Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus (original) (raw)
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Neurosteroids, GABAA receptors, and ethanol dependence
Psychopharmacology, 2006
Changes in the expression of type A receptors for gamma-aminobutyric acid (GABA) represent one of the mechanisms implicated in the development of tolerance to and dependence on ethanol. The impact of such changes on the function and pharmacological sensitivity of GABAA receptors (GABAARs) has remained unclear, however. Certain behavioral and electrophysiological actions of ethanol are mediated by an increase in the concentration of neuroactive steroids in the brain that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Such steroids include potent modulators of GABAAR function. We have investigated the effect of ethanol exposure and withdrawal on subunit expression and receptor function evaluated by subunit selective compounds, as well as the effects of short-term exposure to ethanol on both neurosteroid synthesis and GABAAR function, in isolated neurons and brain tissue. Chronic treatment with and subsequent withdrawal from ethanol alter the expression of g...
Neuropharmacology, 2004
Both short-term (48 h) exposure to the neuroactive steroid 3a,5a[b]-THP and its withdrawal increase expression of the benzodiazepine (BDZ)-insensitive GABA A receptor (GABAR) a4 subunit in hippocampus. This increase in a4 subunit expression was associated with a relative insensitivity of CA1 hippocampal pyramidal cells to modulation of GABA-gated current by the BDZ lorazepam (LZM), assessed using whole cell patch clamp techniques. Chronic ethanol is also known to regulate expression of the a4 subunit. Thus, in the present study we investigated the capacity of ethanol, administered in low doses across a 2 h period (0.5 g/kg, i.p., 3Â), to suppress a4 expression produced by 48 h exposure to 3a,5 b-THP in adult female rats. We show here that 2 h ethanol administration reverses the increase in a4 expression normally observed following 48 h steroid treatment. This effect was correlated with a recovery of responses recorded from CA1 hippocampal pyramidal cells to the GABA-modulatory effects of LZM. Similar effects of ethanol in suppressing a4 expression and restoring LZM responsiveness were seen following steroid withdrawal when a4 expression is normally increased. These results suggest that increases in expression of the a4 subunit produced by steroid exposure or withdrawal are altered by other GABA-modulatory drugs, such as ethanol. #
Psychopharmacology, 2005
Rationale Acute systemic ethanol administration is known to elevate plasma and cerebral levels of neuroactive steroid 3α-hydroxy-5α-pregnane-20-one (3α, 5α-THP; allopregnanolone) to a concentration sufficient to potentiate GABAA receptors. We have earlier demonstrated that 3α, 5α-THP mediates the antidepressant-like effect of ethanol in Porsolt forced swim test. Objective The aim of the present study is to explain the relationship between endogenous GABAergic neurosteroids and anxiolytic effect of ethanol in Sprague–Dawley rats. Method The mediation of 3α, 5α-THP in the anti-anxiety effect of ethanol was assessed by pharmacological interactions of ethanol with various endogenous neurosteroidal modulators and using simulated physiological conditions of altered neurosteroid content in elevated plus maze (EPM) test. Results Pretreatment of 3α, 5α-THP (0.5–2.5 μg/rat, i.c.v.) or neurosteroidogenic agents such as 3α, 5α-THP precursor progesterone (5 or 10 mg/kg, i.p.), 11-β hydroxylase inhibitor metyrapone (50 or 100 mg/kg, i.p.) or the GABAA receptor agonist muscimol (25 ng/rat, i.c.v.) significantly potentiated the anti-anxiety effect of ethanol (1 g/kg, i.p.). On the other hand, the GABAergic antagonistic neurosteroid dehydroepiandrosterone sulphate (DHEAS) (1 mg/kg, i.p.), the GABAA receptor blocker bicuculline (1 mg/kg, i.p.), the 5α-reductase inhibitor finasteride (50×2 mg/kg, s.c.) or the mitochondrial diazepam binding inhibitory receptor antagonist PK11195 (1 mg/kg, i.p.) reduced ethanol-induced preference of time spent and number of entries into open arms. Anti-anxiety effect of ethanol was abolished in adrenalectomized (ADX) rats as compared to sham-operated control. This ADX-induced blockade was restored by prior systemic injection of progesterone, signifying the contribution of peripheral steroidogenesis in ethanol anxiolysis. Socially isolated animals known to exhibit decreased brain 3α, 5α-THP and GABAA receptor functions displayed reduced sensitivity to the effects of ethanol and 3α, 5α-THP in EPM test. Conclusions Our results demonstrated the contributory role of neuroactive steroid 3α, 5α-THP in the anti-anxiety effect of ethanol. It is speculated that ethanol-induced modulation of endogenous GABAergic neurosteroids, especially 3α, 5α-THP, might be crucial pertinent to the etiology of ‘trait’ anxiety (tension reduction) and ethanol abuse.
