cyclic AMP and related cyclic nucleotides profoundly influence the function of the central nervous system, and there is strong evidence that these nucleotides may be involved in the pathogenesis of mental illnesses such as schizophrenia. This hypothesis is supported by the data showing that many antipsychotic agents alter the cyclic nucleotide system of brain. We propose to study the mechanisms by which these agents alter the cyclic nucleotide system. Antipsychotic drugs have two clear and apparently antagonistic actions on the enzymes involved in the synthesis and hydrolysis of cyclic nucleotides: 1) they inhibit a specific catecholamine-sensitive adenylate cyclase in brain, and 2) they inhibit a specific activatable form of phosphodiesterase present in brain. Data from our laboratory showed that the antipsychotics inhibit this activatable form of phosphodiesterase by interfering with a protein activator of phosphodiesterase found in brain. Interestingly, this activator has recently been shown to activate a solubilized form of adenylate cyclase as well. These findings have raised some intriguing questions: 1) Do the antipsychotics inhibit specific adenylate cyclases by interfering with this protein activator?, and 2) Is this activator necessary for the hormonally-induced stimulation of adenylate cyclase? Our objectives, therefore, are to separate the multiple forms of phosphodiesterase and adenylate cyclase from different brain areas and to determine the specific mechanism by which antipsychotic agents interact with the protein activator and with the activatable forms of adenylate cyclase and phosphodiesterase. We hope that these studies will provide further insight into the biochemical defect that may exist in mental disease and may provide the information that will lead to the design of more selective agents for treating mental illness.