Norepinephrine suppresses gonadotropin-releasing hormone neuron excitability in the adult mouse.

Norepinephrine (NE) is considered to exert an important modulatory influence upon the activity of GnRH neurons. In the present study, we used a transgenic GnRH-green fluorescent protein mouse model to examine the effects of NE on the electrical excitability of GnRH neurons in male and female mice. Gramicidin-perforated patch recordings demonstrated that NE (10-100 mum) exerted a robust membrane hyperpolarization, with associated suppression of firing, in more than 85% of male prepubertal and adult GnRH neurons (n = 25). The same hyperpolarizing action was observed in female GnRH neurons from diestrous (91%, n = 11), proestrous (50%, n = 14), estrous (77%, n = 13), and ovariectomized (82%, n = 11) mice. A subpopulation (<10%) of silent GnRH neurons in all groups responded to NE with hyperpolarization followed by the initiation of firing upon NE washout. The hyperpolarizing actions of NE were mimicked by alpha1-adrenergic (phenylephrine) and beta-adrenergic (isoproterenol) receptor agonists, but alpha2 receptor activation (guanabenz) had no effect. Approximately 75% of the NE-evoked hyperpolarization was blocked by the alpha1 receptor antagonist prazosin, and 75% of GnRH neurons responded to both phenylephrine and isoproterenol. These findings indicate that NE acts through both alpha1- and beta-adrenergic receptors located on the soma/dendrites of GnRH neurons to directly suppress their excitability throughout the estrous cycle and after ovariectomy. These data force a reanalysis of existing models explaining the effects of NE on gonadotropin secretion.