a) Our findings in healthy volunteers (MH-0l85-10) provide evidence that imaging the metabolic effect of idazoxan is sensitive to functional differences in the response to alpha-2 blockade. Accordingly, we studied the FDG PET response to acute idazoxan in unipolar and bipolar depressed patients. In a subset of these patients we also compared idazoxan responses before and after ECT treatment. Preliminary analyses indicate that bipolar depressed males show an attenuated metabolic response to idazoxan, and that resting brain metabolism is lower following a course of ECT. b) We have now completed two independent studies utilizing patients in Israel and at the NIMH and found significantly increased levels of the stimulatory G protein G-alpha, in peripheral cells from manic depressive patients compared to controls. Moreover, out study of post-mortem brain from manic depressive patients reveals decreases of selected protein kinase C isozymes, alpha and epsilon, in cytosol but not membranes fractions and a modest increase in G-alpha protein but decrease in its mRNA. Taken together, the direct in vivo investigations using peripheral cells and idazoxan effects on brain metabolism and direct ex vivo post- mortem studies indicate there are abnormalities of G protein regulation and function in the human CNS of patients with manic depressive illness. c) We have undertaken a series of studies to elucidate the mechanism(s) underlying the regulation of intracellular calcium in platelets. Using the fluorescent indicator Fura-2, we have found that subjects with a Tyr to His substitution in aa residue 445 of the serotonin 5HT(2A) receptor exhibit marked alterations in the latency period to maximal stimulation with serotonin. These major differences in receptor responsiveness may be major implications for population differences in response to various pharmacologic agents, and is being studied further.
