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Sunday, July 20, 2008

Zolpidem Generalization and Antagonism in Male and Female Cynomolgus Monkeys Trained to Discriminate 1.0 or 2.0 g / kg Ethanol
Alcoholism: Clinical and Experimental ResearchPublished Online: 14 May 2008

The subtypes of γ-aminobutyric acid (GABA)A receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABAA receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing α1, α2/3, and α5 subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for α4/6-containing receptors, higher affinity for α5- and lower, but equal, affinity for α1- and α2/3-, containing GABAA receptors, and antagonizes the discriminative stimulus effects of ethanol.

Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (≥80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose–response curve to the right in all monkeys showing generalization. Analysis of apparent pKB from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro15-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol.

Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABAA receptors that contain α1 subunits, however, antagonism by Ro15-4513 of zolpidem generalization from the lower training dose of ethanol (1.0 g/kg) may involve additional zolpidem-sensitive GABAA receptor subtypes (e.g., α2/3 and α5)

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