Potentiation of the action of anandamide on hippocampal slices by the fatty acid amide hydrolase inhibitor, palmitylsulphonyl fluoride (AM 374).
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.
Gifford
A N
AN
Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. gifforda@bnl.gov
Bruneus
M
M
Lin
S
S
Goutopoulos
A
A
Makriyannis
A
A
Volkow
N D
ND
Gatley
S J
SJ
D000109:Acetylcholine / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D048588:Benzoxazines; D002186:Cannabinoids / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D004357:Drug Synergism; D004558:Electric Stimulation; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists; D000099252:Fatty Acid Amide Hydrolases
D000109:Acetylcholine; D000581:Amidohydrolases; D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D010168:Palmitates; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C104963:AM 374; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide