title: Differential effects of the sleep-inducing lipid oleamide and cannabinoids on the induction of long-term potentiation in the CA1 neurons of the rat hippocampus in vitro.
abstract: Cannabinoids have been shown to impair cognition in vivo and block long-term potentiation (LTP), a candidate experimental model of learning and memory in vitro, via cannabinoid receptor (CB1) activation. cis-Oleamide (cOA) is an endogenous sleep-inducing lipid with putative cannabinomimetic properties. We hypothesise that cOA is cannabinomimetic and perform a comparative study with synthetic and endogenous cannabinoids on their effects on synaptic conditioning via two different patterns of stimulation in the hippocampal slice. CB1 agonists, R(+)-WIN55212-2 and anandamide, but not cOA blocked high frequency stimulation (HFS)-LTP. R(+)-WIN55212-2 and cOA (stereoselectively) attenuated responses to theta-burst-LTP, while anandamide did not. The anandamide transport inhibitor, AM404, attenuated HFS-LTP, an effect reversed by the CB1 receptor antagonist SR141716A but not mimicked by the vanilloid receptor agonist capsaicin. TFNO, an inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for degrading anandamide, failed to block HFS-LTP alone or in combination with cOA. On the contrary, this combination was as effective as cOA on its own in attenuating theta-burst-LTP. cOA effects on theta-burst-LTP were prevented in the presence of the GABA(A) receptor blocker picrotoxin, but not by pretreatment with SR141716A. These findings suggest that cOA neither directly activates CB1 receptors nor acts via the proposed "entourage" effect [Nature 389 (1997) 25] to increase titres of anandamide through FAAH inhibition. The selective effects of cOA on theta-burst-conditioning may reflect modulation of GABAergic transmission. Anandamide uptake inhibition, but not blockade of FAAH, effectively increases synaptic concentrations of endocannabinoids.
authors.affiliation: Sunderland Pharmacy School, School of Health, Natural and Social Sciences, University of Sunderland, Wharncliffe Street, Sunderland, SR1 3SD, UK. george.lees@sunderland.ac.uk
authors.forename: George
authors.initials: G
authors.lastname: Lees
authors.forename: Antonios
authors.initials: A
authors.lastname: Dougalis
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D004594:Electrophysiology / Q000379:methods; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D009829:Oleic Acids / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D000077285:Rimonabant; D012890:Sleep / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D002211:Capsaicin; D063388:Endocannabinoids; D006993:Hypnotics and Sedatives; D009025:Morpholines; D009281:Naphthalenes; D009829:Oleic Acids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C029407:oleylamide; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide