Short-term steroid treatment increases δ GABAA receptor subunit expression in rat CA1 hippocampus: Pharmacological and behavioral effects

Abstract

In this study, 48 h administration of 3α-OH-5β-pregnan-20-one (3α,5β-THP) or 17β-estradiol (E 2 )+progesterone (P) to female rats increased expression of the δ subunit of the GABA A receptor (GABAR) in CA1 hippocampus. Coexpression of α4 and δ subunits was suggested by an increased response of isolated pyramidal cells to the GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), following 48 h steroid treatment, and nearly complete blockade by 300 μM lanthanum (La 3+ ). Because α4βδ GABAR are extrasynaptic, we also recorded pharmacologically isolated GABAergic holding current from CA1 hippocampal pyramidal cells in the slice. The La 3+ -sensitive THIP current, representative of current gated by α4βδ GABAR, was measurable only following 48 h steroid treatment. In contrast, the bicucullinesensitive current was not altered by steroid treatment, assessed with or without 200 nM gabazine to block synaptic current. However, 48 h steroid treatment resulted in a tonic current insensitive to the benzodiazepine agonists lorazepam (10 μM) and zolpidem (100 nM). These results suggest that 48 h steroid treatment increases expression of α4βδ GABAR which replace the ambient receptor population. Increased anxiolytic effects of THIP were also observed following 48 h steroid treatment. The findings from the present study may be relevant for alterations in mood and benzodiazepine sensitivity reported across the menstrual cycle.

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

“…Preclinical studies indicate that the impact of neurosteroids on the GABA receptor is mediated by changes in their levels rather than their absolute concentration. Both increases and decreases in progesterone metabolite neurosteroids induce changes in the alpha 4 subunit conformation of the GABA A R sufficient to produce anxiety-like behaviors (Gulinello et al, 2001;Gulinello and Smith, 2003;Shen et al, 2005). Thus, it is possible that effects of progesterone to precipitate PMDD symptoms (Schmidt et al, 1998) could be mediated by changes in allopregnanolone and/or an abnormal conversion of progesterone to its neurosteroid metabolites.…”

Ethanol effects on GABA-gated current in a model of increased α4βδ GABAA receptor expression depend on time course and preexposure to low concentrations of the drug

“…In fact, our earlier studies have demonstrated that 48 h THP administration also increases anxiety in female rats (Gulinello et al, 2001), an effect closely correlated with increased expression of α4 and δ GABAR subunits (Shen et al, 2005). Interestingly, one study reported increased responsiveness to low concentrations of ethanol in women with PMDD (Sundstrom et al, 1998), although a second study (Nyberg et al, 2004a) by the same group found this increased sensitivity to be nonsignificant due to variability in response.…”

“…Our previous work demonstrated that 48 h THP administration paradigm increases expression of both the α4 and δ GABAR subunits in CA1 hippocampus (Shen et al, 2005). Coexpression of α4 and δ subunits was suggested (Shen et al, 2005) by pharmacological findings demonstrating an increased response to the GABA agonist gaboxadol and inhibitory effects of the trivalent cation, La 3+ on CA1 pyramidal cells, acutely isolated or recorded in the slice. These findings are characteristic of increased expression of α4βδ GABAR, for which gaboxadol produces a greater maximal current than GABA and which are nearly completely inhibited by La 3+ (Brown et al, 2002).…”

“…For this study, we tested effects of ethanol on CA1 hippocampal pyramidal cells after 48 h exposure of female rats to THP when we have shown that α4 and δ subunits are increased in CA1 hippocampus (Shen et al, 2005). This has been verified both using Western blot procedures and selective pharmacological tests on the tonic current.…”

“…In attempting to resolve these issues in the present study, we tested the possibility that these differences might be due to the time course of exposure required for ethanol effects and possible effects of prolonged ethanol exposure on receptor desensitization. To this end, we tested ethanol responsiveness of acutely isolated CA1 pyramidal cells which we have shown have elevated expression of α4 and δ GABAR subunits (Shen et al, 2005) to ethanol applied either with or without a 2-min preapplication period to mimic the conditions used in these two recombinant studies. Differential effects of ethanol across these two different exposures may be relevant for the well-established relationship between the speed of ethanol consumption and ethanol effect (Hiltunen et al, 2000).…”