Shigeo Miyata1, Shoko Hirano, Junzo Kamei. 1. Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo, 142-8501, Japan.
Abstract
RATIONALE: We previously reported that the head-twitch responses induced by the 5-HT2 receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) (DOI-HTRs) were decreased in streptozotocin-induced diabetic mice. OBJECTIVES: We examined the involvement of gamma-aminobutyric acid (GABA)/benzodiazepine system on the suppression of DOI-HTRs in diabetic mice. RESULTS: The benzodiazepine receptor antagonist flumazenil (0.1-1 mg/kg, i.v.) dose-dependently and significantly increased DOI-HTRs in diabetic mice to the same levels as in nondiabetic mice. However, flumazenil (0.1-1 mg/kg, i.v.) did not affect DOI-HTRs in nondiabetic mice. The benzodiazepine receptor agonist diazepam (0.1-1 mg/kg, i.p.) had no effect on DOI-HTRs in either nondiabetic or diabetic mice. The GABAA receptor antagonist bicuculline (0.1-1 mg/kg, i.p.) and the benzodiazepine receptor partial inverse agonist Ro 15-4513 (0.1-1 mg/kg, i.v.) dose-dependently and significantly suppressed DOI-HTRs in nondiabetic mice to the same levels as in diabetic mice. Ro 15-4513-induced reduction of DOI-HTRs in nondiabetic mice was completely antagonized by flumazenil (1 mg/kg, i.v.), but not diazepam (0.3 mg/kg, i.p.). CONCLUSIONS: We suggest that the abnormal diazepam-insensitive benzodiazepine receptor function partly underlies the suppression of DOI-HTRs in diabetic mice.
RATIONALE: We previously reported that the head-twitch responses induced by the 5-HT2 receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) (DOI-HTRs) were decreased in streptozotocin-induced diabeticmice. OBJECTIVES: We examined the involvement of gamma-aminobutyric acid (GABA)/benzodiazepine system on the suppression of DOI-HTRs in diabeticmice. RESULTS: The benzodiazepine receptor antagonist flumazenil (0.1-1 mg/kg, i.v.) dose-dependently and significantly increased DOI-HTRs in diabeticmice to the same levels as in nondiabetic mice. However, flumazenil (0.1-1 mg/kg, i.v.) did not affect DOI-HTRs in nondiabetic mice. The benzodiazepine receptor agonist diazepam (0.1-1 mg/kg, i.p.) had no effect on DOI-HTRs in either nondiabetic or diabeticmice. The GABAA receptor antagonist bicuculline (0.1-1 mg/kg, i.p.) and the benzodiazepine receptor partial inverse agonist Ro 15-4513 (0.1-1 mg/kg, i.v.) dose-dependently and significantly suppressed DOI-HTRs in nondiabetic mice to the same levels as in diabeticmice. Ro 15-4513-induced reduction of DOI-HTRs in nondiabetic mice was completely antagonized by flumazenil (1 mg/kg, i.v.), but not diazepam (0.3 mg/kg, i.p.). CONCLUSIONS: We suggest that the abnormal diazepam-insensitive benzodiazepine receptor function partly underlies the suppression of DOI-HTRs in diabeticmice.
Authors: J H Meyer; S Kapur; S Houle; J DaSilva; B Owczarek; G M Brown; A A Wilson; S H Kennedy Journal: Am J Psychiatry Date: 1999-07 Impact factor: 18.112