Differential effects of Delta(9)-THC on spatial reference and working memory in mice

Rationale: Marijuana remains the most widely used illicit drug in the U.S., and recent attention has been given to putative therapeutic uses of mariju ana and cannabinoid derivatives. Thus, developing a better understanding of Delta (9)-THC (tetrahydrocannabinol)-induced mnemonic deficits is of criti cal importance. Objectives: These experiments were conducted to determine w hether Delta (9)-THC has differential effects on spatial reference and work ing memory tasks, to investigate its receptor mechanism of action, and to c ompare these effects with those produced by two other compounds - scopolami ne and phencyclidine - known to produce mnemonic deficits. In addition, the potency of Delta (9)-THC in these memory tasks was compared with its poten cy in other pharmacological effects traditionally associated with cannabino id activity. Methods: Two different versions of the Morris water maze were employed: a working memory task and a reference memory task. Other effects of Delta (9)-THC were assessed using standard tests of hypomotility, antino ciception, catalepsy, and hypothermia. Results: Delta (9)-THC disrupted per formance of the working memory task (3.0 mg/kg) at doses lower than those r equired to disrupt performance of the reference memory task (100 mg/kg), or elicit hypomotility, antinociception, catalepsy, and hypothermia. These pe rformance deficits were reversed by SR 141716A. The effects of Delta (9)-TH C resembled those of scopolamine, which also selectively disrupted the work ing maze task. Conversely, phencyclidine disrupted both tasks only at a dos e that also produced motor deficits. Conclusions: These data indicate that Delta (9)-THC selectively impairs performance of a working memory task thro ugh a CB1 receptor mechanism of action and that these memory disruptions ar e more sensitive than other pharmacological effects of Delta (9)-THC.