Behavioral analysis indicates benzodiazepine-tolerance mediated by the benzodiazepine binding-site at the GABA(A)-receptor.
1. GABA(A)-receptor induced changes in locomotion and anxiety-like behaviors were studied in rats using an open-field and an elevated plus-maze. Acute and chronic doses of the benzodiazepine diazepam without and in combination with the GABA uptake inhibitor SKF-89976A were investigated. 2. Fifty-six male rats of the strain PVG/OlaHsd (PVG; 180-200 g body wt) were used to assess the influence of the benzodiazepine binding-site to the development of tolerance. Rats were divided into six groups: The first receiving saline (0.9%), the second and third diazepam (10.0 mg/kg) daily for 23 days with or without an acute challenge of 2.0 mg/kg diazepam. The fourth group received diazepam (10.0 mg/kg) daily and acutely SKF-89976A (15.0 mg/kg) plus diazepam and the fifth and sixth group received acute treatment with diazepam (2.0 mg/kg) or SKF-89976A (15.0 mg/kg). 3. Under chronic treatment with diazepam the animals became tolerant to acute doses of diazepam in activity and anxiety-related behaviors. Acute treatment with SKF-89976A increased exploration. Parameters expressing anxiolytic-like behaviors were increased, too, but not all of them significantly. In diazepam tolerant animals SKF-89976A produced anxiolytic-like behaviors 4. We conclude that the BZ- and not the GABA-binding site at the GABA(A)-receptor is involved in the development of BZ-tolerance.
Schmitt
U
U
Department of Psychiatry, University of Mainz, Germany.
Lüddens
H
H
Hiemke
C
C
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects*; D018682:GABA Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology*
D014151:Anti-Anxiety Agents; D018682:GABA Agents; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D003975:Diazepam