This is a request for a continuation of RSDA Level 11 support which was originally provided to evaluate the effects of thymic peptides on central nervous system (CNS) function. The original study has now evolved to include assessment of the CNS effects of interferon alpha which appears to have opioid-like properties. Although all aspects of interferon's effects are of interest, we are focusing upon its ability to attenuate naloxone precipitated withdrawal symptoms in morphine-dependent rats. This model is being used to identify specific brain sites where interferon is active as well as neurotransmitter systems that may be involved. In addition, the component behaviors of withdrawal will be carefully evaluated in order to gain insights as to where and how the CNS effects of this cytokine are mediated. RSDA support is being sought in order to make available the time and resources to become more proficient in the area of neuropharmacology. This will be done by spending time in the laboratory of Dr. Martin Adler who is a consultant to the currently funded R01 grant. I also wish to begin evaluating changes in neurotransmitters and neuropeptides using in vitro perifusion and the push-pull cannula technique which I will need to learn. This will be accomplished through collaborations with Dr. Chris Phelps with whom I am already collaborating. The net result will be a more sensitive assessment of the neurochemical effects of interferon alpha as well as more versatility in expanding upon the future directions that this project will take. These studies have wide ranging implications in the areas of AIDS and drug abuse. Clinical trials have revealed severe psychiatric complications following the administration of interferon which have some similarities to the symptoms of AIDS related dementia. These include depression, paranoia as well as suicidal potential which usually resolve once the therapy is stopped. An acid labile form of interferon has been found at high levels in AIDS patients and may well be contributing to some of the CNS symptoms. In the context of drug abuse, it is possible that measures of immunologic status may have predictive value in determining the severity of withdrawal symptoms in addition to furthering our understanding of the bidirectional links between the CNS and the immune system.
