Ethanol-like discriminative stimulus effects of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in femaleMacaca fascicularis monkeys

Grant, Kathleen A.; Азаров, А. В.; Bowen, Carrie A.; Mirkis, Serene; Purdy, Robert H.

doi:10.1007/bf02247439

Cited by 76 publications

(65 citation statements)

References 26 publications

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“…Consistent with previous reports, pentobarbital (Ator et al, 1993;Grant et al, 1996;Hodge et al, 2001;Shelton and Grant, 2002) and diazepam (Jarbe and McMillan, 1983;Ator et al, 1993;Kostowski and Bienkowski, 1999;Green-Jordan and Grant, 2000;Shelton and Grant, 2002) dose dependently substituted for the stimulus effects of ethanol. MPEP pretreatment did not alter pentobarbital (1-10 mg/kg) substitution for ethanol.…”

Section: Discussionsupporting

confidence: 91%

“…For example, positive modulators of GABA A receptors, such as barbiturates, benzodiazepines, and neurosteroids, produce ethanollike stimulus effects (Ator et al, 1993;Barry, 1991;Evans and Balster, 1991;Grant et al, 1996Grant et al, , 1997Jarbe and McMillan, 1983;Shelton and Grant, 2002) in multiple species. MGluR5 activity has the potential to influence ethanol discrimination based on evidence that mGluR5 can influence GABA neurotransmission (de Novellis et al, 2003;Hoffpauir and Gleason, 2002;Diaz-Cabiale et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

Besheer

Hodge

2004

Neuropsychopharmacol

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The discriminative stimulus properties of ethanol are mediated in part by positive modulation of GABA A receptors. Recent evidence indicates that metabotropic glutamate receptor subtype 5 (mGluR5) activity can influence GABA A receptor function. Therefore, the purpose of this work was to examine the potential involvement of mGluR5 in the discriminative stimulus effects of ethanol. In rats trained to discriminate ethanol (1 g/kg, intragastric gavage (i.g.)) from water, 2-methyl-6-(phenylethyl)-pyridine (MPEP) (1-50 mg/kg, i.p.) a selective noncompetitive antagonist of the mGlu5 receptor did not produce ethanol-like stimulus properties. However, pretreatment with MPEP (30 mg/kg) reduced the stimulus properties of ethanol as indicated by significant reductions in ethanol-appropriate responding, specifically at 0.5 and 1 g/kg ethanol, and a failure of ethanol test doses (1 and 2 g/kg) to fully substitute for the ethanol training dose. To test whether mGluR5 antagonism altered the GABA A receptor component of the ethanol stimulus, the ability of MPEP to modulate pentobarbital and diazepam substitution for ethanol was assessed. Pentobarbital substitution (1-10 mg/kg, i.p.) for ethanol was not altered by MPEP pretreatment. However, MPEP pretreatment inhibited the ethanol-like stimulus properties of diazepam (5 mg/ kg, i.p.). To examine a potential anatomical basis for these pharmacological findings, expression patterns of mGluR5-and benzodiazepinesensitive GABA A a1-containing receptors were examined by dual-label fluorescent immunohistochemistry with visualization by confocal microscopy. Results indicated that mGluR5-and GABA A a1-containing receptors were both coexpressed in limbic brain regions and colocalized on the same cells in specific brain regions including the amygdala, hippocampus, globus pallidus, and ventral pallidum. Together, these findings suggest an interaction between mGluR5-and benzodiazepine-sensitive GABA A receptors in mediating ethanol discrimination.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

Besheer

Hodge

2004

Neuropsychopharmacol

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“…Even though Gabriel et al (2004) found that allopregnanolone did not influence ethanol-induced place preference, other work emphasized a relationship of neurosteroid action to ethanol pharmacology by demonstrating that discrimination for ethanol generalized to neurosteroids (Ator et al, 1993;Bowen et al, 1999;Grant et al, 1996). Additionally, exogenous neurosteroid altered the reinforcement responding for ethanol (Janak et al, 1998) and reinstated previously extinguished responding for ethanol (Nie and Janak, 2003).…”

Section: Neurosteroid Involvement In the Gabamimetic Profile Of Ethanmentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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“…These behavioral effects of ALLO are similar to those exhibited by ethanol, which exerts some of its effects through an interaction with GABA A receptors (for review, see [18]). Furthermore, ALLO is capable of substituting for ethanol's stimulus effects within drug discrimination procedures employing rodents and primates [3,17,19]. This indicates that the complex interoceptive cue elicited by ethanol (see [16]) demonstrates considerable overlap with ALLO.…”

Section: Introductionmentioning

confidence: 99%

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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Ethanol-like discriminative stimulus effects of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in femaleMacaca fascicularis monkeys

Cited by 76 publications

References 26 publications

Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

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

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