Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol

Background: 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 α ₁, α _2/3, and α ₅ subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for α _4/6-containing receptors, higher affinity for α ₅- and lower, but equal, affinity for α ₁- and α _2/3-, containing GABA _A receptors, and antagonizes the discriminative stimulus effects of ethanol. Methods: This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval. Results: 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 pK _B from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro1 5-4513 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. Conclusions: Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABA _A receptors that contain α ₁ 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 GABA _A receptor subtypes (e.g., α _2/3 and α ₅).