OPIOIDS AND THE PHYSIOLOGY OF THE VENTRAL PALLIDUM

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The ventral pallidum (VP) may be a neurobiological substrate for the motivational aspects of opiate addiction, such as drug craving. To date, however, the effects of chronic opiate exposure on the physiology of the VP have not been explored. The neural adaptations that occur during the enhanced behavioral responding that is induced by repeated intermittent exposure to opiates in rats likely parallel those mediating drug craving in the addict. Chronic opiates appear to induce long lasting changes in the ventral tegmental area (VTA) and the nucleus accumbens (NA). We hypothesize that VP neurons also undergo a persistent adaptation to chronic opiate exposure. We also pose that this reflects an alteration in VTA and NA inputs, as well as changes in VP neurons themselves. To test these hypotheses, electrophysiological comparisons will be made between the NA and VP to rats that demonstrate morphine-induced behavioral sensitization. Specific Aim 1. To determine the ability of chronic morphine treatments to alter responses of VP and NA neurons to opioid agonists and antagonists. The opioid receptors that mediate morphine-induced sensitization and the physiological parallels to these changes are not known. Experiments in Aim 1 will use extracellular electrophysiology in combination with microiontophoretic application of opioid receptor subtype-specific drugs to provide the first examination of these issues for the VP and NA. Specific Aim 2. To determine if chronic morphine treatments alter opioid modulation of dopaminergic transmission from the VTA to the VP and NA. With extracellular electrophysiology, we recently revealed that opioids modulate dopamine transmission in the VP. As neuromodulation can occur on membrane events that are subthreshold to the generation of an action potential, intracellular recordings of VP and NA neurons in vivo will be conducted to evaluate ability of morphine to alter these parameters. Dopaminergic transmission is altered in the NA with chronic morphine treatments. However, the physiological underpinnings of this change have not been explored. Thus, using the same treatment paradigm as that employed in Aim 1, experiments in this Aim will be conducted to determine if chronic morphine treatments alter the ability of the opiate to modulate dopamine transmission. Because the VP serves as a major output for the mesolimbic system, studies on this region are critical to understanding the consequences of neural adaptations of the brain's reward system. The proposed experiments should provide new insights for the development of more efficacious therapy for compulsive drug use and craving.