Stimulation of cyclic adenosine 3′,5′-monophosphate production enhances hypothalamic luteinizing hormone-releasing hormone release without increasing prostaglandin e₂ synthesis: Studies in prepubertal female rats

A role for cAMP in the process of LHRH release was suggested several years ago, but only recently has the validity of this notion come under close scrutiny. In the present experiments we have used three probes, which stimulate adenylate cyclase activity via different mechanisms, to determine whether an increase in endogenous cAMP results in LHRH release from the hypothalamus of prepubertal female rats. Median eminences from juvenile, 28-day-old animals were incubated in vitro with either forskolin (F), cholera toxin (CT), or pertussis toxin (PT). All three substances enhanced LHRH release. The estimated ED₅₀ values were 28.7 μM and 20.0 ng/ml, for F and PT¹ respectively. The effect of CT appeared biphasic and thus no ED₅₀ could be calculated. None of these agents increased the release of prostaglandin E₂ (PGE₂), an obligatory component in the process of norepinephrine-induced LHRH secretion. Doses of PGE₂ and F, which were maximally effective in stimulating LHRH release when administered separately, did not produce any further response when administered concomitantly, thus suggesting that PGE₂ and F act along a common pathway. Blockade of phosphodiesterase activity with l-methyl-3-isobutylxanthine increased LHRH secretion without enhancing PGE₂ release, implying that cAMP metabolism was elevated in the median eminence nerve terminals in vitro. Addition of 1-methyl- 3-isobutylxanthine augmented the LHRH response to CT and PT, but it did not increase further the already marked LHRH response to PGE₂ or F. The results indicate that both an increase in adenylate cyclase activity and a decrease in phosphodiesterase activity lead to LHRH release from the median eminence. They also suggest that, upon proper (neurotransmitter?) stimulation, cAMP production increases subsequent to the activation in PGE₂ synthesis, which itself causes LHRH release. Furthermore, the capacity of PT to induce LHRH release suggests the involvement of an inhibitory guanine nucleotide-binding regulatory protein in transducing inhibitory inputs impinging on LHRHsecreting neurons.