Alpha-2 agonits induce amnesia through activation of the Gi-protein signalling pathway.

The post-receptorial mechanism of the amnesic action of the 2-agonists clonidine and guanabenz was investigated in the mouse passive avoidance test. Animals were i.c.v. injected with pertussis toxin (PTX) or with antisense oligonucleotides, complementary to the sequence of the -subunit mRNA of Gi1, Gi2, Gi3, Go1 and Go2 proteins. The administration of PTX (0.25 g per mouse i.c.v.) reversed the amnesia induced by both 2-agonists. Similarly, anti-Gi1 (6.25–12.5 g per mouse i.c.v.), anti-Gi3 (3.12–12.5 g per mouse i.c.v.), anti-Go1 (12.5–25 g per mouse i.c.v.) antagonised the detrimental effect induced by clonidine and guanabenz. By contrast, pretreatment with anti-Gi2 (3.12–25 g per mouse i.c.v.) and anti-Go2 (12.5–25 g per mouse i.c.v.) never modified the impairment of memory processes induced by the 2-agonists. At the highest effective doses, none of the compounds used impaired motor coordination (rota rod test), nor modified spontaneous motility and inspection activity, (hole board test). These results indicate the involvement of Gi1, Gi3, and Go1, but not Gi2 and Go2, protein subtypes in the transduction mechanism responsible for the induction of amnesia by clonidine and guanabenz.