Involvement of diazepam-insensitive benzodiazepine receptors in the suppression of DOI-induced head-twitch responses in diabetic mice.
BACKGROUND
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.


OBJECTIVE
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.
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo, 142-8501, Japan.
Shigeo
S
Miyata
Shoko
S
Hirano
Junzo
J
Kamei
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003975:Diazepam / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011963:Receptors, GABA-A / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000662:Amphetamines; D001386:Azides; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D017366:Serotonin Receptor Agonists; D001569:Benzodiazepines; D005442:Flumazenil; C042957:Ro 15-4513; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003975:Diazepam; D001640:Bicuculline