Administration of △1-tetrahydrocannabinol (△1-THC), the principal psycho-active ingredient of cannabis, to proestrous rats (2 mg/rat, i.p., between 12.00 and 16.00 h) suppressed the proestrous rise in the plasma levels of LH, FSH and prolactin (Prl) and caused a 24 h delay in ovulation. Furthermore, the increased accumulation of prostaglandins of the E-type (PGE) in the ovaries, normally seen on the evening of proestrus, was prevented. Earlier (08.00–10.30 h) or later (18.00 h) administration of the drug on the day of proestrus was only partially effective in inhibiting ovulation. The suppressive effects of △1-THC on ovulation and gonadotropin secretion were prevented by administration of gonadotropin releasing hormone (GnRH, 0.2 µg/rat) 1 h after the drug, indicating that the central action of △1-THC was exerted on the hypothalamus and not on the pituitary gland. Administration of ovine luteinizing hormone (oLH, 2.5 µg/rat) at 16.30 h on the day of proestrus restored ovulation and ovarian PGE accumulation in Nembutal-treated rats, but not in Δ1-THC-treated rats; higher doses of oLH (5–10 µg/rat) reversed the action of △1-THC on these two parameters.
Addition of GnRH to pituitary gonadotrophs preloaded with Quin 2 resulted in a rapid (approximately 8 s) mobilization of an ionomycin-sensitive intracellular Ca2+ pool. A second component of Ca2+ entry via voltage dependent channels contributed about 45% of the peak cytosolic free Ca2+ concentration ([Ca2+]i). Thereafter, influx of Ca2+ via voltage-sensitive and -insensitive channels is responsible for maintenance of elevated [Ca2+]i during the second phase of GnRH action. Addition of inositol 1,4,5-trisphosphate (IP3) to permeabilized pituitary cells resulted in a Ca2+ transient, released from a nonmitochondrial pool, which maintained ambient free Ca2+ concentration around 170 nM in an ATP-dependent mechanism. Successive stimulations of the cells with IP3 produced an attenuated response. Elevation of the gonadotroph [Ca2+]i by ionomycin, to levels equivalent to that induced by GnRH, resulted in LH release amounting to only 45% of the response to the neurohormone. Activation of the voltage-dependent Ca2+ channels by the dihydropyridine Ca2+-agonist [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine- 5-carboxylate (BAYK8644)] stimulated LH release, 36% of the GnRH (100 nM) response being reached by 10(-8) M of the drug, both [Ca2+]i elevation and GnRH-induced LH release were inhibited similarly (40-50%) by the dihydropyridine Ca2+-antagonist nifedipine. The results indicate that peak [Ca2+]i induced by GnRH in pituitary gonadotrophs is derived mainly from ionomycin-sensitive cellular stores most likely via IP3 formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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