Cannabinoid-induced working memory impairment is reversed by a second generation cholinesterase inhibitor in rats

Cannabinoids which impair rat working memory appear to inhibit hippocampal extracellular acetylcholine (Ach) release and reduce choline uptake through an interaction with CB1 cannabinoid receptors. Here we report that CP 55,940, a potent bicyclic synthetic cannabinoid analog, dose-dependently impaired rat performance, when given i.p. 20 min before an eight-arm radial maze test. The selective CB1 cannabinoid receptor antagonist SR 141716A, given i.p. 20 min earlier, significantly reduced the memory deficit Pretreatment with eptastigmine, a second generation cholinesterase inhibitor, given orally 100 min before the cannabinoid agonist, relieved the memory impairment without affecting CP 55,940-induced behavioural alterations such as reduced spontaneous motor activity, analgesia and hind limb splaying. These data suggest that cannabinoid-induced working memory impairment is mediated through a central cholinergic blockade.