Genetic deletion of fatty acid amide hydrolase alters emotional behavior and serotonergic transmission in the dorsal raphe, prefrontal cortex, and hippocampus.
Pharmacological blockade of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), produces CB(1) receptor (CB(1)R)-mediated analgesic, anxiolytic-like and antidepressant-like effects in murids. Using behavioral and electrophysiological approaches, we have characterized the emotional phenotype and serotonergic (5-HT) activity of mice lacking the FAAH gene in comparison to their wild type counterparts, and their response to a challenge of the CB(1)R antagonist, rimonabant. FAAH null-mutant (FAAH(-/-)) mice exhibited reduced immobility in the forced swim and tail suspension tests, predictive of antidepressant activity, which was attenuated by rimonabant. FAAH(-/-) mice showed an increase in the duration of open arm visits in the elevated plus maze, and a decrease in thigmotaxis and an increase in exploratory rearing displayed in the open field, indicating anxiolytic-like effects that were reversed by rimonabant. Rimonabant also prolonged the initiation of feeding in the novelty-suppressed feeding test. Electrophysiological recordings revealed a marked 34.68% increase in dorsal raphe 5-HT neural firing that was reversed by rimonabant in a subset of neurons exhibiting high firing rates (33.15% mean decrease). The response of the prefrontocortical pyramidal cells to the 5-HT(2A/2C) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI) revealed desensitized 5-HT(2A/2C) receptors, likely linked to the observed anxiolytic-like behaviors. The hippocampal pyramidal response to the 5-HT(1A) antagonist, WAY-100635, indicates enhanced tonus on the hippocampal 5-HT(1A) heteroreceptors, a hallmark of antidepressant-like action. Together, these results suggest that FAAH genetic deletion enhances anxiolytic-like and antidepressant-like effects, paralleled by altered 5-HT transmission and postsynaptic 5-HT(1A) and 5-HT(2A/2C) receptor function.
Bambico
Francis Rodriguez
FR
Department of Psychiatry, McGill University, Montréal, QC, Canada.
Cassano
Tommaso
T
Dominguez-Lopez
Sergio
S
Katz
Noam
N
Walker
Claire Dominique
CD
Piomelli
Daniele
D
Gobbi
Gabriella
G
D000200:Action Potentials / Q000187:drug effects; D000581:Amidohydrolases / Q000172:deficiency*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension / Q000379:methods; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019964:Mood Disorders / Q000235:genetics* / Q000473:pathology*; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011903:Raphe Nuclei / Q000378:metabolism; D000077285:Rimonabant; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001549:Benzamides; D063387:Cannabinoid Receptor Antagonists; D002219:Carbamates; D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant; D012701:Serotonin; D018490:Serotonin Agents; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester