This is a competing renewal application to continue to study the neural mechanisms of cocaine reinforcement. Work during the previous funding period has established the mesolimbic dopamine (DA) system and its connections as the substrate for the acute reinforcing effects of cocaine. DA denervation of the region of the nucleus accumbens selectively blocked cocaine self-administration but not responding for food in a multiple schedule of food and cocaine self-administration. Microinjections of DA antagonists into the terminal regions of the mesolimbic DA system also blocked cocaine reinforcement with preliminary results showing particularly active sites in the extended amygdala (shell region of the nucleus accumbens and central nucleus of the amygdala). DA receptor subtypes implicated in cocaine reinforcement include the D-1, D-2, and D-3 receptors with preliminary results suggesting a particularly important role for D-1 and D-3 receptors. Another source of reinforcement in drug dependence is the negative reinforcement associated with drug abstinence. The negative affective state characterizing cocaine withdrawal has been hypothesized to be a motivating factor contributing to negative reinforcement processes. Withdrawal from prolonged self-administration of cocaine results in dose-and time-dependent elevations in reward thresholds as measured by intracranial self-stimulation that provides an operational measure of this affective state. It is hypothesized that these elevations in reward threshold are mediated by the same neural substrates that underlie the acute reinforcing effects of cocaine. The purpose of the proposed studies is to test this hypothesis by exploring the neural bases for both the positive and negative reinforcement associated with cocaine dependence. Local intracerebral microinjections of antagonists to specific DA receptor subtypes will be used to explore the role of the subregions of the extended amygdala in the acute reinforcing effects of cocaine as measured by intravenous self-administration (Specific Aim l) and the motivational effects of withdrawal as measured by intracranial self-stimulation reward thresholds (Specific Aim 2). An animal model for the conditioned aversive effects of cocaine withdrawal will be developed using the place conditioning paradigm (Specific Aim 3). Finally, the neural substrates for the conditioned positive and negative effects associated with cocaine self- administration and cocaine withdrawal, respectively, will be explored using cell body specific neurotoxin lesions with a focus on amygdala- accumbens interactions (Specific Aim 4). These studies will help elucidate the neural mechanisms mediating brain changes associated with the development of cocaine dependence and the neural mechanisms responsible for the association of negative and positive cocaine effects with previously neutral stimuli. Knowledge of these neural substrates will provide critical information for the prevention, treatment, and medication of cocaine abuse.
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