that previously neutral stimuli that acquire motivational significance through pairing with opiate withdrawal utilize specific neural circuits associated with input to the extended amygdala. To test these hypotheses, the animal models of intravenous self-administration in dependent animals will be validated (Specific Aim 1), the neuropharmacological mechanisms within specific sites of the extended amygdala involved in the aversive motivational state of opiate withdrawal (place aversion) will be explored (Specific Aim 2), the neuropharmacological mechanisms within specific sites within the extended amygdala involved in heroin self-administration in dependent rats will be explored (Specific Aim 3) and the neuroanatomical basis for the conditioned increases in heroin self-administration produced by precipitated opiate withdrawal will be explored (Specific Aim 4). The present proposal will go towards elucidating the neural circuits and neuropharmacological systems within the basal forebrain circuits which are critical for the motivational effects of opiate dependence and will provide critical information important for identifying the basis for individual differences in vulnerability to opiate addiction and help establish the basis for novel approaches to prevention and treatment.
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