Non-adrenergic exploratory behavior induced by moxonidine at mildly hypotensive doses

Moxonidine is a centrally-active imidazoline compound with preferential affinity for imidazoline receptors (IR) over alpha(2)-adrenoceptors (alpha(2)AR). Clinically, moxonidine has proven advantageous for treating hypertension over pure alpha(2)-adrenergic agonists (i.e., guanabenz) due to its lowered incidence of sedative side effects. The present experiments reveal divergent behavioral effects of low doses of moxonidine and guanabenz in C57Bl/6 mice in an exploratory arena. Low-dose moxonidine (0.05 mg kg(-1) i.p.) elicited an increase in novel object contacts (+36%) and more movement into central space (+56%; P<0.01) compared to saline-injected controls; whereas guanabenz induced only dose-responsive sedative-like behaviors in the same paradigm. Yet, the two agonists were indistinguishable in terms of blood pressure changes over a similar dose range (0.025-0.1 mg kg(-1) i.p.) in consciously free-moving mice (Delta mean+/-S.E.M.=-12.3+/-3.2 mm Hg for moxonidine versus -13.5+/-1.9 mm Hg for guanabenz). As expected of alpha(2)AR involvement, the sedative-like effects of guanabenz were completely blocked by pretreatment with the non-imidazoline alpha(2)AR-antagonist, SKF86466 (0.5 or 1.0 mg kg(-1) i.p.). However, the pro-exploratory effects of low doses of moxonidine (0.05 or 0.1 mg kg(-1)) were not antagonized by SKF86466. These results suggest that moxonidine acts preferentially through a non-adrenergic mechanism, possibly IR-mediated, to elicit pro-exploratory behavior.