The long-term objective of this research proposal is to determine functional consequences of changed gene expression in neurons of the basal ganglia after chronic treatment with psychomotor stimulants such as cocaine. The reinforcing effects of such drugs of abuse are thought to be mediated by the dopamine neurotransmission in the forebrain. Evidence has been presented that excessive stimulation of dopamine receptors produced by such drugs results in neuroadaptive changes in dopamine-receptive neurons including changes in gene expression. Such neuronal alterations may play a role in the behavioral changes that occur during chronic cocaine use/treatment. Research in animal models and studies of brains of human cocaine addicts have shown that changes in gene regulation produced by cocaine include increased expression of the opioid peptide dynorphin in neurons of the striatum that project to the basal ganglia output nuclei (e.g., substantia nigra). Our previous results indicate that such increased dynorphin levels function to reduce or blunt dopamine input to striatonigral neurons. The proposed research will investigate functional consequences of increased dynorphin expression on different levels. (1) We will determine whether dynorphin/kappa opioid receptor agonists can act in the striatum to inhibit dopamine receptor responses (i.e., induction of immediate-early genes) in striatonigral neurons. (2) Our studies will also determine whether repeated cocaine treatment affects gene expression in target neurons of the striatonigral pathway, and whether such changes are related to the increased dynorphin expression. (3) In these studies, changes in gene regulation will be correlated with behavioral changes that occur during repeated cocaine treatment, to determine the contribution of changed dynorphin function to behavioral effects of chronic cocaine treatment. Changes in gene expression will be assessed with quantitative in situ hybridization histochemistry. This work will provide new insights into mechanisms of opioid and dopamine receptor regulation of basal ganglia function. Furthermore, by showing how altered dynorphin function during chronic cocaine treatment affects the striatonigral pathway and behavior, this work may help to establish a cellular basis for new approaches in the treatment of cocaine abuse.
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