title: Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid.
abstract: The endogenous cannabinoid system regulates neuronal excitability. The effects of inhibiting fatty acid amide hydrolase (FAAH), the enzyme responsible for metabolism of the endocannabinoid anandamide, on kainic acid (KA)-induced neuronal activity were investigated in the rat in vivo, using the selective FAAH inhibitor URB597. Hippocampal neuronal ensemble unit activity was recorded in isoflurane-anesthetized rats using 16-wire microelectrode arrays. Separate groups of rats were administered with single doses of KA alone, KA and URB597 (0.3 or 1 mg kg(-1), i.p.), or URB597 (1 mg kg(-1)) alone. The role of the cannabinoid CB1 receptor in mediating the effects of URB597 was explored using the CB1 selective antagonists AM251, either alone or prior to KA and URB597 (1 mg kg(-1)) administration, and SR141716A, administered prior to KA and URB597 (1 mg kg(-1)). Neuronal firing and burst firing rates were examined in animals with confirmed dorsal hippocampal placements. KA induced an increase in both firing and burst firing rates, effects which were attenuated by URB597 in a dose-related manner. Pretreatment with AM251 or SR141716A partly attenuated the URB597-mediated effects on firing and burst firing rate. Rats treated with AM251 or URB597 alone did not exhibit any significant change in either firing or burst firing rates compared with basal activity. These results suggest that the inhibition of endocannabinoid metabolism can suppress hyperexcitability in the rat hippocampus, partly via a CB1 receptor-mediated mechanism.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom. mbxbc@nottingham.ac.uk
authors.forename: Ben
authors.initials: B
authors.lastname: Coomber
authors.forename: Michael F
authors.initials: MF
authors.lastname: O'Donoghue
authors.forename: Robert
authors.initials: R
authors.lastname: Mason
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats
chemical_list: D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; D007608:Kainic Acid