DELTA(9)-TETRAHYDROCANNABINOL IMPAIRS SPATIAL MEMORY THROUGH A CANNABINOID RECEPTOR MECHANISM

The purpose of the present study was to investigate whether the cannab inoid and cholinergic systems impair working memory through a common m echanism. This hypothesis was tested by examining whether the cannabin oid antagonist SR141716A would ameliorate radial-arm performance defic its caused by either the naturally occurring cannabinoid, Delta(9)-THC , or scopolamine, a muscarinic antagonist. In addition, we evaluated w hether the cholinesterase inhibitor, physostigmine, would prevent Delt a(9)-THC-induced impairment of spatial memory. Finally, because the lo comotor suppressive effects of cannabinoids may decrease radial arm ch oice accuracy independent of a direct effect on memory, we examined th e impact of increasing the intertrial error on radial arm choice accur acy. As previously reported, Delta(9)-THC impaired maze performance (E D(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 co mplete the maze without affecting choice accuracy. Importantly, SR1417 16A prevented Delta(9)-THC-induced deficits in radial-arm choice accur acy in a dose-dependent manner (AD(50)=2.4 mg/kg); however, the cannab inoid antagonist failed to improve the disruptive effects of scopolami ne. Conversely, physostigmine failed to improve performance deficits p roduced by Delta(9)-THC. These data provide strong evidence that Delta (9)-THC impairs working memory through direct action at cannabinoid re ceptors. Moreover, these results suggest that scopolamine and Delta(9) -THC do not impair spatial memory in a common serial pathway, though t hey may converge on a third neurochemical system.