OPIOIDS AND THE PHYSIOLOGY OF THE VENTRAL PALLIDUM

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The ventral pallidal and nucleus basalis (VP/nB) are limbic brain regions that exhibit high concentrations of mu, delta and kappa opioid receptors, and are densely innervated by nucleus accumbens projections that contain opioid peptides. A consensus exists regarding the central role of limbic systems in the function of endogenous opioids and reward mechanisms associated with (e.g.) heroin administration. However, the particular contribution of the VP/nB to this role is not known. Fundamental to this deficit is our lack of understanding of VP/nB opioid physiology. Experiments in the present competitive renewal will fill this gap by characterizing the electrophysiological pharmacology of VP/nB opioids, with focus on the propensity of opioids to modulate secondary neurotransmitters contained in limbic afferents to the VP/nB. To that end, two general Specific Aims will be addressed: Specific Aim 1 is to characterize the electrophysiologic properties of VP/nB neuronal membranes, and to evaluate the pharmacology of opioid receptor subtypes that regulate these properties. It is proposed that neuronal subpopulations in the VP/nB may exhibit distinct pharmacologic profiles to opioid administration. To address this hypothesis, a newly developed VP/nB neurons will be described and correlated to neuronal subpopulations identified via immunohistochemical markers for the predominant somatic transmitters. Subsequent experiments will detail the pharmacology of opioid receptor-subtypes, identify the ionic conductances altered by opioids, and examine the ability of opioid agonists to alter presynaptic and/or postsynaptic events for these neuronal subpopulations. Specific Aim 2 seeks to characterize opioid modulation of transmitter systems converging within the VP/nB. It is proposed that VP/nB opioids have the capacity to modify the threshold of detection of afferent signals as well as the signal-to-noise relationship of these input influences. To test these hypotheses, in vivo electrophysiological procedures will be used in which single neurons are monitored extracellularly. Opioid modulation of signal gain will be examined by comparing the effects of iontophoretically applied opioids on activity elicited by other transmitters versus opioid effects on spontaneous activity. Additionally, prominent limbic afferents to the VP/nB will be electrically stimulated, and the ability of (1) nucleus accumbens conditioning (which releases endogenous opioids), and (2) iontophoretically applied opioids, to influence responses evoked in the VP/nB will be ascertained. This will indicate if VP/nB opioids can modulate the synaptic efficacy of activated inputs. The studies directed by these two Specific Aims will evaluate the physiology of VP/nB opioid receptor-subtypes at the level of the neuronal membrane and the intact circuit. Such efforts will contribute substantially to our understanding of VP/nB opioid function, and provide a foundation for future work on VP/nB involvement in opioid abuse.