Characterization of the discriminative stimulus effects of GABA A receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions

Grant, Kathleen A.; Waters, Courtney A.; Green-Jordan, Kristen; Азаров, А. В.; Szeliga, Kendall T.

doi:10.1007/s002130000510

Cited by 48 publications

(77 citation statements)

References 18 publications

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“…In contrast, the direct GABA A agonist muscimol engendered primarily saline-lever responding up to doses that have been shown to produce convulsions in squirrel monkeys (Spealman, 1985). This finding also is consistent with earlier studies in rodents and monkeys in which muscimol was administered peripherally (Shelton and Balster, 1994;Grant et al, 2000). Neither the GABA B agonist baclofen nor the opioid agonist morphine produced significant ethanol-appropriate responding at doses that either induced untoward side effects or eliminated responding.…”

Section: Discussionsupporting

confidence: 92%

Contribution of α₁GABA_Aand α₅GABA_AReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Platt¹,

Duggan²,

Spealman³

et al. 2005

J Pharmacol Exp Ther

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Ethanol's ability to enhance GABA neurotransmission via GABA A receptors has been implicated as an important mechanism underlying its discriminative stimulus (DS) effects in animals and subjective effects in humans. The present study assessed the contribution of ␣ 1 GABA A and ␣ 5 GABA A receptors to the DS effects of ethanol. Squirrel monkeys were trained to discriminate i.v. ethanol from saline under a fixed-ratio schedule of food delivery. Under test conditions, ethanol engendered a dose-dependent increase in drug-lever responding, reaching an average maximum of Ͼ80%. In substitution experiments, the ␣ 1 GABA A agonists zolpidem, zaleplon, and CL 218, Alcoholism is a worldwide public health problem that is associated with debilitating medical, social, and psychological consequences (e.g., Whitmore et al., 2002). The ability of ethanol to engender subjective effects may contribute importantly to its abuse. For example, it has been suggested that subjective effects of drugs of abuse may contribute to the initiation of drug taking in intermittent users and to the relapse process in drug abusers (Stolerman, 1992). Understanding the neurobiological mechanisms contributing to the subjective effects of ethanol should provide valuable information for the development of effective pharmacotherapies to treat alcohol addiction.The ability of ethanol to modulate GABA receptors has been proposed as an important mechanism underlying its behavioral effects in humans (e.g., Korpi, 1994). Results from behavioral studies in animals support a key role for specific subtypes of the GABA A receptor in the effects of ethanol related to its abuse. For example, self-administration of ethanol, but not saccharin or sucrose, can be reduced by 3-propoxy-␤-carboline hydrochloride and ␤-carboline-t-butyl

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Section: Discussionsupporting

confidence: 92%

Contribution of α₁GABA_Aand α₅GABA_AReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Platt¹,

Duggan²,

Spealman³

et al. 2005

J Pharmacol Exp Ther

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“…Three male (4890, 4891, and 5496) and four female (2835, 3220, 5400, and 5999) monkeys were trained to discriminate 2.0 g/kg ethanol (20% w/v, 10 ml/kg) from water. The training conditions were the same as those described in Grant et al (1997Grant et al ( , 2000.…”

Section: Methodsmentioning

confidence: 99%

“…The luteal phase was indicated by progesterone levels Ն4 ng/ml. The origin and housing conditions of the monkeys have been described previously (Grant et al, 1996(Grant et al, , 2000. The study was conducted in accordance with the Wake Forest University Animal Care and Use Committee and the Institute of Laboratory Animal Resources (1996).…”

mentioning

confidence: 99%

Neuroactive Steroid Stereospecificity of Ethanol-Like Discriminative Stimulus Effects in Monkeys

Grant

Helms²,

Rogers

et al. 2008

J Pharmacol Exp Ther

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“…Most convincing was the early recognition that behavioral consequences of moderate doses of ethanol had similarities to those of BZDs and barbiturates (Breese et al, 1983;Frye et al, 1979, White et al, 1997, drugs known to rely on GABA A receptor function (see Harris, 1990;Ticku, 1989). Further, BZDs and barbiturates enhanced ethanol-induced motor impairment (Martz et al, 1983) and substituted for ethanol in drug discrimination studies (Grant et al, 2000;Shannon et al, 2004). On the other hand, a BZD-inverse agonist minimized ethanol-induced sedation (McCown and Breese, 1989;Suzdak et al, 1986a;Ticku and Kulkarni, 1988) and GABA A receptor antagonists decreased the antipunishment action of ethanol (Koob et al, 1986(Koob et al, , 1988Liljequist and Engel, 1984).…”

Section: Interaction Of Ethanol With the Gaba System In Vivomentioning

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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Characterization of the discriminative stimulus effects of GABA A receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions

Cited by 48 publications

References 18 publications

Contribution of α₁GABA_Aand α₅GABA_AReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Contribution of α₁GABA_Aand α₅GABA_AReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Neuroactive Steroid Stereospecificity of Ethanol-Like Discriminative Stimulus Effects in Monkeys

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

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Characterization of the discriminative stimulus effects of GABA A receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions

Cited by 48 publications

References 18 publications

Contribution of α1GABAAand α5GABAAReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Contribution of α1GABAAand α5GABAAReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Neuroactive Steroid Stereospecificity of Ethanol-Like Discriminative Stimulus Effects in Monkeys

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

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Contribution of α₁GABA_Aand α₅GABA_AReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys

Contribution of α₁GABA_Aand α₅GABA_AReceptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys