Cannabinoid CB1 receptor-mediated inhibition of acetylcholine release in the brain of NMRI, CD-1 and C57BL/6J mice

Cannabinoid CB, receptors occur as presynaptic receptors producing inhibiti on of neurotransmitter release. To elucidate their physiological role, expe riments on tissues from CB1 receptor knockout mice would be helpful. We stu died whether CB, receptor-mediated inhibition of acetylcholine release is d etectable in the brain of NMRI mice and of CD-1 and C57BL/6J mice (the latt er two strains representing the wild-type strains of the two CB, receptor k nockout mouse models). Brain slices preincubated with [H-3]choline were sup erfused and tritium overflow was evoked electrically (3 Hz) or by introduct ion of Ca2+ into Ca2+-free K+-rich medium (35 mM) containing tetrodotoxin. The electrically evoked tritium overflow from NMRI mouse hippocampal slices was inhibited (maximally by 60%) by the cannabinoid receptor agonists CP-5 5,940 and WIN 55,212-2 but not affected by WIN 55,212-3 (the inactive enant iomer of WIN 55,212-2; pEC(50) = 7.9, 7.4 and <5.5). The concentration-resp onse curve of WIN 55,212-2 was shifted to the right by the CB, receptor ant agonist SR 141716 (apparent pA(2) = 8.6). Compared to hippocampal slices fr om NMRI mice, WIN 55,212-2 1 <mu>M inhibited the electrically evoked overfl ow (1) from cortical slices from NMRI mice to a lesser extent and from stri atal slices not at all, (2) from hippocampal slices from CD-1 and C57BL/6J mice to an identical extent and (3) from hippocampal slices from Sprague-Da wley rats to at least the same extent. SR 141716 0.32 muM abolished the eff ect of WIN 55,212-2 1 muM in hippocampal slices from NMRI, CD-1 and C57BL/6 J mice and in cortical slices from NMRI mice. The electrically evoked triti um overflow from NMRI mouse hippocampal slices was also inhibited by the mu scarinic receptor agonist oxotremorine (maximum effect of 85%; pEC(50) = 6. 5) and this effect was antagonized by the muscarinic receptor antagonist AF -DX 384 (apparent pA(2) = 8.3). The Ca2+-evoked tritium overflow from NMRI mouse hippocampal slices was inhibited by WIN 55,212-2 in a manner sensitiv e to SR 141716. In conclusion, the cholinergic axon terminals of the NMRI mouse hippocampus are endowed with presynaptic CB1 receptors. Such receptors are also detect able in the hippocampus of CD-1 and C57BL/6J mice. The maximum extent of th e CBI receptor-mediated inhibition of acetylcholine release is lower than t he maximum effect mediated via the autoreceptor.