Abstract
The electrically-evoked release of [3H]acetylcholine from hippocampal brain slices is inhibited by cannabinoid receptor agonists. The effect of palmitylsulphonyl fluoride (AM 374), a recently developed inhibitor of fatty acid amide hydrolase, in influencing the potency of exogenously added anandamide in this preparation was examined. Anandamide alone had relatively little effect on [3H]acetylcholine release. By contrast, in the presence of AM 374 (0.1 microM), anandamide produced a significant inhibition of [3H]acetylcholine release at all concentrations tested (0.1-10 microM). In addition to experiments with AM 374 the effects of N-(4-hydroxyphenyl)arachidonamide (AM 404), a putative anandamide uptake inhibitor, was also examined. However, AM 404 at concentrations up to 10 microM, was not found to significantly enhance the effect of anandamide on electrically-evoked [3H]acetylcholine release. These results indicate that AM 374 potently inhibits endogenous amidase activity and thus facilitates access of exogenous anandamide to cannabinoid receptors in the hippocampal tissue.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcholine / metabolism
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Amidohydrolases / antagonists & inhibitors*
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Animals
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Arachidonic Acids / pharmacology*
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Benzoxazines
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Cannabinoids / metabolism
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Cyclohexanols / pharmacology
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Drug Synergism
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Electric Stimulation
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Endocannabinoids
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Enzyme Inhibitors / pharmacology*
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Hippocampus / drug effects*
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Hippocampus / metabolism
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In Vitro Techniques
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Male
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Morpholines / pharmacology
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Naphthalenes / pharmacology
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Palmitates / pharmacology*
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Polyunsaturated Alkamides
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Rats
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Rats, Sprague-Dawley
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Receptors, Cannabinoid
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Receptors, Drug / agonists
Substances
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AM 374
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Arachidonic Acids
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Benzoxazines
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Cannabinoids
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Cyclohexanols
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Endocannabinoids
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Enzyme Inhibitors
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Morpholines
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Naphthalenes
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Palmitates
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Polyunsaturated Alkamides
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Receptors, Cannabinoid
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Receptors, Drug
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
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Amidohydrolases
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fatty-acid amide hydrolase
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Acetylcholine
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anandamide
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N-(4-hydroxyphenyl)arachidonylamide