Differential effects of Δ9-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 marijuana and cannabinoid derivatives. Thus, developing a better understanding of Δ9-THC (tetrahydrocannabinol)-induced mnemonic deficits is of critical importance. Objectives: These experiments were conducted to determine whether Δ9-THC has differential effects on spatial reference and working memory tasks, to investigate its receptor mechanism of action, and to compare these effects with those produced by two other compounds - scopolamine and phencyclidine - known to produce mnemonic deficits. In addition, the potency of Δ9-THC in these memory tasks was compared with its potency in other pharmacological effects traditionally associated with cannabinoid activity. Methods: Two different versions of the Morris water maze were employed: a working memory task and a reference memory task. Other effects of Δ9-THC were assessed using standard tests of hypomotility, antinociception, catalepsy, and hypothermia. Results: Δ9-THC disrupted performance of the working memory task (3.0 mg/kg) at doses lower than those required to disrupt performance of the reference memory task (100 mg/kg), or elicit hypomotility, antinociception, catalepsy, and hypothermia. These performance deficits were reversed by SR 141716A. The effects of Δ9-THC resembled those of scopolamine, which also selectively disrupted the working maze task. Conversely, phencyclidine disrupted both tasks only at a dose that also produced motor deficits. Conclusions: These data indicate that Δ9-THC selectively impairs performance of a working memory task through a CB1 receptor mechanism of action and that these memory disruptions are more sensitive than other pharmacological effects of Δ9-THC.