Exogenous and Endogenous Cannabinoids and Their Role in Endocrine Regulation

It has been known for a long time that exogenous canna-binoids are able to affect secretion of pituitary hormones, thus having a strong effect on peripheral target organ functions. Notably, in 1972 the first report of an induction of gynecomastia due to marijuana consumption led to a dramatic acceleration of studies on this topic (134). The hypothalamus is generally considered as the main site of canna-binoid action on neuroendocrine functions. This view is elegantly supported by a recent publication showing that endocannabinoids act as retrograde messengers activating CB1 receptors expressed at presynaptic glutamatergic ter minals in the hypothalamus (103). The subsequent activation of the CB1 receptor signaling cascade leads to the inhibition of the release of the excitatory neurotransmitter glutamate onto the neuroendocrine cells of the PVN and the supraoptic nucleus (103). This leads to a general suppressive effect on neuroendocrine cells and a final inhibitory effect on neuroendocrine function.

However, it was recently proposed that the endocannabi-noid system might control hormonal balance also through a direct effect at the level of the peripheral target organs. An overview of the cannabinoid actions on endocrine axes is given in Table 1.

A. Cannabinoids and the hypothalamic-pituitary-adrenal axis

Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis is a crucial neuroendocrine response to stress. Psychological or physiological stressors are known to induce CRH production in the PVN of the hypothalamus, eventually leading to a release of this hypothalamic peptide onto the anterior pituitary gland. In turn, this leads to increased circulating levels of ACTH and, finally, to an increase of corticosteroids secreted by the adrenal gland.

Until a few years ago, the impact of the cannabinoids on the HPA axis was considered as an exception. Whereas the commonly accepted view attributes the cannabinoid system with a general inhibitory role on neuroendocrine functions, it was suggested that cannabinoids are, on the contrary, able to stimulate the HPA axis. In fact, many studies in animals point to a CB1 receptor-dependent (135) increase of circulating ACTH and glucocorticoid levels after pharmacological administration of plant-derived (136), synthetic (137,138), or endogenous cannabinoid agonists (139, 140). In agreement with this, a simultaneous elevation of CRH in the PVN and of proopiomelanocortin in the anterior pituitary after chronic treatment (18 d) with the CB1 receptor agonist CP-55,940 was observed in rats (138). Cannabinoids were proposed to act exclusively at hypothalamic sites after the finding that A9-THC did not induce hyperactivation of the HPA axis in hypophysectomized rats (141), and that A9-THC or WIN 55,212-2 was unable to stimulate ACTH release from basal and CRH-stimulated dispersed pituitary cells or isolated pituitary slices, respectively (135, 142).

However, this concept was recently challenged by several reports showing a different function of endocannabinoids on the HPA axis. In fact, some studies showed that administration of the CB1 receptor antagonist SR141716 in rats is able to induce ACTH and corticosterone release and to produce anxiety-like behavior (143, 144). It is well known that this behavior represents part of the physiological response to stressful stimuli and is, indeed, associated with the hyper-activation of the HPA axis (145). Moreover, compounds able to increase endocannabinoid tone by inhibiting FAAH activity were recently proposed as treatment for anxiety-related disorders because they were shown to reduce restraint-induced corticosterone release (146) and to diminish the anxiety-like response in different tasks (147). In addition, mice lacking CB1 receptor (CB1_/~) are resistant to some actions of anxiolytic drugs (148). In support of the existence of a close interaction between the endocannabinoid system and CRH, it is important to mention that CB1 receptor and CRH mRNAs are coexpressed in PVN neurons, and that CB1_/~ mice present increased CRH mRNA levels in this region, indicative of a possible basal alteration of the HPA axis activity due to the disruption of CB1 receptor signaling (58). Therefore, a novel view seems to attribute the endo-cannabinoid system with a critical inhibitory action on HPA functions. A recent elegant report by Patel et al. (146) shed light on this issue. The authors confirmed previous studies showing that systemic treatment with SR141716 is able to increase serum corticosterone concentrations in basal conditions; more importantly, they found that pretreatment of mice with the same CB1 receptor antagonist before acute restraint stress provokes a potentiation of the restraint-induced rise in serum corticosterone concentrations. In addition, endogenous cannabinoids and, in particular 2-AG, were found to be decreased after a short period of restraint stress, whereas a condition of prolonged stress was associated with an increase in 2-AG concentrations (146). Accordingly, they concluded that endocannabinoid signaling negatively modulates the stress-induced activation of the HPA axis, confirming the notion that a pharmacological increase in endo-cannabinoid signaling activity may constitute a novel approach to the treatment of anxiety-related disorders (146). These findings reinforce the general concept that the pharmacological administration of cannabinoids may lead to a

Table 1. Overview of the cannabinoid action by CB1 activation in the various endocrine axes

Endocrine axis

Cannabinoid actions

Ref.

HPA axis

Acute stimulation of CRH by CB1 agonists

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