Abstract

The endocannabinoid system has been proposed to modulate a variety of physiological processes, including those that underlie cognition. The present study tested whether this system is tonically active in learning and memory by comparing CB₁ receptor knockout mice (CB₁^−/−) to wild-type mice (CB₁^+/+) in several Morris water maze tasks. Also, the effects of three cannabinoid agonists, Δ⁹-tetrahydrocannabinol (Δ⁹-THC),R-(+)-[2,3-dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1, 4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2), and methanandamide, were evaluated in a working memory procedure. Both genotypes exhibited identical acquisition rates in a fixed platform procedure; however, the CB₁^−/− mice demonstrated significant deficits in a reversal task in which the location of the hidden platform was moved to the opposite side of the tank. This phenotype difference was most likely due to an increased perseverance of the CB₁^−/− mice in that they continued to return to the original platform location, despite being repeatedly shown the new platform location. In addition, Δ⁹-THC (ED₅₀ = 1.3 mg/kg), WIN 55,212-2 (ED₅₀ = 0.35 mg/kg), and methanandamide (ED₅₀ = 3.2 mg/kg) disrupted the performance of CB₁^+/+ mice in the working memory task at doses that did not elicit motivational or sensorimotor impairment as assessed in a cued version of the task. Furthermore, doses of each drug that were maximally disruptive in CB₁^+/+ mice were ineffective in eitherN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A)-treated CB₁^+/+ or CB₁^−/− mice. These results provide strong evidence that cannabinoids disrupt working memory through a CB₁ receptor mechanism of action, and suggest that the endocannabinoid system may have a role in facilitating extinction and/or forgetting processes.