Cerebral glucose metabolic and plasma catecholamine responses to the α2 adrenoceptor antagonist ethoxyidazoxan given to healthy volunteers

Rationale: Methods that test for the central effects of α2-adrenoceptor antagonists can facilitate the clinical development of such compounds. Recently we evaluated the effects of idazoxan (IDX), an α2-adrenoceptor antagonist with high affinity for imidazoline sites, on a variety of measures potentially sensitive to blockade of α2-adrenoceptors including regional brain glucose metabolic rate. Objective: To test whether these effects on brain metabolic rate could have been mediated by imidazoline binding sites, single dose challenges of 9 or 12 mcg/kg ethoxyidazoxan (ETX; an α2-adrenoceptor antagonist which does not bind to imidazoline sites) were given to healthy male volunteers. Methods: The effects on brain glucose metabolism, blood pressure, catecholamines, and behavior were assessed. Results: Blood pressure increased 10–15% after both doses. Plasma catecholamines increased 2- to 2.5-fold and responses were dose dependent. There was no evidence of either dose being anxiogenic. Both doses of ETX produced diffuse increases in brain glucose metabolism. Conclusions: Brain glucose metabolic responses were more widespread and monotonic than we had observed with IDX. ETX also produced robust increases in glucose metabolism in cerebellum. While we were unable to exclude the possibility that some of the brain metabolic responses we had observed with IDX were mediated by imidazoline sites, ETX may be sufficiently distinct from IDX in α2-adrenoceptor affinity that differences in acute metabolic responses occurred.