Evaluation of GABAergic neuroactive steroid 3α-hydroxy-5α-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats

Hirani, Khemraj; Sharma, Ajay; Jain, Nishant; Ugale, Rajesh R.; Chopde, Chandrabhan T.

doi:10.1007/s00213-005-2169-7

Cited by 88 publications

(74 citation statements)

References 78 publications

(102 reference statements)

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“…Pre-treatment with finasteride (5α-reductase inhibitor) that reduces the synthesis of ALLO and THDOC, diminishes the subjective response to a moderate dose of alcohol in social drinkers (Pierucci-Lagha et al, 2005). Several studies in rodents have shown that ethanol-induced neuroactive steroids contribute to the acute behavioral effects of ethanol such as sedative-hypnotic (Van Doren et al, 2000;Khisti et al, 2003), anti-depressant (Hirani et al, 2002) and anxiolytic (Hirani et al, 2005). Moreover a relationship exists between the time course of ethanol-induced neurosteroids and specific behavioral and neural effects of ethanol ).…”

Section: Ethanol and Neurosteroidsmentioning

confidence: 99%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

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Section: Ethanol and Neurosteroidsmentioning

confidence: 99%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

196

181

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“…ADX or inhibition of 5a-reduced steroid synthesis with the 5a-reductase (5a-R) inhibitor finasteride reduces some of the behavioral effects of ethanol, including the anticonvulsant (VanDoren et al, 2000), antidepressant-like (Hirani et al, 2002), and anxiolytic-like (Hirani et al, 2005) effects in rats. Finasteride also blocks ethanol inhibition of neuron firing in the medial septum (VanDoren et al, 2000), the hippocampus both in vivo (Tokunaga et al, 2003) and in vitro (Sanna et al, 2004), and long-term potentiation (LTP) in hippocampal slices (Tokuda et al, 2011).…”

Section: Introductionmentioning

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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“…GABAergic neurons are one of the most important components prevalent in all areas of the brain and its neurotransmission is vital for brain function (5). Although GABA plays a major role in the modulation of virtually all cognitive and behavioural processes, several basic and clinical studies have particularly highlighted the role of this neurotransmitter in the central modulation of anxiety and stress responses (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Activation of GABA_A receptors in the medial prefrontal cortex produces an anxiolytic-like response

Solati

Hajikhani

Golub

2013

Acta Neuropsychiatr.

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Solati J, Hajikhani R, Golub Y. Activation of GABA A receptors in the medial prefrontal cortex produces an anxiolytic-like response.Objectives: There has been increasing evidence that the g-aminobutyric acid (GABA)ergic system is involved in the neurobiology of anxiety. The present study aimed to investigate the role of GABAergic systems in the modulation of anxiety in the medial prefrontal cortex (mPFC) of rats using the elevated plus maze test. Methods: Rats were anaesthetised with a mixture of ketamine and xylazine, and then special cannulae were inserted stereotaxically into the mPFC. After 5-7 days of recovery, the effects of intra-mPFC administration of GABAergic agents were studied. Results: Bilateral injection of the GABA A receptor agonist muscimol (0.25, 0.5 and 1 mg/rat) produces an anxiolytic-like effect, shown by significant increases in the percentage of open-arm time (%OAT) and percentage of open-arm entries (%OAE). Intra-mPFC administration of the GABA A receptor antagonist bicuculline (0.25, 0.5 and 1 mg/rat) produces significant anxiogenic-like behaviour. However, intra-mPFC injection of the GABA B receptor agonist baclofen (0.05, 0.1 and 0.2 mg/rat) and the GABA B receptor antagonist CGP35348 (5, 10 and 15 mg/rat) did not alter %OAT and %OAE significantly. Conclusion:The results of the present study demonstrate that the GABAergic system of the mPFC modulates anxiety-related behaviours of rats through GABA A receptors. Significant outcomes> Anxiety behaviours of animals are controlled by the g-aminobutyric acid (GABA)ergic system of the medial prefrontal cortex (mPFC).

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Evaluation of GABAergic neuroactive steroid 3α-hydroxy-5α-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats

Cited by 88 publications

References 78 publications

The role of GABAA receptors in the development of alcoholism

The role of GABAA receptors in the development of alcoholism

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

Activation of GABA_A receptors in the medial prefrontal cortex produces an anxiolytic-like response

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Evaluation of GABAergic neuroactive steroid 3α-hydroxy-5α-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats

Cited by 88 publications

References 78 publications

The role of GABAA receptors in the development of alcoholism

The role of GABAA receptors in the development of alcoholism

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

Activation of GABAA receptors in the medial prefrontal cortex produces an anxiolytic-like response

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Activation of GABA_A receptors in the medial prefrontal cortex produces an anxiolytic-like response