Alpha-2 agonist-induced memory impairment is mediated by the alpha-2A-adrenoceptor subtype.
The activation of alpha2-adrenoceptors has been reported to impair memory functions in both rats and humans. The alpha2-adrenoceptor subtype responsible for this detrimental effect is still unknown. The effect of the alpha2-agonists clonidine and guanabenz on memory processes, in dependence to the time of administration, was evaluated in the mouse passive avoidance test. Clonidine (0.02-0.2 mg kg(-1) i.p.) and guanabenz (0.1-0.3 mg kg(-1) i.p.) induced amnesia in a dose-dependent manner. From time-course experiments emerged that the impairment of memory function was detectable only when clonidine and guanabenz were administered 60 min before or immediately after the training test, respectively. This detrimental effect was prevented by pretreatment with the alpha2-antagonist yohimbine (1-3 mg kg(-1) i.p.) and by the alpha2A-antagonist BRL-44408 (0.3-1 mg kg(-1) i.p.). By contrast, the alpha(2B,C) antagonists ARC-239 (10 mg kg(-1) i.p.) and prazosin (1 mg kg(-1) i.p.) did not revert the amnesia induced by both clonidine and guanabenz. At the highest effective doses, clonidine and guanabenz were devoid of behavioral side-effects as well as maintained unaltered the motor coordination, as revealed by the rota-rod test. Furthermore, none of the compounds used modified the spontaneous motility as indicated by the Animex apparatus. These results indicate that clonidine and guanabenz impaired memory processes in a mouse passive avoidance paradigm through the selective activation of the alpha2A-adrenoceptor subtype.
Galeotti
Nicoletta
N
Department of Preclinical and Clinical Pharmacology, Viale G. Pieraccini 6, I-50139 Florence, Italy.
Bartolini
Alessandro
A
Ghelardini
Carla
C
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D005239:Fear / Q000187:drug effects; D006143:Guanabenz / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D054833:Isoindoles; D008297:Male; D011939:Mental Recall / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine / Q000494:pharmacology
C547768:ADRA2A protein, human; C547769:Adra2a protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D006143:Guanabenz; D003000:Clonidine; C072125:BRL 44408