Strain differences in sensitivity to the hypothermic effects of benzodiazepine receptor ligands in mice.
The hypothermic effects of intraperitoneal (IP) administration of the full benzodiazepine agonist loprazolam (1, 10 mg/kg); the partial agonist Ro 17-1812 (1, 10 mg/kg); the benzodiazepine receptor antagonist flumazenil (10, 20 mg/kg); the benzodiazepine inverse agonists Ro 15-4513 (1, 3, 10 mg/kg) and Ro 19-4603 (0.03, 0.1, 0.3 mg/kg) and the beta-carboline inverse agonists FG 7142 (10, 30 mg/kg) and DMCM (1, 3, 10 mg/kg) were investigated in three strains of mice. TO mice were less sensitive than CBA/cA and DBA/2 mice, since only loprazolam and the partial and full beta-carboline inverse agonists FG 7142 and DMCM lowered body temperature in these animals. CBA/cA mice were particularly sensitive to the hypothermic effects of loprazolam and Ro 17-1812, and also responded to the beta-carboline but not the benzo diazepine inverse agonists. In contrast, DBA/2 mice responded with moderate hypothermia to loprazolam, Ro 17-1812, and to the partial inverse agonist Ro 15-4513, and exhibited marked hypothermia in response to the more efficacious benzodiazepine inverse agonist Ro 19-4603 and to FG 7142 and DMCM. Flumazenil did not alter body temperature. DBA/2 mice were also more sensitive to the convulsant activity of inverse agonists than TO mice. CBA/cA mice exhibited enhanced sensitivity to the convulsant, but not the hypothermic, effects of Ro 19-4603, showing dissociation of these responses. The mechanisms underlying the genetic differences in sensitivity of mice to the hypothermic and convulsant action of the different ligands are unknown and warrant further investigation.
Reckitt & Colman Psychopharmacology Unit, Department of Pharmacology, School of Medical Sciences, Bristol, UK.
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Jackson
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Nutt
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D001665:Binding Sites; D001831:Body Temperature / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D007035:Hypothermia / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011963:Receptors, GABA-A / Q000187:drug effects*; D012680:Sensitivity and Specificity; D013045:Species Specificity
D014151:Anti-Anxiety Agents; D002243:Carbolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines