Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function

Cagetti, Elisabetta; Pinna, Graziano; Guidotti, Alessandro; Baicy, Kate; Olsen, Richard W.

doi:10.1016/j.neuropharm.2003.10.001

Cited by 96 publications

(100 citation statements)

References 37 publications

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“…Sensitivity to the other ALLO doses for each convulsion endpoint was unchanged during ethanol withdrawal, consistent with recent results in male WSR mice . However, the enhanced sensitivity to the anticonvulsant effect of ALLO during ethanol withdrawal at selected doses is consistent with previous findings in male C57BL/6 mice (Finn et al, 2000) and in male and female rats in which sensitivity to the anticonvulsant effect of GABAergic steroids such as ALLO, pregnanolone and alphaxalone was enhanced during ethanol withdrawal (e.g., Alele and Devaud, 2007;Cagetti et al, 2004;Devaud et al, 1996). Taken in conjunction with the findings that functional sensitivity of GABA A receptors to ALLO was unchanged in male WSR mice but was enhanced in male (Devaud et al, 1996) and female rats (Alele and Devaud, 2007) during ethanol withdrawal, it is possible that functional sensitivity of GABA A receptors to ALLO might be enhanced during ethanol withdrawal in female WSR mice.…”

Section: Discussionsupporting

confidence: 90%

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Beckley¹,

Fretwell²,

Tanchuck³

et al. 2008

Neuropharmacology

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SUMMARYThe GABAergic neurosteroid allopregnanolone (ALLO) has been repeatedly shown to have an increased anticonvulsant effect during ethanol withdrawal in rats and in C57BL/6J mice. In contrast, the seizure prone DBA/2J inbred strain and the Withdrawal Seizure-Prone (WSP) selected line exhibited decreased sensitivity to ALLO's anticonvulsant effect during ethanol withdrawal, with no change in sensitivity in the Withdrawal Seizure-Resistant (WSR) line. To date, only male mice have been tested. Thus, the present study examined ALLO sensitivity during ethanol withdrawal in female WSP and WSR mice, since females display less severe physical symptoms of withdrawal and have higher circulating ALLO levels than males. Female WSP and WSR mice were exposed to ethanol vapor or air for 72 hr. During peak ethanol withdrawal, separate groups of mice were injected with vehicle or ALLO (0, 3.2, 10, or 17 mg/kg, ip) prior to the timed tail vein infusion of pentylenetetrazol (PTZ). ALLO injection significantly increased the threshold dose for onset to PTZ-induced convulsions, indicating an anticonvulsant effect, in female WSP and WSR mice. During ethanol withdrawal, sensitivity to ALLO's anticonvulsant effect was slightly increased in female WSR mice but was significantly decreased in female WSP mice. This line difference in sensitivity to ALLO during ethanol withdrawal in female mice was similar to that in the male mice. Notably, all seizure prone genotypes tested to date displayed tolerance to the anticonvulsant effect of ALLO during ethanol withdrawal, suggesting that decreased sensitivity of GABA A receptors to ALLO may contribute to the increased ethanol withdrawal phenotype.

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Section: Discussionsupporting

confidence: 90%

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Beckley¹,

Fretwell²,

Tanchuck³

et al. 2008

Neuropharmacology

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“…For example, as is the case with THIP, the anxiolytic actions of diazepam (Cagetti et al, 2003) and alphaxalone (Cagetti et al, 2004) are maintained in CIE rats. Recent point mutation studies in mice have suggested that the anxiolytic properties of benzodiazepines such as diazepam are mediated through potentiation of ␣2-containing GABA A Rs (reviewed in Mohler et al, 2002).…”

Section: Discussionmentioning

confidence: 94%

Altered Pharmacology of Synaptic and Extrasynaptic GABA_AReceptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence

