Guanylate cyclase and adenylate cyclase, the enzymes which generate the intracellular 'second messengers' cyclic GMP and cyclic AMP, will be examined in human brain, human platelets and mouse brain with the goal of finding parameters of enzyme activity which are appropriate for human biochemical-genetic investigations of individual differences in the enzymes which may represent a genetic vulnerability to neurological or psychiatric disease. Due to results of studies on the mechanism of action of antipsychotic and other centrally active drugs, current research on the biochemistry of schizophrenia has focused on the role of central dopaminergic and cholinergic synapses in the pathogenesis of the disorder; since dopamine receptors have been shown to be linked to adenylate cyclase and muscarinic receptors to guanylate cyclase, we propose to begin our biochemical genetic investigations with comparisons of adenylate and guanylate cyclase activity in platelets from consensus diagnosed schizophrenic patients and non-hospitalized controls. Platelet enzyme activity will be measured in schizophrenic patients before and after treatment (1 and 2 months) with phenothiazines. Companion experiments on the acute and chronic effects of chlorpromazine on parameters of brain guanylate and adenylate cyclase will be conducted with mice. Human brain guanylate and adenylate cyclase will be characterized (Vmax and substrate Km plus agonists; ka's and ki's for agonists and inhibitors) at various post-mortem intervals in autopsy material from accident victims where toxicology screens and medical histories indicate no recent or chronic drug use or illness. If enzyme parameters can be found which are independent of post-mortem changes (over a reasonable interval) in brain tissue from these subjects, guanylate and adenylate cyclase will be examined in brain tissue from subjects with various drug and neurological/psychiatric histories.