The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic gamma-aminobutyric acid neurons: Pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis

The present study sought to determine whether small-conductance, Ca2+-actlv ated K+ currents underlie the afterhyperpolarization (AHP) in neurons of th e preoptic area (POA), a brain region important in controlling reproduction . We used an ovariectomized, female guinea pig model to test two hypotheses : 1) the current associated with the AHP (I-AHP) regulates the firing rate of POA neurons and 2) amine neurotransmitters modulate it in a gonadal ster oid-sensitive manner. Intracellular recordings followed by combined histofl uorescence/in situ hybridization for glutamic acid decarboxylase, 65-kDa is omer, revealed that POA neurons, including gamma -aminobutyric acid (GABA)e rgic neurons, exhibited an AHP and spike frequency adaptation. The correspo nding I-AHP was sensitive to antagonism by CdCl2 (200 muM), apamin (0.3-1 m uM), and dequalinium (3 muM). The beta -adrenergic receptor agonist isoprot erenol inhibited the I-AHP in a dose-dependent, timolol-sensitive fashion. In addition, the alpha (1)-adrenergic receptor agonist methoxamine dose dep endently inhibited the I-AHP in a prazosin-sensitive manner and increased n euronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 mug, s.c.) markedly potentiated the inhibitory effect of methoxamin e on the I-AHP, whereas that for isoproterenol was unaffected. Similarly, b ath application of 17 beta -estradiol (100 nM; 15-20 min) mimicked the effe ct of EB on the methoxamine-induced inhibition of the I-AHP. Thus, POA GABA ergic neurons express an apamin-sensitive channel that mediates, at least i n part, the I-AHP, and tempers the excitability of these cells. Furthermore , these studies demonstrate that estrogen enhances the alpha (1)-adrenergic receptor-mediated inhibition of this current.