Anxiolytic Effect of Progesterone is Mediated by the Neurosteroid Allopregnanolone at Brain GABA_A Receptors

Abstract

Previous studies from this laboratory have shown that progesterone (PROG) treatment in ovariectomized rats produces an anti-anxiety response similar to that observed after the administration of prototypical anxiolytic benzodiazepine (BDZ) compounds. The PROG-induced anxiolytic response was highly correlated with an increased level of 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in the blood and brain, and was also associated with a facilitation of GABA-stimulated chloride ion (Cl-) influx in cortical synaptoneurosomes. This correlative evidence suggested that the anxiolytic effect of PROG was a result of its in vivo reduction to the neuroactive steroid, allopregnanolone. In this report, a series of studies was conducted to determine the mechanism(s) by which PROG alters behavior in animal models of anxiety. In the first experiment, ovariectomized rats were injected with PROG (1 mg/0.2 ml, SC) 4 h prior to a test in the elevated plus-maze. Some animals also received an injection of picrotoxin (0.75 mg/kg, IP), a GABAA receptor-gated Cl- channel antagonist, whereas other animals were pretreated with RU 38486 (5 mg/0.2 ml, SC), a progestin receptor antagonist. PROG elicited anxiolytic behavior in the plus-maze, an effect that was blocked by picrotoxin administration. Pretreatment with RU 38486 was not effective in altering PROG-induced anxiolytic behavior in the plus-maze. In a second experiment, the effect of PROG on behavior in the plus-maze was determined in the presence of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; 10 mg/0.2 ml, SC), a 5 alpha-reductase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder

“…In this case, mice were tested, following 3 days of finasteride administration to decrease hippocampal levels of THP ("THP Wd", see (Pellow et al 1995), and as expected, these parameters were increased by 54±5.2 and 42±4%, respectively, in control mice in response to THP administration (P<0.05, Fig. 3) compared to vehicle-treated mice, consistent with the well-known anxiolytic action of this steroid (Akwa et al 1999;Bitran et al 1995). The addition of a shock preceding the plus maze test did not alter the effect of THP in control mice.…”

“…Behaviorally, THP produces anxiolytic (Bitran et al 1995;Akwa et al 1999), anticonvulsant (Frye 1995) and sedative effects (Korneyev and Costa 1996) in a dose-dependent fashion. Although the site of action of this steroid may be distributed throughout brain circuits, anxiolytic actions of the steroid have been reported after local application of THP to the dorsal hippocampus (Bitran et al 1999) similar to BDZs (Menard and Treit 2001).…”

Neurosteroids in the context of stress: Implications for depressive disorders

“…In rodents, the behavioral effects seen following administration of certain A-ring reduced steroid derivatives, particularly allopregnanolone and allotetrahydroDOC, including anxiolytic (Bitran et al, 1995;Akwa et al, 1999), anti-conflict (Perche et al, 2001;Pinna et al, 2003;Pibiri et al, 2006), antiseizure (Frye, 1995), and antinociceptive effects (Kavaliers & Wiebe, 1987;Wiebe & Kavaliers, 1988;Frye & Duncan, 1994), are consistent with an integrated and adaptive response to stress (Purdy et al, 1991). The pretreatment of animals with the 5α-reductase inhibitor, finasteride (an inhibitor of the rate limiting step in the conversion of progesterone and DOC to their metabolite precursors of allopregnanolone and allotetrahydroDOC) or the administration of GABA antagonists, bicuculline, or picrotoxin (Kavaliers & Wiebe, 1987;Wiebe & Kavaliers, 1988) eliminates many of these behavioral responses to stress, suggesting that these behavioral adaptations to acute stressors are mediated by the 5α-reduced neurosteroids (Reddy, 2003).…”

“…The neuroactive steroids, allopregnanolone and allotetrahydroDOC, are among the most potent allosteric modulators of the GABA A receptors (nanomolar concentrations) via dose-dependent enhancement of GABA-induced Cl-ion channels (Morrow et al, 1987), and it is through this mechanism that they exert profound anxiolytic effects (Bitran et al, 1995;Brot et al, 1997;Bitran et al, 1999Bitran et al, , 2000. Allopregnanolone is the A-ring reduced metabolite of progesterone and is synthesized not only in ovary and adrenals but also de novo in brain (Paul & Purdy, 1992).…”

Progesterone selectively increases amygdala reactivity in women

“…[11][12][13] This neurosteroid potentiates the inhibitory actions of g-aminobutyric acid (GABA) by modulation of the GABA A receptor. 14 Consistent with this GABAergic mechanism, progesterone and allopregnanolone administration usually produce an anxiolytic effect 11,13 by the action on the amygdala. 15 Also pregnanolone, the less potent 5b stereoisomer of allopregnanolone that has a similar effect, 16,17 can produce anxiolysis.…”