title: Evidence against a critical role of CB1 receptors in adaptation of the hypothalamic-pituitary-adrenal axis and other consequences of daily repeated stress.
abstract: There is evidence that endogenous cannabinoids (eCBs) play a role in the control of the hypothalamic-pituitary-adrenal (HPA) axis, although they appear to have dual, stimulatory and inhibitory, effects. Recent data in rats suggest that eCBs, acting through CB1 receptors (CB1R), may be involved in adaptation of the HPA axis to daily repeated stress. In the present study we analyze this issue in male mice and rats. Using a knock-out mice for the CB1 receptor (CB1-/-) we showed that mutant mice presented similar adrenocorticotropic hormone (ACTH) response to the first IMO as wild-type mice. Daily repeated exposure to 1h of immobilization reduced the ACTH response to the stressor, regardless of the genotype, demonstrating that adaptation occurred to the same extent in absence of CB1R. Prototypical changes observed after repeated stress such as enhanced corticotropin releasing factor (CRH) gene expression in the paraventricular nucleus of the hypothalamus, impaired body weight gain and reduced thymus weight were similarly observed in both genotypes. The lack of effect of CB1R in the expression of HPA adaptation to another similar stressor (restraint) was confirmed in wild-type CD1 mice by the lack of effect of the CB1R antagonist AM251 just before the last exposure to stress. Finally, the latter drug did not blunt the HPA, glucose and behavioral adaptation to daily repeated forced swim in rats. Thus, the present results indicate that CB1R is not critical for overall effects of daily repeated stress or proper adaptation of the HPA axis in mice and rats.
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rabasa
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Pastor-Ciurana
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Delgado-Morales
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Gómez-Román
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Carrasco
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: Humberto
authors.initials: H
authors.lastname: Gagliano
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. Ramón y Cajal s/n, 03550 San Juan de Alicante, Alicante, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: García-Gutiérrez
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. Ramón y Cajal s/n, 03550 San Juan de Alicante, Alicante, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS-Trastornos Adictivos), Madrid, Spain. Electronic address: antonio.armario@uab.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Armario
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000378:metabolism*; D013550:Swimming
chemical_list: C578453:CNR1 protein, mouse; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D000324:Adrenocorticotropic Hormone; D005947:Glucose; D003345:Corticosterone
keywords: AM251; Cannabinoids; Chronic stress; Habituation