NEUROCHEMICAL ACTIONS OF PSYCHOTROPIC DRUGS

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The long-term goal of this application is to elucidate neurochemical aspects of signal transduction systems in the brain which may be the site of action for psychotropic drug actions. Studies are proposed to clarify properties of the phosphoinositide and nitric oxide messenger systems. Properties of the inositol-1,4,5-triphosphate (IP3) receptor protein will be characterized. The biochemical and functional role of phosphorylation and glycosylation of the receptor will be examined. Functional role of phosphorylation and glycosylation of the receptor will be evaluated through a reconstituted system of the IP3 receptor protein in liposomes whereby calcium flux is stimulated selectively by IP3 Properties of IP3 receptor protein in peripheral tissues will be compared with the central receptor. The receptor protein for inositol (1,3,4,5) tetrakisphosphate (IP4) will be purified. Antisera will be developed to the IP4 receptor protein to permit its immunohistochemical localization. Utilizing the purified IP4 receptor protein reconstituted into liposomes, efforts will be made to identify potential functions ,such as mediation of ion flux. Calmedin, a membrane associated protein in the brain which mediates the ability of calcium to inhibit IP3 receptor binding, will be purified Interactions between purified calmedin and IP3 receptor protein will be examined in kinase, which generates IP4, will be purified. Antisera to the purified enzyme proteins will be employed for immunohistochemistry. Nitric oxide (NO) will be characterized as a possible messenger in neuronal interactions in the brain. The relationship between the conversion of arginine to citrulline and the formation of NO will be examined in a variety of systems. The nature of the endogenous arginine pool employed for NO biosynthesis will be explore by examining the uptake of 3H-arginine and alterations in endogenous arginine levels. The influence of agents that affect free radical formation will be examined on NO and cyclic GMP formation. The cellular source of NO synthesis will be explored utilizing neurologic mutant mice. The NO forming enzyme will be purified and antisera raised for immunohistochemical localization.