Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.
Endocrinology. 2007-04-01; 148(4): 1574-1581
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1. Endocrinology. 2007 Apr;148(4):1574-81. Epub 2006 Dec 28.
Requirement of cannabinoid receptor type 1 for the basal modulation of
hypothalamic-pituitary-adrenal axis function.
Cota D(1), Steiner MA, Marsicano G, Cervino C, Herman JP, Grübler Y, Stalla J,
Pasquali R, Lutz B, Stalla GK, Pagotto U.
(1)Group of Clinical Neuroendocrinology, Max Planck Institute of Psychiatry,
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.
PMID: 17194743 [Indexed for MEDLINE]