title: The fatty acid amide hydrolase inhibitor URB597 modulates serotonin-dependent emotional behaviour, and serotonin1A and serotonin2A/C activity in the hippocampus.
abstract: The fatty acid amide hydrolase (FAAH) inhibitor URB597 increases anandamide, resulting in antidepressant/anxiolytic-like activity, likely via CB1 receptor-mediated modulation of serotonin (5-HT) and norepinephrine (NE) neurotransmission. However, the relative importance of the 5-HT and NE systems in these effects and on effects of URB597 on postsynaptic 5-HT receptors remain to be determined. Using behavioural and electrophysiological approaches, we assessed the effects of acute-single and repeated URB597 treatment on responses predicting antidepressant/anxiolytic activity, and on hippocampal 5-HT1A and 5-HT2A/C receptor sensitivity. Acute-single or serial URB597 treatment, compared to vehicle, reduced immobility in the forced swim test (FST), increased open arm visits in the elevated plus maze and shortened feeding latency in the novelty-suppressed feeding test (NSFT). Repeated URB597 treatment yielded more profound behavioural effects, which were associated with an increase in hippocampal brain-derived neurotrophic factor (BDNF). The 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA), but not the NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) prevented URB597-mediated antidepressant/anxiolytic-like response in the FST and NSFT, while DSP4 did not further affect URB597-mediated increase in raphe 5-HT neuron firing. Repeated URB597 administration decreased hippocampal pyramidal firing in response to 5-HT2A/C and 5-HT1A stimulation with 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) and 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), respectively, suggesting plastic adaptation of these receptors. The effects of acute-single and repeated URB597 administration on hippocampal cell firing in response to DOI or 8-OH-DPAT were similar in magnitude and intensity to the positive control citalopram. These data indicate that URB597 acts, either directly or indirectly, on the 5-HT system, increases hippocampal BDNF expression, and modifies 5-HT1A and 5-HT2A/C function.
authors.affiliation: Neurobiological Psychiatry Unit, McGill University, McGill University Health Center, Montreal, Quebec, Canada; Behavioral Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada. Electronic address: francis.bambico@camh.ca.
authors.forename: Francis R
authors.initials: FR
authors.lastname: Bambico
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.affiliation: Behavioral Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
authors.affiliation: Neurobiological Psychiatry Unit, McGill University, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D018663:Adrenergic Agents / Q000633:toxicity; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D001596:Benzylamines / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004644:Emotions / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D046353:Immobility Response, Tonic / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D018663:Adrenergic Agents; D000581:Amidohydrolases; D001549:Benzamides; D048588:Benzoxazines; D001596:Benzylamines; D002121:Calcium Channel Blockers; D002219:Carbamates; D009025:Morpholines; D009281:Naphthalenes; D011985:Receptors, Serotonin; D012701:Serotonin; D018490:Serotonin Agents; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C012102:DSP 4
keywords: 5-HT(1A); 5-HT(2A/C); Electrophysiology; Endocannabinoids; Fatty acid amide hydrolase