European Journal of Neuroscience, 2007
We previously found that ethanol has complex effects on hippocampal synaptic plasticity, inhibiting long‐term potentiation (LTP) and long‐term depression by different mechanisms. The block of long‐term depression appears to be mediated by effects on N‐methyl‐d‐aspartate receptors, whereas the block of LTP involves augmented inhibition via γ‐aminobutyric acid‐A receptors (GABAARs). To pursue factors contributing to effects on LTP, we examined the ability of various concentrations of ethanol to block LTP in the CA1 region of rat hippocampal slices. Complete LTP block required 60 mm ethanol. LTP block was enhanced at lower ethanol concentrations in the presence of (3α5α)‐3‐hydroxypregnan‐20‐one, a GABAAR‐potentiating neurosteroid, suggesting that neurosteroids may be important contributors to the effects of ethanol on LTP. Consistent with this, we found that block of LTP by 60 mm ethanol was overcome by coadministration of a cyclodextrin that binds and removes lipophilic neurosteroids....
Neuroactive Steroids and Ethanol
Alcoholism: Clinical & Experimental Research, 2005
chairperson was Robert H. Purdy. The presentations were (1) Fetal ethanol-induced increase in brain levels of pregnenolone sulfate, by C. Fernando Valenzuela; (2) GABAergic neuroactive steroids after ethanol selfadministration and relapse, by Patricia H. Janak; (3) Neuroactive steroid modulation of ethanol intake patterns in C57BL/6J mice, by Deborah A. Finn; (4) Role of neurosteroids in ethanol dependence and GABA A receptor plasticity, by Giovanni Biggio; and (5) Alcohol and neuroactive steroid interactions in the menstrual cycle, by Torbjörn Bäckström.
Addiction biology, 2015
Neuroactive steroids such as (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) enhance the gamma-aminobutyric acid (GABA)-ergic effects of ethanol and modulate excessive drinking in rodents. Moreover, chronic ethanol consumption reduces 3α,5α-THP levels in human plasma, rat hippocampus and mouse limbic regions. We explored the relationship between 3α,5α-THP levels in limbic brain areas and voluntary ethanol consumption in the cynomolgus monkey following daily self-administration of ethanol for 12 months and further examined the relationship to hypothalamic-pituitary-adrenal (HPA) axis function prior to ethanol exposure. Monkeys were subjected to scheduled induction of ethanol consumption followed by free access to ethanol or water for 22 h/day over 12 months. Immunohistochemistry was performed using an anti-3α,5α-THP antibody. Prolonged voluntary drinking resulted in individual differences in ethanol consumption that ranged from 1.2 to 4.2 g/kg/day over 12 months. Prolong...
Alcoholism: Clinical and Experimental Research, 2005
Background-Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of GABA A receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. Methods-Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hour limited access sessions beginning 1 hour after dark phase onset. Cumulative lick responses were recorded for 10E and water using lickometer circuits. After establishing 10E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v β-cyclodextrin; i.p.), and then were treated with either VEH or neurosteroid immediately prior to the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17 and 24 mg/kg) alone and EPI doses (0.15, 1, 3 and 10 mg/kg) alone in a counterbalanced withingroup design. Results-The GABA A receptor positive modulator, ALLO, dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus vehicle pretreatment. ALLO-evoked alterations in intake corresponded with a significant, dose-dependent alterations in bout frequency and inter-bout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5-minutes of access, but subsequently resulted in a dosedependent suppression of 10E licks during session minutes 20-80. In contrast, the partial agonist/ antagonist neurosteroid, EPI, exhibited no influence on any consumption parameter evaluated. Conclusions-The present findings suggest that GABA A receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABAergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA A receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.
