Neurosteroids Modulate Nicotinic Receptor Function in Mouse Striatal and Thalamic Synaptosomes

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 a4~2-type nicotinic receptors and [3H]dopaminerelease, which may be modulated by an cr3-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 ssRb* efflux assay was slightly more sensitive than was the dopamine release assay to steroid inhibition. Inhibition developed slowly for both assays (ti/ 2 = 0.4 mm) and was reversed even more slowly (t112 = 10-15 mm). Steroid addition did not alter either the rate of association of [ 3H]nicotinebinding to brain membranes, nor was equilibrium binding changed. These findings argue that neurosteroids are allosteric inhibitors of brain nicotinic receptors.

7α-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system

“…Similar effects of the progesterone metabolite allopregnanolone on locomotion (37) and dopamine release (38,39) have been reported in rats. These effects of allopregnanolone may be through the modulation of GABA type A receptors, because allopregnanolone is considered to be a potent 244.5 Ϯ 57.0* 10 Ϫ6 220.8 Ϯ 14.7* Newts in the nonbreeding period (November and December) were used.…”

Sex differences in nicotine substitution to a pentylenetetrazol discriminative stimulus during ethanol withdrawal in rats

“…Tetrahydrodeoxycorticosterone elevated seizure thresholds in ethanol-withdrawn female rats but not in ethanol-withdrawn male rats (Devaud et al 1998). Further, nicotinic acetylcholine receptors have a modulatory site for progesterone (Lena and Changeux 1993), and progesterone inhibits these receptors significantly more than testosterone (Bertrand et al 1991;Valera et al 1992;Bullock et al 1997). In addition, the anticonvulsant effects of the neuroactive steroid 3 α-hydroxy-5 α-pregnan-20-one (3 α, 5 α-THP) were larger in ethanol-withdrawn rats than control rats (Devaud et al 1996).…”

Electrophysiological Perspectives on the Therapeutic Use of Nicotinic Acetylcholine Receptor Partial Agonists

“…Smoking behavior itself produces increases in ␣4␤2-type receptors relative to ␣7-type receptors (Lester et al, 2009), and in circuits mediating nicotine reward these receptors can play opposing functions (Mansvelder et al, 2002). In addition, depression is strongly associated with stress and stressrelated increases in glucocorticoids (Pittenger and Duman, 2008), and chronic elevations in corticoids have been shown to reduce the expression and function of homomeric ␣7-type receptors in the brain (Bullock et al, 1997).…”