A Norepinephrine-Dependent Mechanism in the Preoptic/Anterior Hypothalamic Area but Not in the Mediobasal Hypothalamus Is Involved in the Regulation of the Gonadotropin-Releasing Hormone Pulse Generator in Ovariectomized Rats

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Abstract
Pulsatile gonadotropin secretion from the pituitary is dependent upon the gonadotropin-releasing hormone (Gn-RH) pulse generator producing intermittent release of the neuropeptide into the portal vessels. Various neurotransmitters seem to be involved in the regulation of pulsatile Gn-RH release. The present study was an attempt to determine in vivo the temporal relation of preoptic/anterior hypothalamic area (PO/AH) norepinephrine (NE) release and pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To assess whether NE acts in the PO/AH to maintain pulsatile Gn-RH release, we applied locally an αi-receptor antagonist into this structure. Push-pull cannulae (PPC) were implanted into the PO/AH of ovariectomized rats. The contralateral, not PPC-implanted PO/AH was lesioned electrochemically. Another group of ovariectomized rats was implanted with a PPC into the mediobasal hypothalamus. Two experiments were performed: (1) To determine whether the PO/AH or the mediobasal hypothalamus is the site where NE exerts its stimulatory effect on LH secretion, we applied doxazosine, a new specific αi-receptor antagonist, locally into these structures by means of PPC. The effect of this adrenergic drug on the Gn-RH pulse generator was examined by measuring blood LH levels. (2) To study the temporal relation between in vivo release rates of NE and amine metabolites in the preoptic area and pulsatile pituitary LH secretion, preoptic perfusates and blood samples were collected at 5-min intervals. Brain perfusates were subjected to high-performance liquid chromatography-electrochemical analysis. In blood samples LH concentrations were determined. Local application of doxazosine into the PO/AH, but not into the mediobasal hypothalamus caused a reduction of average LH secretion and reduced markedly LH pulsatility. This is suggestive that preoptic NE is indispensable for proper function of the Gn-RH pulse generator and that NE exerts its stimulatory effect on LH release via αi-receptive mechanisms in the PO/AH. Preoptic perfusates contained readily detectable amounts of NE which is secreted in a pulsatile manner. Frequency analysis revealed that the number of NE pulses in the PO/AH is significantly higher than the number of LH pulses in the blood. Using two different statistical approaches, we failed to demonstrate a temporal correlation between preoptic NE release and pituitary LH secretion. Based on these data, we hypothesize that phasic activitity of Gn-RH neurons is achieved by NE which exerts a permissive function rather than a direct stimulatory effect of Gn-RH neurons. Our data do not support the assumption that, at least in the rat, each Gn-RH pulse is triggered by a NE pulse.

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