This application proposes to continue and extend cellular neurophysiological studies on opioid peptides and opiates in a brain region, the nucleus accumbens septi (NAcc), containing proenkephalin- and prodynorphin-derived peptides. This region was chosen because of its reported role in heroin self-administration, thus to be developed as a cellular model for opiate reward or dependence, with the ultimate goal of testing therapeutic interventions. The overall objective is to determine the physiological role of central opioid peptide-containing neurons in normative and opiate seeking behavior, using intracellular (current- and voltage-clamp) and whole-cell clamp recording in brain slices in vitro. Our previous studies have confirmed an opiate reduction of synaptic transmission in the NAcc, similar to that produced by dopamine (DA) and ethanol. Studies in other labs have noted interactions of opiates with DA and glutamate. Therefore, our specific aims are to: 1) Study possible opiate and glutamate (especially NMDA) interactions in NAcc neurons, since recent reports show that NMDA antagonists can block opiate dependence and tolerance, and since ethanol also blocks NMDA currents; 2) Continue to examine the role of DA in the responses of NAcc neurons to opiates and opioid peptides using exogenous DA, DA antagonists and DA uptake blockers. We will seek interactions of DA and opiates and alterations of opiate effects by DA antagonists and uptake blockers. 3) Test opiate effects on voltage-dependent Ca++ and K+ (e.g., M and inward rectifying) currents in NAcc neurons using intracellular and whole-cell clamp methods. If such effects are found, we will test for possible mediation by second messengers or 0-proteins; as such K+ and Ca++-current effects of opiates in other neurons or cell lines appear to involve such mediators. 4) Repeat specific aims #1-3 in slices from animals that have been self- administering heroin for various periods of time under different reinforcement schedules. These animals will be provided by the George Koob and Steven Henriksen groups and will have a well-defined dossier of behaviors for statistical comparison and correlation to the electrophysiological and pharmacological (opiate and transmitter sensitivity) data we will provide. We will be especially alert for possible 'switch-points' in the transition from non-dependent to dependent states. In these specific aims we will look for the possibility of different cell types in NAcc contributing to heterogeneity in electrophysiological and pharmacological responses, using the infrared DIC videomicroscopic method. These studies should help more clearly specify the role of opioid peptides and their receptors in normal, opiate-seeking and opiate addictive-tolerant behavior, and help to provide a cellular basis for therapeusis of """"""""craving.""""""""
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