Evaluation of the novel antiepileptic drug, AWD 131-138, for benzodiazepine-like discriminative stimulus and reinforcing effects in squirrel monkeys

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• 作者：Yasar ; Sevil ; Bergman ; Jack ; Munzar ; Patrik ; Redhi ; Godfrey ; Tober ; Christine ; Knebel ; Norbert ; et. al.
• 关键词：Anticonvulsant ; Benzodiazepine ; AWD 131-138 ; Midazolam ; Diazepam ; Drug discrimination ; Self-administration ; monkey
• 刊名：European Journal of Pharmacology
• 出版年：2003
• 出版时间：April 4, 2003
• 年：2003
• 卷：465
• 期：3
• 页码：257-265
• 全文大小：253 K

文摘

AWD 131-138 {1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one}, a new low-affinity partial benzodiazepine receptor agonist with potent anticonvulsant and anxiolytic properties in rodent models, was studied in squirrel monkeys trained to discriminate intramuscular (i.m.) injections of midazolam (0.3 mg/kg) from injections of vehicle. Diazepam produced midazolam-like responding at cumulative doses of 1.0 and 3.0 mg/kg i.m. and decreased rates of responding at 3.0 mg/kg (plasma levels of about 400 ng/ml). In contrast, AWD 131-138 did not produce midazolam-like responding or alter response rates at cumulative doses up to 18.0 mg/kg i.m. (plasma levels over 2100 ng/ml). Other monkeys were trained to intravenously (i.v.) self-administer cocaine (56.0 μg/kg/injection). When AWD 131-138 (10–100 μg/kg/injection) was studied by substitution, responding declined to vehicle substitution levels within three sessions. At the dose of 100 μg/kg i.v. AWD 131-138, sufficient drug was self-administered during the first session (about 3.5 mg/kg) to produce plasma levels above 1000 ng/ml, yet responding over the next two sessions dropped to vehicle levels. The failure of AWD 131-138 to produce benzodiazepine-like discriminative effects and the absence of drug self-administration behavior when substituted for cocaine suggest that its abuse liability is low.