CANNABINOIDS DECREASE ACETYLCHOLINE-RELEASE IN THE MEDIAL-PREFRONTAL CORTEX AND HIPPOCAMPUS, REVERSAL BY SR 141716A

The effect of Delta(9)-tetrahydrocannabinol, the psychoactive principl e of marijuana, and 3-de-]-1,4-benzoxazin-6y)(1-naphthalenyl)methanone monomethanesulfonate} (WIN 55,212-2), a synthetic cannabinoid recepto r agonist, on the acetylcholine output in the medial-prefrontal cortex and hippocampus was studied by microdialysis in freely moving rats. T he administration of Delta(9)-tetrahydrocannabinol (1 and 5 mg/kg i.p. ) and WIN 55,212-2 (5 and 10 mg/kg i.p.) produced a long lasting inhib ition of acetylcholine release in both areas. The inhibitory effect of hg-tetrahydrocannabinol and WIN 55,212-2 was suppressed in both areas by the specific cannabinoid CB1 receptor antagonist, chlorophenyl)-1- (2,4-dichloro-phenyl)-4-methyl-1H- pyrazole-3carboxamide}HCl (SR 14171 6A), at the dose of 0.1 mg/kg i.p., per se ineffective to modify basal acetylcholine release. Most interestingly, SR 141716A alone at higher doses increased acetylcholine release both in the medial-prefrontal c ortex (3 mg/kg i.p.) and hippocampus (1 and 3 mg/kg i.p.), suggesting that acetylcholine output is tonically inhibited by endogenous cannabi noids. Since the inhibitory effect of Delta(9)-tetrahydrocannabinol is produced by doses within those relevant to human use of marijuana, ou r results suggest that the negative effects of the latter on cognitive processes may be explained by its ability to reduce acetylcholine rel ease in the medial-prefrontal cortex and hippocampus. Conversely, cann abinoid receptor antagonists may offer potential treatments for cognit ive deficits. (C) 1998 Elsevier Science B.V. All rights reserved.