Zolpidem Generalization and Antagonism in Male and Female Cynomolgus Monkeys Trained to Discriminate 1.0 or 2.0 g / kg EthanolAlcoholism: Clinical and Experimental Research
Published 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 GABA
A 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 GABA
A 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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Zolpidem Generalization and Antagonism in Male and Female Cynomolgus Monkeys Trained to Discriminate 1.0 or 2.0 g / kg Ethanol
