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Department of Cell and Molecular Biology Tulane University New Orleans, Louisiana 70118
Address all correspondence and requests for reprints to: Dr. Jeffrey Tasker, Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118.
Exogenous cannabinoids exert robust effects on hormone secretion from the pituitary gland, having an inhibitory impact on neuroendocrine function that leads to the suppression of pituitary hormone release. For example, marijuana consumption in humans or 
9-tetrahydrocannabinol application in rats results in increased diuresis (1, 2) and suppression of the milk ejection reflex (3) by inhibiting the release, respectively, of the posterior pituitary hormones vasopressin and oxytocin. Similarly, exogenous cannabinoids have been shown to inhibit the release of the anterior pituitary hormones TSH, gonadotropin, GH, and prolactin (4, 5, 6). Although cannabinoids may have effects directly at the level of the pituitary gland, a major site of cannabinoid action on neuroendocrine function and pituitary hormone release is in the brain, at the hypothalamus, where the neuroendocrine cells that control pituitary hormone secretion are located (7). Consistent with a brain site of cannabinoid actions on neuroendocrine function is the recent observation that cannabinoids suppress the release of the excitatory neurotransmitter glutamate onto neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) (8) and supraoptic nucleus (9, 10) by acting directly at synapses on neuroendocrine cells via activation of CB1-type cannabinoid receptors. This appears to be a fairly generalized effect of cannabinoids on neuroendocrine cells, at least within the PVN because it occurs in multiple subpopulations of neuroendocrine cells that control hormone secretion from both the anterior and posterior lobes of the pituitary, including CRH-, TRH-, oxytocin-, and vasopressin-secreting parvocellular and magnocellular neurons (8, 9).
One notable exception to the cannabinoid inhibition of hypothalamic neuroendocrine function is the reported stimulatory effect that exogenous cannabinoids have on the hypothalamic-pituitary-adrenal (HPA) axis. Activation of the HPA axis is the main neuroendocrine response to both psychological and physiological stress. Thus, stress leads to the activation of CRH neurons in the PVN and results in CRH release onto the anterior pituitary gland, which triggers ACTH secretion from the anterior pituitary into the systemic circulation, which, in turn, stimulates the synthesis and systemic release of corticosteroids by the adrenal glands. Exogenous cannabinoids, rather than suppressing this neuroendocrine axis, have been shown to enhance the secretion of the HPA hormones (11, 12), despite the observation that endogenous cannabinoids suppress excitatory synaptic inputs to the CRH neurons locally in the PVN, described above (8). One possible explanation for this disconnect between the effects of exogenous cannabinoids applied systemically and endogenous cannabinoid effects in the PVN is that the stimulatory action of exogenous cannabinoids occurs upstream from the hypothalamus and is relayed synaptically to the CRH neurons in the PVN. This notion is supported by the observation that the cannabinoid-induced increase in HPA hormone release was attenuated by blocking opioid receptors (13), that deafferentation of the paraventricular nucleus blocked cannabinoid activation of the HPA axis (12), and that the HPA response to exogenous cannabinoids is maintained in CB1 receptor knockout mice (14).
Hillard and colleagues (15) put this issue to rest in their report in the current issue of Endocrinology, in which they show that endocannabinoids suppress the HPA response to stress (Fig. 1
). Furthermore, their data confirm earlier reports that endocannabinoids exert a tonic inhibitory tone on the HPA axis (13), possibly via direct basal inhibition of the CRH neurons. Thus, they report that systemic treatment with a CB1 cannabinoid receptor antagonist/reverse agonist, SR141716, before acute restraint stress caused a dramatic potentiation of the stress-induced corticosterone (CORT) response in rats, more than doubling the stress CORT response at the highest dose of the CB1 antagonist (5 mg/kg). They confirmed that administration of the cannabinoid antagonist alone, in the absence of exogenous agonist, caused a small, but significant, increase in circulating CORT levels, supporting the idea of a basal tonic inhibition of the HPA axis by endogenous cannabinoids. The potentiation of stress-induced CORT release by the cannabinoid antagonist was paralleled by an increase in the activity of PVN neurons, as measured by FOS expression. Although neither the cannabinoid antagonist nor the restraint stress alone caused a significant induction of FOS expression in the PVN, the combination of both caused a dramatic increase in the number of PVN FOS expressing cells. These findings, then, suggest an inhibition of stress-induced CRH neuron activation by endocannabinoids and are consistent with our data supporting an endocannabinoid suppression of the synaptic excitation of CRH neurons (8).
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Interestingly, this study found that endogenous cannabinoid levels were decreased in the hypothalamus in response to acute stress. Thus, mass spectrometry analysis of the endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG) revealed a significant decrease in 2-AG after 30 min of restraint stress, whereas this was reversed with repeated restraint stress, which caused an increase in 2-AG concentration (15). These data are consistent with an inhibitory effect of endogenous cannabinoids on HPA function—a reduction in endogenous cannabinoids in the hypothalamus would disinhibit the CRH neurons—and suggest that there is a tonic cannabinoid inhibition of the HPA axis under nonstressed conditions. Chronic stress, on the other hand, leads to a blunting of the HPA response, and Hillard and colleagues (15) propose that the inhibitory effect of the increased 2-AG concentration found in the hypothalamus with repeated stress may be a cause of the reduced responsiveness of the HPA axis. This finding runs counter to our in vitro data showing that acute administration of stress levels of glucocorticoids causes a rapid release (i.e. increase) of endocannabinoids in the PVN (8). However, the differences in the respective time frames and spatial resolution of endocannabinoid assay in the two studies, on the scale of a few minutes at individual synapses in vitro to 30 min in the whole hypothalamus in vivo, suggest that this discrepancy may relate to localized, time-dependent changes in endocannabinoid levels during the progression of the stress response. Indeed, this raises the intriguing possibility that endocannabinoids may play different roles in the stress-induced feedforward activation of the HPA axis and the glucocorticoid-mediated feedback inhibition of the HPA axis, a possibility ripe for further study.
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Footnotes |
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Received September 13, 2004.
Accepted for publication September 23, 2004.
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References |
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 Top References |
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9-tetrahydrocannabinol, cannabidiol, cannabinol and hydrochlorothiazide in the rat. Arch Int Pharmacodyn Ther 225:77–87[Medline]
9-tetrahydrocannabinol. Endocrinology 123:469–472[Abstract]
9-tetrahydrocannabinol on serum thyrotropin levels in the rat. Pharmacol Biochem Behav 20:547–550[CrossRef][Medline]
-9-tetrahydrocannabinol on reproductive neuroendocrine function in the female: animal studies. NIDA Res Monogr 55:42–51[Medline]
1-tetrahydrocannabinol, in intact and in hypothalamic deafferentated male rats. Exp Brain Res 46:85–88[Medline]
(9)-tetrahydrocannabinol in rats. Brain Res 839:173–179[CrossRef][Medline]
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