Involvement of reduced acetylcholine release in Δ9-tetrahydrocannabinol-induced impairment of spatial memory in the 8-arm radial maze

To clarify the mechanism by which Delta(9)-tetrahydrocannabinol, a major psychoactive component of marijuana, impairs spatial memory in the 8-arm radial maze in rats via the cholinergic system, we used two acetylcholinesterase inhibitors, physostigmine and tetrahydroaminoacridine. Moreover, we examined the effect of Delta(9)-tetrahydrocannabinol on acetylcholine release in the frontal cortex and dorsal and ventral hippocampus using in vivo microdialysis. Physostigmine (0.01-0.05 mg/kg, i.p.) and tetrahydroaminoacridine (1-5 mg/kg, p.o.) improved the impairment of spatial memory induced by Delta(9)-tetrahydrocannabinol (6 mg/kg, i.p.) in the 8-arm radial maze. Delta(9)-tetrahydrocannabinol (6 mg/kg, i.p.) produced a significant decrease in acetylcholine release in the dorsal hippocampus as assessed by microdialysis. Moreover, tetrahydroaminoacridine at a dose of I mg/kg, which improved the impairment of spatial memory, reversed the decrease in acetylcholine release induced by Delta(9)-tetrahydrocannabinol in the dorsal hippocampus during 60-120 min after the Delta(9)-tetrahydrocannabinol injection. These findings suggest that inhibition of the cholinergic pathway by reduced acetylcholine release is one of the means by which Delta(9)-tetrahydrocannabinol impairs spatial memory in the 8-arm radial maze. (C) 2002 Published by Elsevier Science Inc.