The LONG TERM OBJECTIVE of this application is to better understand the biological basis of narcotic abuse. Morphine is a potent reinforcer, a manifestation of the drug interacting with brain opioid receptors. The ventral pallidum/nucleus basalis (VP/nB) is rich with opioid binding sites. A major neuronal population of the VP/nB is the acetylcholine-containing cells and these cells exhibit conditioning-related responses to stimuli preceding reinforcement. Enkephalinergic terminals make synaptic contact with VP/nB cholinergic neurons; however, the functional consequences of this interaction is largely unknown. HYPOTHESIS: Enkephalinergic inputs to VP/nB cholinergic neurons mediate aspects of reinforcement. Proposed SPECIFIC AIMS: I. To characterize the pharmacology and physiology of enkephalinergic projections to the VP/nB. Putative cholinergic neurons will be electrophysiologically characterized in vivo, and the synaptic pharmacology of opioid receptors will be evaluated using microiontophoretic application of receptor-specific opioid agonists and antagonists. Hemicholinium binding, which is indicative of cholinergic activity, will be used to assess cholinergic terminal function after intra-VP/nB microinjection of the opioid agents. II. To study the involvement of VP/nB neurons and opioid receptors in the abuse potential of narcotics. The reinforcing properties of receptor- specific opioid agonists microinjected into the VP/nB will be assessed using a condition place preference paradigm. Electrophysiologic recordings in behaving rats will examine single-unit activity recorded from the VP/nB while the animal is in an environment previously paired with morphine (CS+), or paired with vehicle (CS-). Comparisons also will be made between neuronal firing and the animals' spontaneous behavior. To determine if tolerance develops to the above parameters, experiments will be conducted in rats chronically treated with morphine. VP/nB cholinergic neurons are involved with reinforcement, and yet these cells have not been investigated with regard to the neurobiological mechanisms underlying opioid abuse. Results obtained in the proposed experiments should impart needed information on the neurobiology of the VP/nB, and also provide significant information useful in devising appropriate pharmacological strategies for the treatment of narcotic abuse.
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