Alcohol Intoxication Increases Allopregnanolone Levels in Female Adolescent Humans

Torres, Juan Antonio Vera; Ortega, Esperanza

doi:10.1038/sj.npp.1300170

Cited by 76 publications

(50 citation statements)

References 18 publications

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“…When taken in conjunction with the recent observations that ethanol consumption increased endogenous ALLO concentrations in B6 mice [10] and human adolescents [43,44], and that the inhibition of ALLO biosynthesis attenuated ethanol intake [13], the current findings are consistent with the hypothesis that alterations in endogenous ALLO levels may influence the regulatory processes governing ethanol consumption and reinforcement. The development of pharmacological interventions that manipulate endogenous ALLO concentrations may prove to be a beneficial treatment strategy.…”

Section: Discussionsupporting

confidence: 87%

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

Ford

Mark

Nickel

et al. 2007

Behavioural Brain Research

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Although systemic allopregnanolone (ALLO; a positive modulator of GABA A receptors) has been shown to enhance ethanol-reinforced responding and to modulate drinking patterns in rodents, the effects of centrally administered ALLO on ethanol intake are not known. The current work examined the effects of intracranial ALLO on operant ethanol self-administration in food-and water-satiated mice, with a procedure designed to estimate ALLO's influence on appetitive versus consummatory processes. Male C57BL/6J (B6) mice were trained to press an ethanol-appropriate lever by being reinforced with 30-min of continuous access to a 10% ethanol solution. Following surgical implantation of a guide cannula aimed at the lateral ventricle and subsequent habituation to vehicle infusions, ALLO (50-400 ng; ICV) was delivered immediately prior to session start. ALLO doses of 100 and 400 ng were further evaluated for their effects on locomotor behavior within activity chambers. ALLO selectively modulated ethanol intake patterns associated with the onset and maintenance of self-administration, while leaving appetitive (i.e., ethanol seeking) measures unaltered. The effects of ALLO on drinking patterns were dissociable from changes in locomotor behavior, as evidenced by the absence of ALLO's influence on response frequency and horizontal distance traveled. These findings support the premise that manipulations in brain ALLO levels may influence the regulatory processes governing ethanol consumption.

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Section: Discussionsupporting

confidence: 87%

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

Ford

Mark

Nickel

et al. 2007

Behavioural Brain Research

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“…Electrophysiologically, ethanol has been shown to have a direct and indirect effect to potentiate GABA A receptor function, with the indirect effect related to an increase in steroidogenesis (Sanna et al, 2004). This finding is consistent with reports that acute exposure to ethanol by injection or consumption in rodents (Barbaccia et al, 1999;Finn et al, 2004b;Morrow et al, 1999;VanDoren et al, 2000) or consumption in human adolescents (Torres & Ortega, 2003 significantly increased endogenous ALLO levels to pharmacologically active concentrations. The fact that the 5α-reductase inhibitor finasteride (which decreases endogenous ALLO levels) reduced sensitivity to some, but not all, effects of ethanol (e.g., Dazzi et al, 2002;Gabriel et al, 2004;Hirani et al, 2002Hirani et al, , 2005Khisti et al, 2004;Murphy et al, 2006;VanDoren et al, 2000) suggests that there is a complex interaction between ALLO and ethanol in biological systems.…”

Section: Introductionsupporting

confidence: 88%

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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“…Preliminary clinical evaluations of neurosteroid concentrations in patients afflicted with premenstrual syndrome, major depression, seizure disorders, and alcoholism have indicated an inverse relationship between neurosteroids and symptoms of these disease states, since restoration of neurosteroids to normal levels alleviates adverse symptomology (Griffin et al, 2001). Taken in conjunction with the recent findings that ethanol self-administration led to significantly elevated plasma ALLO levels in male and female adolescents (Torres and Ortega, 2003;Torres and Ortega, 2004) and brain ALLO concentrations in male mice (Finn et al, 2004), it is tempting to speculate that a treatment strategy that involves manipulation of endogenous levels of ALLO and related agonist neurosteroids could yield beneficial outcomes in the management of ethanol's abuse-related effects. The purported involvement of GABAergic neurotransmission in the development of ethanol dependence and withdrawal warrants extensive investigation into GABA-active compounds (Johnson et al, 2005).…”

Section: Discussionsupporting

confidence: 61%

Neurosteroid Modulators of GABAA Receptors Differentially Modulate Ethanol Intake Patterns in Male C57BL/6J Mice

Ford

Nickel

Phillips

et al. 2005

Alcoholism: Clinical and Experimental Research

102

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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.

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Alcohol Intoxication Increases Allopregnanolone Levels in Female Adolescent Humans

Cited by 76 publications

References 18 publications

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

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

Neurosteroid Modulators of GABAA Receptors Differentially Modulate Ethanol Intake Patterns in Male C57BL/6J Mice

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