Role of the hypothalamic-pituitary-adrenal axis in the suppression of luteinizing hormone release by delta-9-tetrahydrocannabinol.

The ability of cannabinoids to affect anterior pituitary luteinizing hormone (LH) secretion has been largely attributed to a central nervous system site of action, however, the mechanism(s) by which cannabinoids alter LH release remains unclear. In the present study, the acute administration of delta-9-tetrahydrocannabinol (THC) produced a dose-related suppression of plasma LH and stimulation of adrenocorticotropin (ACTH) levels in ovariectomized female rats. To determine if activation of the hypothalamic-pituitary-adrenal axis was involved in the ability of THC to inhibit LH release, female rats were either pretreated with the corticotropin-releasing hormone (CRH) receptor antagonist, alpha-helical CRH, or were adrenalectomized prior to acute THC administration, in order to assess the roles of CRH and corticosterone in the ability of THC to suppress LH secretion. A low dose of THC (0.5 mg/kg b.w., iv) produced a decrease in plasma LH levels at 20 and 40 min posttreatment in ovariectomized, sham adrenalectomized rats. However, in adrenalectomized animals, plasma LH levels were suppressed at 40 min and remained decreased at 80 min following THC administration. Thus, the duration of LH suppression following THC treatment was significantly increased in adrenalectomized versus sham adrenalectomized rats (p < 0.05). Furthermore, pretreatment with the CRH receptor antagonist, alpha-helical CRH (100 micrograms/5 microliters, icv), 30 min before THC administration, attenuated the ability of a high THC dose (1.0 mg/kg) to inhibit LH release in ovariectomized rats. Together, these results demonstrate that THC has significant effects on LH and ACTH secretion in ovariectomized rats and suggest that THC-induced CRH activation, but not corticosterone release, plays a role in the suppression of LH release by cannabinoids.