Neurosteroids Modulate Nicotinic Receptor Function in Mouse Striatal and Thalamic Synaptosomes

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Abstract
Progesterone and its A‐ring reduced metabolites are allosteric activators of GABAA receptors. The studies reported here examined the effects of these steroids on brain nicotinic receptors using an 86Rb+ efflux assay that likely measures the function of α4β2‐type nicotinic receptors and [3H]dopamine release, which may be modulated by an α3‐containing nicotinic receptor. Both of the A‐ring reduced metabolites of progesterone were noncompetitive inhibitors of both assays, whereas progesterone inhibited only the 86Rb+ efflux assay. The 86Rb+ efflux assay was slightly more sensitive than was the dopamine release assay to steroid inhibition. Inhibition developed slowly for both assays (t1/2 = 0.4 min) and was reversed even more slowly (t1/2 = 10–15 min). Steroid addition did not alter either the rate of association of [3H]nicotine binding to brain membranes, nor was equilibrium binding changed. These findings argue that neurosteroids are allosteric inhibitors of brain nicotinic receptors.

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