Dr. Meltzer is applying for renewal of his renewal of his RSA to further study the roles of 5-HT, dopamine (DA) and their interaction in SCH, MD, and OCD, as well as in the mechanism of action of various psychotropic drugs, especially clozapine (CLZ) and other atypical antipsychotic drugs (APD). Pursuant to these goals, 14 study aims are proposed. These are: (1) to test whether melperone (MEL) is a effective as CLZ in treatment-resistant SCH; (2) to test whether amperozide (AMP) is an effective atypical APD; (3) to test the hypothesis that the 5-HT2-D-2 antagonist ratio can contribute to the identification of atypical APD's; (4) to validate buspirone in man as a 5- HT1a probe by testing the ability of pindolol, a 5-HT1ald antagonist to block the buspirone-induced increases in plasma prolactin (PRL) and cortisol; (5) to validate MK-212 in man as a 5-HT2 probe by determining if its effects on plasma PRL, adrenocortiotropic hormone (ACTH) and cortisol can be inhibited by pretreatment with ritanserin, a 5-HT2 antagonist, but not by pindolol; (6) to validate 5-HTP in man as a specific 5-HT2 probe by demonstrating that the effect on 5-HTP, ACTH and cortisol secretion is not blocked by treatment with pinodol as it is by retanserin; (7) to test the hypothesis that ACTH, cortisol, and prolactin responses to buspirone and MK-212 are blunted in patients with SCH; (8) to test the hypothesis that ACTH, cortisol or PRL responses to 5-HTP or MK-212 in SCH are inhibited by treatment with clinically effective doses of MEL and AMP as it is by CLZ; (9) to demonstrate that atypical APD's other than CLZ decrease basal plasma ACTH, cortisol and 24 hour urinary free cortisol and increase lymphocyte glucocorticoid receptor binding sites; (10) to test the hypothesis that APD's other than CLZ will increase 5-HT2 platelet binding sites and this increase will be proportional to their efficacy; (11) to test the hypothesis that atypical APD's occupy brain D2 and 5-HT2 sites through imaging studies; (12) to test the hypothesis that atypical APD's increase 5-HT release in rat striatum and accumbens and do not increase D2 release; (13) to test the hypothesis that there is elevated 5-HT2 and 5- HT1a binding sites in suicide brains after assessing both violence and diagnosis by psychological autopsy; and (14) to test the hypothesis that specific 5-HT uptake blockers enhance the response to MK 212 and 5-HTP but not mCPP in both OCD patients and controls. The human studies involve neuroleptic resistant and neuroleptic responsive patients with schizophrenia recruited from four different Clinical Research Centers, which admit over 100 such patients and treat 30 patients per year on an out-patient basis, as well as normal volunteers. These subjects and/or patients will be recruited from the applicant's hospital and paid for their participation. Informed consent will be obtained and blood samples will be drawn. The animal studies involve about 2,300 Sprague-Dawley rats per year for dialysis and endocrine challenge experiments.