Liang

Cagetti²,

Olsen³

et al. 2004

J Pharmacol Exp Ther

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118

138

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Previously, we reported (Cagetti, Liang, Spigelman, and Olsen, 2003) that chronic intermittent ethanol (CIE) treatment leads to signs of alcohol dependence, including anxiety and hyperactivity, accompanied by reduced synaptic ␥-aminobutyric acid (A) receptor (GABA A R) function and altered sensitivity to its allosteric modulators consistent with a measured switch in subunit composition. In this study, we separated the synaptic and extrasynaptic components of GABA A R activation in recordings from pyramidal CA1 cells of hippocampal slices and demonstrated marked differences in the responsiveness of synaptic and extrasynaptic GABA A Rs to agonists and allosteric modulators in control rats, and in the way they are altered following CIE treatment. Notably, tonic inhibition mediated by extrasynaptic GABA A Rs was differentially sensitive to the partial agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; THIP) and the allosteric modulator zolpidem, compared with the miniature inhibitory synaptic currents (mIPSCs) in the same cells from saline-treated rats. After CIE treatment, potentiation of tonic currents by diazepam and zolpidem was lost, whereas potentiation by the ␣4 subunit-preferring benzodiazepine Ro15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxylate) and THIP was only partially reduced. Potentiation of synaptic GABA A R currents by zolpidem was eliminated after CIE, whereas THIP slightly inhibited mIPSCs from control rats and greatly enhanced them after CIE treatment. These results are consistent with ␣1 subunit decreases at synaptic and extrasynaptic GABA A Rs, whereas ␣4 subunits are increased at synaptic and decreased at extrasynaptic GABA A Rs. Behaviorally, THIP was active as a hypnotic and anxiolytic but not as an anticonvulsant against pentylenetetrazol seizures in control rats. Only slight tolerance was observed to the sleep time, but not to the anxiolytic, effect of THIP after CIE. Thus, differential alterations in synaptic and extrasynaptic GABA A Rs appear to play an important role in the brain plasticity of alcohol dependence, and withdrawal signs may be profitably treated with GABAergic drugs such as THIP, which does not show cross-tolerance with ethanol.

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“…Similarly, there are no data examining ethanol's effects on steroidogenic enzymes in the NAc or CeA where we observed ethanol-induced reductions in 3a,5a-THP. Chronic intermittent ethanol, however, reduces 3a,5a-THP in the hippocampus with concomitant decreases in 5a-R type I and 3a-HSD mRNA (Cagetti et al, 2004). Therefore, ethanol may alter expression or activity of steroid biosynthetic enzymes and/or cholesterol transporters to produce divergent brain region-specific changes in 3a,5a-THP.…”

Section: Discussionmentioning

confidence: 99%

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

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The neuroactive steroid (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) is a positive modulator of GABA A receptors synthesized in the brain, adrenal glands, and gonads. In rats, ethanol activates the hypothalamic-pituitary-adrenal axis and elevates 3a,5a-THP in plasma, cerebral cortex, and hippocampus. In vivo, these effects are dependent on both the pituitary and adrenal glands. In vitro, however, ethanol locally increases 3a,5a-THP in hippocampal slices, in the absence of adrenal influence. Therefore, it is not known whether ethanol can change local brain levels of 3a,5a-THP in vivo, independent of the adrenals. To directly address this controversy, we administered ethanol (2 g/kg) or saline to rats that underwent adrenalectomy (ADX) or received sham surgery and performed immunohistochemistry for 3a,5a-THP. In the medial prefrontal cortex (mPFC), ethanol increased 3a,5a-THP after sham surgery, compared with saline controls, with no ethanol-induced change in 3a,5a-THP following ADX. In subcortical regions, 3a,5a-THP was increased independent of adrenals in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus. Furthermore, ethanol decreased 3a,5a-THP labeling in the nucleus accumbens shore and central nucleus of the amygdala, independent of the adrenal glands. These data indicate that ethanol dynamically regulates local 3a,5a-THP levels in several subcortical regions; however, the adrenal glands contribute to 3a,5a-THP elevations in the mPFC. Using double immunofluorescent labeling we determined that adrenal dependence of 3a,5a-THP induction by ethanol is not due to a lack of colocalization of 3a,5a-THP with the cholesterol transporters steroidogenic acute regulatory protein (StAR) or translocator protein (TSPO).

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Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function

Cited by 96 publications

References 37 publications

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Altered Pharmacology of Synaptic and Extrasynaptic GABA_AReceptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

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Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function

Cited by 96 publications

References 37 publications

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Decreased anticonvulsant efficacy of allopregnanolone during ethanol withdrawal in female Withdrawal Seizure-Prone vs. Withdrawal Seizure-Resistant mice

Altered Pharmacology of Synaptic and Extrasynaptic GABAAReceptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

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Altered Pharmacology of Synaptic and Extrasynaptic GABA_AReceptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence