INHIBITION OF HIPPOCAMPAL ACETYLCHOLINE-RELEASE BY CANNABINOIDS - REVERSAL BY SR 141716A

Two synthetic cannabinoids, WIN 55,212-2 2,3-dihydro-5-methyl-3-[{4-mo rpholinylmethyl]pyrol -de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methano ne monomethanesulfonate} (5.0 and 10 mg/kg i.p.) and CP 55,940 [1a,2-( R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3 -hydroxypropyl)cyclohexyl] -phenol) 2-[5-hydroxy-2-(3-hydroxpropyl)cyclohexyl]-phenol} (0.5 and 1 .0 mg/kg i.p.), inhibited acetylcholine release in the rat hippocampus . The inhibition was prevented by the cannabinoid receptor antagonist, SR 141716A 1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl- 1H-pyrazole-3-carboxamide} HCl, at the dose of 0.1 mg/kg i.p. Higher d oses of SR 141716A (1.0 and 3.0 mg/kg i.p.) themselves increased hippo campal acetylcholine release, suggesting that acetylcholine output is tonically inhibited by endogenous cannabinoids. The results also sugge st that the negative effects of marijuana on learning and memory may d epend on cannabinoid receptor-mediated inhibition of acetylcholine rel ease.