The overall objective of this proposal is to investigate, in vivo, neuropharmacologic actions of opioids and their role in states of addiction. In designing more effective treatment strategies for addiction, further understanding of the neural mechanisms underlying opiate pharmacology, reinforcement and dependence is required. Toward this end, electrophysiologic studies will be performed in the nucleus accumbens (NAcc) of anesthetized rats. The NAcc is an area of the brain known to be critical for the reinforcing effects of drugs of abuse. Although the role of endogenous opioids will be investigated, emphasis will be placed on the neuropharmacologic changes that occur with opiate tolerance and dependence, and the interaction of these changes on the dopamine system. The proposed studies are designed to test the following two hypotheses: (1) Endogenous opioids act as neurotransmitters in the NAcc to influence cellular activity; (2) During states of opiate tolerance and dependence, changes occur in the neurophysiological responses to opiates. The first Specific Aim proposes to study the effects of locally and systemically administered opioids on single unit activity in the NAcc. Because spontaneous firing rates in the NAcc are extremely low, most studies will employ the use of locally applied, intermittent, glutamate pulses to stimulate single units in rats receiving a slow, continuous, intravenous infusion of chloral hydrate for anesthesia. The influence of opioids on afferent inputs from the hippocampus, amygdala, and ventral pallidum, will be investigated by recording both evoked single units and field potentials. Studies are also proposed to investigate the interaction of opioids with other relevant neurotransmitters, specifically glutamate, GABA, and dopamine. In order for these studies to be relevant to the problem of opiate abuse, the second and third Specific Aims propose to perform similar experiments on rats that are opiate-tolerant and on rats in opiate withdrawal. A final Specific Aim proposes to study the influence of the ventral tegmental area (VTA) on opioid neurophysiology in the NAcc. The VTA is the source of dopaminergic input to the NAcc, and is not only important for the action of opiates, but also for other drugs of abuse, such as cocaine, amphetamines, and alcohol. Taken as a whole, this proposal constitutes a comprehensive, in vivo, study of opioid neurophysiology in the NAcc, and its relation to drug abuse.
