title: Chlormethiazole potentiates the discriminative stimulus effects of methamphetamine in rats.
abstract: Chlormethiazole is a positive modulator of gamma-aminobutyric acid (GABA)(A) receptors used in the treatment of alcohol withdrawal seizures. It recently has been reported to attenuate seizures engendered by acute and repeated exposure to cocaine in mice and neurotoxic effects of methamphetamine in rats. The aim of the present study was to determine whether chlormethiazole could also attenuate the discriminative stimulus effects of methamphetamine, a behavior predictive of the subjective effects of methamphetamine in humans. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine [intraperitoneally (i.p.)] from saline under a fixed-ratio schedule of food delivery, the ability of chlormethiazole (i.p.) to (1) substitute for methamphetamine, (2) antagonize effects of methamphetamine and to (3) shift the methamphetamine dose-effect function was investigated. Chlormethiazole (18 and 30 mg/kg, i.p.) partially substituted for the discriminative stimulus effects of methamphetamine when administered alone (maximum group average, 60% responses on the methamphetamine-appropriate lever). Chlormethiazole did not attenuate effects of methamphetamine when coadministered with the training dose of methamphetamine. Instead, chlormethiazole potentiated the discriminative stimulus effects of methamphetamine as demonstrated by a significant (about 2.5-fold) leftward and upward shift in the methamphetamine dose-effect function in the presence of chlormethiazole (10 mg/kg). In conclusion, the present findings suggest that there is a behavioral interaction between methamphetamine and chlormethiazole. The profile of this interaction is qualitatively different from that of methamphetamine and classical GABAergic drugs (i.e., benzodiazepines and barbiturates), suggesting the involvement of non-GABAergic mechanisms in the effects produced by chlormethiazole.
authors.affiliation: Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, MSC: 1408, Building 10, Room 5N250, Bethesda, MD 20892-1408, USA. gasiorm@ninds.nih.gov
authors.forename: Maciej
authors.initials: M
authors.lastname: Gasior
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldberg
authors.forename: Patrik
authors.initials: P
authors.lastname: Munzar
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology* / Q000633:toxicity; D002719:Chlormethiazole / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018757:GABA Modulators / Q000494:pharmacology*; D005793:Generalization, Psychological / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology* / Q000633:toxicity; D020258:Neurotoxicity Syndromes / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced
chemical_list: D000697:Central Nervous System Stimulants; D018757:GABA Modulators; D002719:Chlormethiazole; D008694:Methamphetamine