Previous work has established that the mesocorticolimbic dopamine projection to the region of the nucleus accumbens has an important role in intravenous cocaine self-administration. Destruction of the dopamine projection to the region of the nucleus accumbens results in decreases in intravenous cocaine self-administration and decreases in motivational measures (progressive ratio performance) of cocaine reinforcement. Progress in the previous funding period has established that the critical terminal regions appear to be the region of the nucleus accumbens and olfactory tubercle. In addition, cell body lesions of the ventral pallidum significantly decreased cocaine self-administration suggesting that the accumbens-pallidal projection is important for processing of the cocaine reinforcement stimulus. The purpose of the present proposal is to extend these observations to other efferent connections of the nucleus accumbens important for cocaine reinforcement by using cell body specific lesions of the identify the neuropharmacological components of the se efferent circuits using intracerebral injection of neurotransmitter agonists and antagonists. In addition, the role in cocaine reinforcement of afferents to the nucleus accumbens will be explored by using cell body selective lesions with ibotenic acid to the inputs to the nucleus accumbens from the amygdala, hippocampus, thalamus and frontal cortex. Finally, neuropharmacological studies of the role in cocaine self-administration of neurotensin, opioid peptides, cholecystokinin, and glutamate will be explored by intracerebral injection of neurotransmitter agonists and antagonists into the nucleus accumbens. Cholecystokinin and neurotensin are colocalized with mesocorticolimbic dopamine neurons, and a high density of glutamate and opioid receptors have been localized to the nucleus accumbens. These studies will provide critical information about the components of limbic-accumbens-pallidal circuitry important for cocaine reinforcement and will establish the contribution of other neuropharmacological elements that influence or interact with the dopamine system. The results obtained will go far to identify the neuropharmacological mechanism of action for cocaine reinforcement and thus should provide important clues to neuropharmacological basis of cocaine dependence and abuse.
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