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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.
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“but their expression in the central amygdala is less clear (Katona et al, 2001;Tsou et al, 1997;Cota et al, 2007; but see Kamprath et al, 2011).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Cota et al, 2007
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“Studies have demonstrated that the CB1 receptor is involved in modulating HPA axis function (Cota et al., 2007).”
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“the endocannabinoids appear to negatively regulate basal and stimulated ACTH release at multiple levels of the HPA axis [”
BackgroundEndogenous cannabinoid signaling is essential for stress adaptation
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“In addition to the data detailed previously, it has also been reported that CB1 receptor knockout mice also exhibit deficits in dexamethasone-mediated suppression of HPA axis activity (Cota et al., 2007), further demonstrating an important role of the endocannabinoid system in glucocorticoid feedback inhibition of the…”
Background
Metadata
- Authors
- Cota, D., Steiner, M.-A., Marsicano, G., Cervino, C., Herman, J. P., Grübler, Y., Stalla, J., Pasquali, R., Lutz, B., Stalla, G. K., & Pagotto, U.
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- Johannes Gutenberg University Mainz (DE)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- University of Cincinnati Medical Center (US)
- Corresponding author
- Pagotto, Uberto
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-04-01
- Volume
- 148
- Issue
- 4
- Pages
- 1574-1581
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2016871471
- Cited by
- 205
- References
- 49
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 11 · 2017: 11 · 2016: 9 · 2015: 17 · 2014: 19 · 2013: 15 · 2012: 7
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- cannabinoid receptor type 1, CB1 knockout mice, hypothalamic-pituitary-adrenal axis, endocannabinoid system, circadian rhythm, corticosterone, ACTH secretion, corticotropin-releasing factor, paraventricular nucleus, glucocorticoid receptor, glucocorticoid negative feedback, dexamethasone suppression test, pituitary cells, hippocampal CA1
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Circadian Rhythm, Corticotropin-Releasing Hormone, Female, Hippocampus, Hypothalamo-Hypophyseal System, Mice, Inbred C57BL, Pituitary-Adrenal System, RNA, Messenger, Growth Hormone, Mice, Knockout, Receptor, Cannabinoid, CB1, Mice
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