NEUROSTEROIDS MODULATE NICOTINIC RECEPTOR FUNCTION IN MOUSE STRIATAL AND THALAMIC SYNAPTOSOMES

Progesterone and its A-ring reduced metabolites are allosteric activat ors of GABA(A) receptors. The studies reported here examined the effec ts of these steroids on brain nicotinic receptors using an Rb-86(+) ef flux assay that likely measures the function of alpha 4 beta 2-type ni cotinic receptors and [H-3]dopamine release, which may be modulated by an alpha 3-containing nicotinic receptor. Both of the A-ring reduced metabolites of progesterone were noncompetitive inhibitors of both ass ays, whereas progesterone inhibited only the Rb-86(+) efflux assay. Th e Rb-86(+) efflux assay was slightly more sensitive than was the dopam ine release assay to steroid inhibition. Inhibition developed slowly f or both assays (t(1/2) = 0.4 min) and was reversed even more slowly (t (1/2) = 10-15 min). Steroid addition did not alter either the rate of association of [H-3]nicotine binding to brain membranes, nor was equil ibrium binding changed. These findings argue that neurosteroids are al losteric inhibitors of brain nicotinic receptors.