title: Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.
abstract: The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1-/-) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1-/- mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1-/--derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice. Both CBL-/- and CB1+/+ mice properly respond to a high-dose dexamethasone test, but response to low-dose dexamethasone is influenced by genotype. In addition, CB1-/- mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized. Finally, CB1-/- mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.
authors.affiliation: Group of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cota
authors.forename: Michel-Alexander
authors.initials: MA
authors.lastname: Steiner
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Cristina
authors.initials: C
authors.lastname: Cervino
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Grübler
authors.forename: Johanna
authors.initials: J
authors.lastname: Stalla
authors.forename: Renato
authors.initials: R
authors.lastname: Pasquali
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005260:Female; D013006:Growth Hormone / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone; D003346:Corticotropin-Releasing Hormone