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.
Zhu
He
H
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Paul
Ian A
IA
Stec
David E
DE
Peeler
Dudley F
DF
Piletz
John E
JE
D000316:Adrenergic alpha-Agonists / Q000009:adverse effects; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D006143:Guanabenz / Q000009:adverse effects; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007022:Hypotension / Q000139:chemically induced; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors; D008297:Male; D051379:Mice; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D001552:Benzazepines; D007093:Imidazoles; D054755:Imidazoline Receptors; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; C043482:moxonidine; D006143:Guanabenz; C039139:benalfocin; D004837:Epinephrine