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

Sevil Yasar, Jack Bergman, Patrik Munzar, Godfrey Redhi, Christine Tober, Norbert Knebel, Michael Zschiesche, Carol Paronis

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)257-265
Number of pages9
JournalEuropean Journal of Pharmacology
Volume465
Issue number3
DOIs
StatePublished - Apr 4 2003

Keywords

  • AWD 131-138
  • Anticonvulsant
  • Benzodiazepine
  • Diazepam
  • Drug discrimination
  • Midazolam
  • Monkey
  • Self-administration

ASJC Scopus subject areas

  • Pharmacology

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