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Vol. 301, Issue 3, 915-924, June 2002
Department of Pharmacology and Toxicology, Medical College of
Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
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,
9-tetrahydrocannabinol (9-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,
9-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 either
N-(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.
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