Evaluation of the novel antiepileptic drug, AWD 131-138, for benzodiazepine-like discriminative stimulus and reinforcing effects in squirrel monkeys.
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 microg/kg/injection). When AWD 131-138 (10-100 microg/kg/injection) was studied by substitution, responding declined to vehicle substitution levels within three sessions. At the dose of 100 microg/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.
Yasar
Sevil
S
Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. syasar@jhmi.edu
Bergman
Jack
J
Munzar
Patrik
P
Redhi
Godfrey
G
Tober
Christine
C
Knebel
Norbert
N
Zschiesche
Michael
M
Paronis
Carol
C
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D003975:Diazepam / Q000097:blood; D004193:Discrimination Learning / Q000187:drug effects*; D018757:GABA Modulators / Q000097:blood; D058785:GABA-A Receptor Agonists; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000097:blood; D003708:Nordazepam / Q000097:blood; D012054:Reinforcement, Psychology; D012453:Saimiri; D012646:Self Administration
C116306:AWD 131-138; D000927:Anticonvulsants; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D003708:Nordazepam; D003042:Cocaine; D003975:Diazepam; D008874:Midazolam