Journal of Neurochemistry, 2010
Neuroactive steroids produce their effects on membrane receptors that regulate central nervous system activity rather than on nuclear receptors that regulate gene expression. Thus, these steroids are capable of eliciting rapid changes in neuronal excitability, primarily through their enhancement of GABA A receptor activity (for review, see . Neuroactive steroids can be synthesized de novo in the brain or produced peripherally in the adrenals and gonads. Potent GABAergic neuroactive steroids (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP) and (3a,5a)-3,21-dihydroxypregnan-20one positively modulate GABA A receptor activity (Majewska Abstract Acute ethanol administration increases potent GABAergic neuroactive steroids, specifically (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP) and (3a,5a)-3,21-dihydroxypregnan-20one. In addition, neuroactive steroids contribute to ethanol actions. Chronic ethanol exposure results in tolerance to many effects of ethanol, including ethanol-induced increases in neuroactive steroid levels. To determine the mechanisms of tolerance to ethanol-induced increases in neuroactive steroids, we investigated critical signaling molecules that are required for acute ethanol effects. Male Sprague-Dawley rats were administered ethanol via liquid diet for 2 weeks and steroid levels, adrenocorticotrophic hormone (ACTH) and adrenal steroidogenic acute regulatory (StAR) protein expression were measured. Chronic ethanol exposure elicits tolerance to ethanol-induced elevation of serum ACTH and the steroids pregnenolone and progesterone. Surprisingly, chronic ethanol exposure does not result in tolerance to eth-anol-induced increases in adrenal StAR protein. However, ethanol-induced StAR phosphorylation is decreased when compared to acute ethanol administration. A separate group of rats exposed to chronic ethanol diet were subsequently challenged with ethanol (2 g/kg) and exhibited a blunted elevation of serum ACTH and progesterone as well as cerebral cortical and hippocampal 3a,5a-THP. Administration of ACTH with the ethanol challenge restored the elevation of serum ACTH and progesterone as well as cerebral cortical 3a,5a-THP levels to those observed in ethanol-naïve rats. Thus, chronic ethanol exposure disrupts ACTH release, which results in tolerance to ethanol-induced increases in neuroactive steroid levels. Loss of the ethanol-induced increases in neuroactive steroids may contribute to behavioral tolerance to ethanol and influence the progression towards alcoholism.
Frontiers in cellular neuroscience, 2015
Corticosterone is known to accumulate in brain after various stressors including alcohol intoxication. Just as severe alcohol intoxication is typically required to impair memory formation only high concentrations of ethanol (60 mM) acutely inhibit long-term potentiation (LTP), a cellular memory mechanism, in naïve hippocampal slices. This LTP inhibition involves synthesis of neurosteroids, including allopregnanolone, and appears to involve a form of cellular stress. In the CA1 region of rat hippocampal slices, we examined whether a lower concentration of ethanol (20 mM) inhibits LTP in the presence of corticosterone, a stress-related modulator, and whether corticosterone stimulates local neurosteroid synthesis. Although low micromolar corticosterone alone did not inhibit LTP induction, we found that 20 mM ethanol inhibited LTP in the presence of corticosterone. At 20 mM, ethanol alone did not stimulate neurosteroid synthesis or inhibit LTP. LTP inhibition by corticosterone plus etha...
Alcoholism: Clinical & Experimental Research, 1997
Chronic ethanol treatment (CET), sufficient for decreasing long-term potentiation (LTP) in rats, also enhances 3H-GABA release from hippocampal slices in these same animals. The mechanism for an increase in GABA release may involve changes in presynaptic receptors. Therefore, we characterized presynaptic autoreceptor modulation of 3H-GABA release in hippocampal slices from control and CET rats. The effects of a GAB& receptor agonist (baclofen) and antagonist [2-hydroxy (OH)-saclofen] were tested for their ability to modulate electrically stimulated 3H-GABA release from superfused hippocampal slices. Baclofen decreased stimulated release in a dose-dependent manner and 2-OH-saclofen increased release consistent with the existence of presynaptic GAB& autoreceptors in hippocampus. The GABA, antagonist bicuculline did not significantly modulate basal or stimulated release. When the effects of baclofen and 2-OH-saclofen were measured in animals 48 hr after withdrawal from CET, presynaptic modulation of release by baclofen and 2-OH-saclofen was decreased. In addition, we examined the density of 3H-baclofen and 3H-bicuculline binding in the hippocampal formation using quantitative autoradiographic techniques. We found that the density of 3H-baclofen binding sites was not affected by CET, whereas the density of 3H-bicuculline binding sites was increased by 28% in ethanol-treated rats. These data may explain how CET increases presynaptic regulation of GABA release from hippocampus that may contribute to the decrease in LTP seen in rats after CET.