The endogenous cannabinoid receptor agonist anandamide impairs memory in rats

Anandamide was recently discovered to be an endogenous substance that acts as a partial agonist at cannabinoid receptors in the central nervous system. Because exogenous cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive ingredient of marijuana, have been found to impair memory, we undertook the present study to examine the mnemonic effects of anandamide. Memory was assessed in rats well-trained in a two-component instrumental discrimination task with a conditional discrimination to test reference memory and a delayed nonmatch-to-position to test working memory. Since anandamide has a short metabolic half-life, we examined the mnemonic effects of anandamide (0.0–2.0 mg/kg) in rats pretreated with the protease inhibitor phenylmethylsulfonyl fluoride (2.0 mg/kg), serving to increase the metabolic half-life of anandamide. Under these conditions, a dose-dependent impairment of the nonmatch-to-position, but not the conditional discrimination component, was found, closely resembling that observed following Δ9-THC (0.0–4.0 mg/kg). This is the first report that anandamide impairs memory; results suggest that endogenous cannabinoids may be involved in cognitive processes influencing memory.