Tolerance to midazolam's anxiolytic effects after short-term nicotine treatment

In the social interaction test of anxiety, microinjections of midazolam (2- 8 mug) into the dorsal hippocampus or dorsal raphe nucleus significantly in creased the time spent in active social interaction, without changing locom otor activity, thus indicating specific anxiolytic effects. However, tolera nce developed to these effects in rats that had been pre-treated for 6 days with (-)-nicotine (0.1 mg/kg/day; subcutaneous). Thus, cross-tolerance to the anxiolytic effects of midazolam develops rapidly following a short peri od of treatment with a low dose of nicotine, which contrasts with the more slowly developing tolerance (about 3 weeks) that develops after benzodiazep ine treatment. Following 6 days of nicotine treatment there was a significa nt reduction in [H-3]flunitrazepam binding at 2 and 10 nM in the hippocampu s, but no change in the midbrain. The: decrease in benzodiazepine binding c ould explain tolerance to the effects of midazolam when administered to the dorsal hippocampus, hut other mechanisms, such as indirect effects on the serotonergic (5-HT) system, might be involved in tolerance to the effects o f dorsal raphe nucleus administration. (C) 2001 Elsevier Science Ltd. All r ights reserved.