title: Antidepressant-like activity and cardioprotective effects of fatty acid amide hydrolase inhibitor URB694 in socially stressed Wistar Kyoto rats.
abstract: In humans, depression is often triggered by prolonged exposure to psychosocial stressors and is often associated with cardiovascular comorbidity. Mounting evidence suggests a role for endocannabinoid signaling in the regulation of both emotional behavior and cardiovascular function. Here, we examined cardiac activity in a rodent model of social stress-induced depression and investigated whether pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid anandamide, exerts antidepressant-like and cardioprotective effects. Male Wistar Kyoto rats were exposed to five weeks of repeated social stress or control procedure. Starting from the third week, they received daily administration of the selective FAAH inhibitor URB694 (0.1 mg/kg, i.p.) or vehicle. Cardiac electrical activity was recorded by radiotelemetry. Repeated social stress triggered biological and behavioral changes that mirror symptoms of human depression, such as (i) reductions in body weight gain and sucrose solution preference, (ii) hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and (iii) increased immobility in the forced swim test. Moreover, stressed rats showed (i) alterations in heart rate daily rhythm and cardiac autonomic neural regulation, (ii) a larger incidence of spontaneous arrhythmias, and (iii) signs of cardiac hypertrophy. Daily treatment with URB694 (i) increased central and peripheral anandamide levels, (ii) corrected stress-induced alterations of biological and behavioral parameters, and (iii) protected the heart against the adverse effects of social stress. Repeated social stress in Wistar Kyoto rats reproduces aspects of human depression/cardiovascular comorbidity. Pharmacological enhancement of anandamide signaling might be a promising strategy for the treatment of these comorbid conditions.
authors.affiliation: Department of Neuroscience, University of Parma, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Carnevali
authors.affiliation: Department of Pharmacy, University of Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Department of Life Sciences, University of Parma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Division of Cardiology, Vaio Hospital, Fidenza (Parma), Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Callegari
authors.affiliation: Department of Life Sciences, University of Parma, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Macchi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Italy.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Italy.
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.affiliation: Department of Pharmacy, University of Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Department of Pharmacy, University of Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Department of Neuroscience, University of Parma, Italy. Electronic address: andrea.sgoifo@unipr.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sgoifo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059445:Anhedonia / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D005518:Food Preferences / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D011921:Rats, Inbred WKY; D013315:Stress, Psychological / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000928:Antidepressive Agents; D001713:Biphenyl Compounds; D002219:Carbamates; D002316:Cardiotonic Agents; D003345:Corticosterone; D019422:Dietary Sucrose; D000099252:Fatty Acid Amide Hydrolases; C555899:cyclohexyl carbonic acid 3'-carbamoyl-3-yl ester
keywords: Arrhythmia; Depression; Endocannabinoid system; Heart rate variability; Stress