Delta(9)-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism

The purpose of the present study was to investigate whether the cannabinoid and cholinergic systems impair working memory through a common mechanism. This hypothesis was tested by examining whether the cannabinoid antagonist SR141716A would ameliorate radial-arm performance deficits caused by either the naturally occurring cannabinoid, Delta(9)-THC, or scopolamine, a muscarinic antagonist. In addition, we evaluated whether the cholinesterase inhibitor, physostigmine, would prevent Delta(9)-THC-induced impairment of spatial memory. Finally, because the locomotor suppressive effects of cannabinoids may decrease radial arm choice accuracy independent of a direct effect on memory, we examined the impact of increasing the intertrial error on radial arm choice accuracy. As previously reported, Delta(9)-THC impaired maze performance (ED(50)=3.0 mg/kg). Increasing the intertrial interval from 5 s to 30 s resulted in a three-fold increase in the amount of time required to complete the maze without affecting choice accuracy. Importantly, SR141716A prevented Delta(9)-THC-induced deficits in radial-arm choice accuracy in a dose-dependent manner (AD(50)=2.4 mg/kg); however, the cannabinoid antagonist failed to improve the disruptive effects of scopolamine. Conversely, physostigmine failed to improve performance deficits produced by Delta(9)-THC. These data provide strong evidence that Delta(9)-THC impairs working memory through direct action at cannabinoid receptors. Moreover, these results suggest that scopolamine and Delta(9)-THC do not impair spatial memory in a common serial pathway, though they may converge on a third neurochemical system.