Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes.
Progesterone and its A-ring reduced metabolites are allosteric activators of GABA(A) 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 alpha4beta2-type nicotinic receptors and [3H]dopamine release, which may be modulated by an alpha3-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.
Bullock
A E
AE
Institute for Behavioral Genetics, University of Colorado, Boulder 80309-0447, U.S.A.
Clark
A L
AL
Grady
S R
SR
Robinson
S F
SF
Slobe
B S
BS
Marks
M J
MJ
Collins
A C
AC
D043582:5-alpha-Dihydroprogesterone; D000494:Allosteric Regulation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D017072:Neostriatum / Q000166:cytology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D011277:Pregnanediones / Q000737:chemistry / Q000494:pharmacology; D011280:Pregnanolone / Q000737:chemistry / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D012414:Rubidium Radioisotopes; D013574:Synaptosomes / Q000737:chemistry*; D013788:Thalamus / Q000166:cytology*; D014316:Tritium
D000927:Anticonvulsants; D018722:Nicotinic Agonists; D011277:Pregnanediones; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D014316:Tritium; D011374:Progesterone; D009538:Nicotine; D043582:5-alpha-Dihydroprogesterone; D011280:Pregnanolone; D004298:Dopamine