Acquired Immunodeficiency Syndrome (AIDS) and intravenous drug abuse are overlapping epidemics. The extent of overlap raises the possibility that vulnerability to opiate dependence may be directly or indirectly linked to virus-induced neurochemical and molecular changes in the CNS. The objective of this proposal is to study viral-induced changes in vulnerability to opiate reinforcement and dependence. Using a small animal model of a chronic viral encephalitis with neuropathologic similarities to human HIV neuropathology, the hypothesis that viral-induced changes in endogenous opioid expression are linked to behavioral effects on opiate reinforcement and dependence can be tested. An animal model of a persistent CNS viral infection based on experimental Borna disease virus infection of the rat will be developed then tested for 1) the reinforcing effects of opiates as measured by intravenous self-administration of heroin (Specific Aim 1) and 2) the dependence-inducing effects of opiates, as measured by the somatic signs of opiate withdrawal, and the affective (emotional) effects of opiate withdrawal as measured by place aversion (Specific Aim 2). The neural substrates for altered opiate sensitivity will be established by examination of opiate-rich structures using quantitative neuroanatomic techniques (Specific Aim 3). Finally, in vitro, the viral mechanisms for altered opioid expression will be investigated by examination of the effects of viral infection on transcriptionally active host cell proteins (Specific Aim 4). These studies will go far toward elucidating viral-induced neural mechanisms mediating opiate dependence. Knowledge of how viruses contribute to the development of vulnerability to opiate use will provide new insights into treatment and prevention of opiate abuse and drug abuse in general. The work proposed in this MCSDA application is designed to provide training in neuropharmacology, neurobehavior, virology, and molecular biology. The research program was developed with the assistance of George Koob (Ph.D.) of The Scripps Research Institute (TSRI) and W. Ian Lipkin (M.D.) of the University of California, Irvine (UCI). The research plan will allow for the development of new skills and techniques in several disciplines: the learning of methodologies utilizing animal models of drug abuse, plus molecular, cell culture and viral preparative techniques. Because of the scope and multidisciplinary nature of the proposal, the work will be conducted jointly at TSRI and UCI. At the conclusion of the grant period, the requisite skills in behavioral pharmacology, neuropharmacology and molecular biology for continued work in the study and treatment of drug addiction will have been acquired by the candidate.
