Cannabidiol reverses memory impairments and activates components of the Akt/GSK3β pathway in an experimental model of estrogen depletion

•Cannabidiol reverses estrogen depletion-induced memory deficits in rats.•Estrogen depletion lessens Akt/GSK3β survival pathway in the hippocampus.•The levels of the antiapoptotic protein Bcl2 are reduced by estrogen depletion.•Cannabidiol enhances Akt/GSK3β pathway’s activation and increases Bcl2.•Cannabidiol may be a useful treatment for estrogen depletion-induced memory decline. Clinical and preclinical evidence has indicated that estrogen depletion leads to memory impairments and increases the susceptibility to neural damage. Here, we have sought to investigate the effects of Cannabidiol (CBD) a non-psychotomimetic compound from Cannabis sativa, on memory deficits induced by estrogen depletion in rats, and its underlying mechanisms. Adult rats were subjected to bilateral ovariectomy, an established estrogen depletion model in rodents, or sham surgery and allowed to recover for three weeks. After that, they received daily injections of CBD (10 mg/kg) for fourteen days. Rats were tested in the inhibitory avoidance task, a type of emotionally-motivated memory. After behavioral testing they were euthanized, and their hippocampi were isolated for analysis of components of the Akt/GSK3β survival pathway and the antiapoptotic protein Bcl2. Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment. Ovariectomy also reduced Akt/GSK3β pathway’s activation by decreasing the phosphorylation levels of Akt and GSK3β and Bcl2 levels, which were ameliorated by CBD. The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3β survival pathway’s activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance.