Diphenhydramine-induced amnesia is mediated by Gi-protein activation.

The effect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the subunit of different Gi-proteins (anti-Gi1, anti-Gi2, anti-Gi3, anti-Go1, anti-Go2) on the amnesia induced by the H1-antihistamine diphenhydramine (20 mg kg1 s.c.) was evaluated in the mouse passive avoidance test. Pretreatment with anti-Gi1 (12.5–25 g per mouse i.c.v.) and anti-Gi2 (25 g per mouse i.c.v.), administered 24 and 18 h before test, prevented antihistamine- induced amnesia. By contrast, pretreatment with an anti-Gi3 (25 g per mouse i.c.v.), anti-Go1 (25 g per mouse i.c.v.) and anti-Go2 (25 g per mouse i.c.v.) did not modify the detrimental effect induced by diphenhydramine. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest the important role played by the Gi1- and Gi2-protein pathway in the transduction mechanism involved in the impairment of memory processes produced by the H1-antihistamine diphenhydramine