a) We have continued to study effects of intravenous idazoxan, a selective alpha-2 antagonist in volunteers using paired FDG PET scans. Robust quantitative and/or qualitative effects of gender have been found: men show a higher catecholamine response whereas, in brain, with regard to metabolic response, men show decreases in frontal cortex and women show increases. b) While the central and peripheral responses we observe following acute idazoxan are consistent with central and peripheral alpha-2 blockade, idazoxan also interacts with the recently described "imidazoline rceptors." To determine whether imidazoline interactions are involved in the observed responses to idazoxan we initiated a set of parallel studies in volunteers with ethoxyidazoxan, a derivative of idazoxan that does not interact with imidazoline sites. We have completed a Phase I dose ranging study of ethoxyidazoxan in healthy males revealing a dose-dependent increase in norepinephrine and blood pressure in the same ranges as those seen with idazoxan. Brain imaging studies will follow. c) Chronic lithium in healthy volunteers has now been found to not only increase pertussis toxin stimulated ribosylation of G(i) in platelets but to decrease the alpha isozyme of protein kinase C, the latter finding consistent with lithium induced decreases in rat hippocampus. This adds to the growing body of evidence that in humans, chronic lithium exerts potent effects both at the level of PKC and G protein, effects which we postulate to be interrelated.
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