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This Article Full Text Full Text (PDF) All Versions of this Article: 573/3/571    most recent jphysiol.2006.106534v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jones, B. L. Articles by Henderson, L. P. Search for Related Content PubMed PubMed Citation Articles by Jones, B. L. Articles by Henderson, L. P. Related Collections Molecular and Genomic

¹ Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire, 03755, USA
² Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Harlow, Essex CM20 2QR, UK

GABAergic transmission regulates the activity of gonadotrophin-releasing hormone (GnRH) neurons in the preoptic area/hypothalamus that control the onset of puberty and the expression of reproductive behaviours. One of the hallmarks of illicit use of anabolic androgenic steroids (AAS) is disruption of behaviours under neuroendocrine control. GnRH neurons are among a limited population of cells that express high levels of the -subunit of the GABA_A receptor. To better understand the actions of AAS on neuroendocrine mechanisms, we have characterized modulation of GABA_A receptor-mediated currents in mouse native GnRH neurons and in heterologous cells expressing recombinant ₂ß₃-receptors. GnRH neurons exhibited robust currents in response to millimolar concentrations of GABA and a picrotoxin (PTX)-sensitive, bicuculline-insensitive current that probably arises from spontaneous openings of GABA_A receptors. The AAS 17-methyltestosterone (17-MeT) inhibited spontaneous and GABA-evoked currents in GnRH neurons. For recombinant ₂ß₃-receptors, 17-MeT inhibited phasic and tonic GABA-elicited responses, accelerated desensitization and slowed paired pulse response recovery. Single channel analysis indicated that GABA-evoked events could be described by three open dwell components and that 17-MeT enhanced residence in the intermediate dwell state. This AAS also inhibited a PTX-sensitive, spontaneous current (open probability, 0.15–0.2) in a concentration-dependent fashion (IC₅₀ 9 µM). Kinetic modelling indicated that the inhibition induced by 17-MeT occurs by an allosteric block in which the AAS interacts preferentially with a closed state and promotes accumulation in that state. Finally, studies with a G302S mutant -subunit suggest that this residue within the transmembrane domain TM2 plays a role in mediating AAS binding and modulation. In sum, our results indicate that inclusion of the -subunit significantly alters the profile of AAS modulation and that this allosteric inhibition of native GnRH neurons should be considered with regard to AAS disruption of neuroendocrine control.

(Received 31 January 2006; accepted after revision 2 March 2006; first published online 16 March 2006)
Corresponding author L. P. Henderson: Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire, 03755, USA. Email: leslie.henderson{at}dartmouth.edu

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