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 behavior s were studied in rats using an open-field and an elevated plus-maze. Acute and chronic doses of the benzodiazepine diazepam without and in combinatio n with the GABA uptake inhibitor SKF-89976A were investigated. 2. Fifty-six male rats of the strain PVG/OlaHsd (PVG; 180-200g body wt) wer e used to assess the influence of the benzodiazepine binding-site to the de velopment of tolerance. Rats were divided into six groups: The first receiv ing 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 g roup received diazepam (10.0 mg/kg) daily and acutely SKF-89976A (15.0 mg/k g) plus diazepam and the fifth and sixth group received acute treatment wit h diazepam (2.0 mg/kg) or SKF-89976A (15.0 mg/kg). 3. Under chronic treatment with diazepam the animals became tolerant to acu te doses of diazepam in activity and anxiety-related behaviors. Acute treat ment with SKF-89976A increased exploration. Parameters expressing anxiolyti c-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)-re ceptor is involved in the development of BZ-tolerance.