Cocaine abuse is a continuing and growing problem. The euphoria it produces is a transient but powerful reinforcer, encouraging repeated administrations. Cocaine is thought to exert most of its behavioral and psychological effects through central monoaminergic systems. However, the in vivo effects of cocaine on these systems, especially after chronic administration, have yet to be studied extensively. This project will focus on the effects of chronic administration of cocaine on central monoaminergic receptors. Electrophysiological and behavioral techniques will be utilized to characterize receptor sensitivity in intact animals. In electrophysiological studies, responses of single-identified noradrenergic neurons (locus coeruleus), dopaminergic neurons (substantia nigra-zona compacta), and serotonergic neurons (dorsal raphe) to transmitters/ligands will be assayed after systemic and iontophoretic administration of agents. In behavioral studies, receptor sensitivity will be assayed by studying behavior elicited by stimulation of identified receptors (e.g. stereotypy; serotonin syndrome; analgesia; sedation; etc.). The data generated should provide information about the plasticity of central neuroreceptors and the associated neuropathology after chronic administration of cocaine. Single Unit and iontophoretic electrophysiological studies will be conducted also in behaving (freely moving) animals. Such electrophysiological studies and concurrently gathered behavioral observations will provide functional correlations for changes in monoaminergic receptors. The effects of chronic cocaine in animals simultaneously treated with possible therapeutic agents (e.g. lithium, neuroleptics) will be studied also. In summary, this proposal will examine electrophysiological and behavioral effects of chronic cocaine administration on several identified neuroreceptors located on single identified monoamine neurons.
