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The Journal of Neuroscience, November 5, 2003, 23(31):10013-10020

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Cellular/Molecular
The Contraceptive Agent Provera Enhances GABA_A Receptor-Mediated Inhibitory Neurotransmission in the Rat Hippocampus: Evidence for Endogenous Neurosteroids?

Delia Belelli and Murray B. Herd

Department of Pharmacology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Ninewells Hospital, Dundee, DD1 9SY United Kingdom

Neurosteroids typified by 5-pregnan-3-ol-20-one (53) have emerged as the most potent endogenous positive modulators of the GABA_A receptor, the principal mediator of fast inhibitory transmission within the CNS. Neurosteroids can be synthesized de novo in the brain in levels sufficient to modulate GABA_A receptor function and, thus, might play an important physiological-pathophysiological role. Indirect support for this proposal comes from the observation that neurosteroid action is region and neuron selective. However, the mechanism(s) that imparts specificity of action remains primarily elusive. Although neurosteroids are relatively promiscuous toward different GABA_A receptor isoforms, the contribution of local neurosteroid metabolism has been relatively unexplored. Here, we investigate the role of neurosteroid metabolism by using electrophysiological techniques to compare the actions of 53 and its metabolically stable synthetic analog ganaxolone on inhibitory neurotransmission in CA1 and dentate gyrus neurons. Furthermore, we evaluate the contribution of a key enzyme in neurosteroid metabolism [i.e., 3-hydroxysteroidoxidoreductase (3-HSOR)] to the inactivation of endogenous, or exogenously applied 53. We show that low concentrations of ganaxolone, but not of 53, enhance inhibitory transmission in dentate gyrus, whereas both steroids are similarly effective in CA1 neurons. Furthermore, inhibition of 3-HSOR by the contraceptive agent Provera results in enhanced synaptic and extrasynaptic GABA_A receptor-mediated inhibition in the dentate gyrus but not in the CA1 region. Collectively, these findings advocate a crucial role for local steroid metabolism in shaping GABA_A receptor-mediated inhibition in a regionally dependent manner and suggest a novel action by the contraceptive agent on inhibitory centers in the CNS.

Key words: neurosteroid; inhibitory synaptic transmission; GABA_A receptor; tonic current; hippocampus; patch-clamp

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Received July 30, 2003; revised September 12, 2003; accepted September 16, 2003.

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