Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats.

The memory-disruptive effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and the synthetic cannabinoid WIN 55,212-2 (WIN-2) were assessed in rats exposed to varying doses of each drug (Delta(9)-THC, 0.5-2.0 mg/kg; WIN-2, 0.25-0.75 mg/kg) during performance of a delayed nonmatch to sample (DNMS) task. Cannabinoids affected performance in a dose x delay-dependent manner, with WIN-2 showing a potency more than four times that of Delta(9)-THC. These effects on DNMS performance were eliminated if the cannabinoid CB1 receptor antagonist SR141617A (Sanofi Research Inc.) was preadministered, but doses of the antagonist alone had no effect on performance. Simultaneous recording from ensembles of hippocampal neurons revealed that both WIN-2 and Delta(9)-THC produced dose-dependent reductions in the frequency (i.e., "strength") of ensemble firing during the sample phase of the task to the extent that performance was at risk for errors on >70% of trials as a function of delay. This decrease in ensemble firing in the Sample phase resulted from selective interference with the activity of differentiated hippocampal functional cell types, which conjunctively encoded different combinations of task events. A reduction in ensemble firing strength did not occur in the nonmatch phase of the task. The findings indicate that activation of CB1 receptors renders animals at risk for retention of item-specific information in much the same manner as hippocampal removal.