These studies examined the behavioral effects of two novel BZ ligands, NsA and NsB. These compounds nonselectively bind GABAA1, GABAA2, and GABAA3 receptors with little or no efficacy at GABAA1 receptors and weak positive modulatory actions at GABAA2 and GABAA3 receptors. Effects were evaluated in squirrel monkeys (n=3–4) trained to respond either under a multiple fixed-ratio (FR) schedule of punished and nonpunished behavior or to discriminate 0.3 mg/kg midazolam from saline. NsA and NsB, 1-30 mg/kg, had mild and inconsistent effects on punished responding, and produced greater than 90% drug-lever responding in only one monkey. Neither of the novel compounds had response rate-decreasing effects over the doses tested. Further studies examined the abilities of NsA and NsB to antagonize the antipunishment and discriminative stimulus effects of three commonly used BZ agonists, midazolam (0.1–10 mg/kg), lorazepam (0.3–18 mg/kg), and zolpidem (0.1–10 mg/kg). NsA, 1–10 mg/kg, effectively antagonized the antipunishment effects of midazolam, lorazepam and zolpidem, and the discriminative stimulus effects of midazolam and lorazepam, but not zolpidem. In contrast, 1–10 mg/kg NsB antagonized the discriminative stimulus effects of midazolam but not zolpidem or lorazepam, and the antipunishment effects of lorazepam but not midazolam or zolpidem. These results suggest that ligands with varying efficacy at GABAA subtypes may differentially antagonize the behavioral effects of benzodiazepines, and may yield useful tools for understanding BZ pharmacology. (PHS: DA15723, DA11453, DA7252)
1Preclinical Pharmacology, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA 2Drug Discovery, NeuroSearch A/S, Ballerup, Denmark Abstracts of the 11th Biennial EBPS Meeting
1Preclinical Pharmacology, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA 2Drug Discovery, NeuroSearch A/S, Ballerup, Denmark Abstracts of the 11th Biennial EBPS Meeting
