title: The dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses the behavioral despair induced by stress in rats and modulates the HPA-axis.
abstract: In recent years, several studies have explored the involvement of the deregulation of the hypothalamus-pituitary-adrenal (HPA) axis in the pathophysiology of stress-related disorders. HPA hyper-activation as a consequence of acute/chronic stress has been found to play a major role in the neurobiological changes that are responsible for the onset of such states. Currently available medications for depression, one of the most relevant stress-related disorders, present several limitations, including a time lag for treatment response and low rates of efficacy. N-Arachidonoylserotonin (AA-5-HT), a dual blocker at fatty acid amide hydrolase (FAAH, the enzyme responsible for the inactivation of the endocannabinoid anandamide) and transient receptor potential vanilloid type-1 channel (TRPV1), produces anxiolytic-like effects in mice. The present study was designed to assess the capability of AA-5-HT to reverse the behavioral despair following exposure to stress in rats and the role of the HPA-axis. Behavioral tasks were performed, and corticosterone and endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in selected brain areas critically involved in the pathophysiology of stress-related disorders (medial PFC and hippocampus) under basal and stress conditions, and in response to treatment with AA-5-HT. Our data show that AA-5-HT reverses the rat behavioral despair in the forced swim test under stress conditions, and this effect is associated with the normalization of the HPA-axis deregulation that follows stress application and only in part with elevation of anandamide levels. Blockade of FAAH and TRPV1 may thus represent a novel target to design novel therapeutic strategies for the treatment of stress-related disorders.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Navarria
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tamburella
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Iannotti
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy; Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Micale
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camillieri
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gozzo
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Verde
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Imperatore
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Leggio
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy. Electronic address: vdimarzo@icb.cnr.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D063388:Endocannabinoids / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System; D008297:Male; D010913:Pituitary-Adrenal System; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013315:Stress, Psychological / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D013550:Swimming; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D019208:Brain-Derived Neurotrophic Factor; D003345:Corticosterone; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D012701:Serotonin; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C493922:Trpv1 protein, rat; C114007:arachidonoylserotonin; C094503:glyceryl 2-arachidonate; C078814:anandamide
keywords: FAAH; HPA-axis; N-Arachidonoylserotonin; Stress; TRPV1