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

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Abstract

The present study sought to determine whether small-conductance, Ca2+-activated K+ currents underlie the afterhyperpolarization (AHP) in neurons of the 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 (IAHP) regulates the firing rate of POA neurons and 2) amine neurotransmitters modulate it in a gonadal steroid-sensitive manner. Intracellular recordings followed by combined histofluorescence/in situ hybridization for glutamic acid decarboxylase, 65-kDa isomer, revealed that POA neurons, including γ-aminobutyric acid (GABA)ergic neurons, exhibited an AHP and spike frequency adaptation. The corresponding IAHP was sensitive to antagonism by CdCl2 (200 μM), apamin (0.3-1 μM), and dequalinium (3 μM). The β-adrenergic receptor agonist isoproterenol inhibited the IAHP in a dose-dependent, timolol-sensitive fashion. In addition, the α1-adrenergic receptor agonist methoxamine dose dependently inhibited the IAHP in a prazosin-sensitive manner and increased neuronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 μg, s.c.) markedly potentiated the inhibitory effect of methoxamine on the IAHP, whereas that for isoproterenol was unaffected. Similarly, bath application of 17β-estradiol (100 nM; 15-20 min) mimicked the effect of EB on the methoxamine-induced inhibition of the IAHP. Thus, POA GABAergic neurons express an apamin-sensitive channel that mediates, at least in part, the IAHP, and tempers the excitability of these cells. Furthermore, these studies demonstrate that estrogen enhances the α1-adrenergic receptor-mediated inhibition of this current.

Original languageEnglish (US)
Pages (from-to)21-30
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume299
Issue number1
StatePublished - Oct 9 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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