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Tolerance to midazolam's anxiolytic effects after short-term nicotine treatment
E E Irvine1, S Cheeta, C Lovelock
1Psychopharmacology Research Unit, Centre for Neuroscience, GKT School of Biomedical Sciences, King's College London, Hodgkin Building, Guy's Campus, London SE1 1UL, UK.
Abstract:
In the social interaction test of anxiety, microinjections of midazolam (2-8 microg) into the dorsal hippocampus or dorsal raphé nucleus significantly increased the time spent in active social interaction, without changing locomotor activity, thus indicating specific anxiolytic effects. However, tolerance 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 period of treatment with a low dose of nicotine, which contrasts with the more slowly developing tolerance (about 3 weeks) that develops after benzodiazepine treatment. Following 6 days of nicotine treatment there was a significant reduction in [(3)H]flunitrazepam binding at 2 and 10 nM in the hippocampus, but no change in the midbrain. The decrease in benzodiazepine binding could explain tolerance to the effects of midazolam when administered to the dorsal hippocampus, but other mechanisms, such as indirect effects on the serotonergic (5-HT) system, might be involved in tolerance to the effects of dorsal raphé nucleus administration.
Insights
Nicotine rapidly induces tolerance to the anxiolytic effects of midazolam in rats, impacting benzodiazepine binding in the hippocampus. This contrasts with slower tolerance development from benzodiazepine treatment alone.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Midazolam exhibits anxiolytic effects by acting on the dorsal hippocampus and dorsal raphe nucleus.
- Nicotine is known to influence various neurotransmitter systems, including those involved in anxiety and tolerance.
- Understanding drug tolerance mechanisms is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the development of tolerance to the anxiolytic effects of midazolam following nicotine pre-treatment.
- To examine the impact of nicotine on benzodiazepine receptor binding in specific brain regions.
- To explore potential mechanisms underlying cross-tolerance between nicotine and midazolam.
Main Methods:
- Social interaction test in rats to assess anxiety-related behavior.
- Microinjections of midazolam into the dorsal hippocampus and dorsal raphe nucleus.
- Subcutaneous administration of (-)-nicotine for 6 days.
- Measurement of [(3)H]flunitrazepam binding in hippocampal and midbrain tissue.
Main Results:
- Midazolam administration increased social interaction time, indicating anxiolytic effects.
- Nicotine pre-treatment led to rapid tolerance to midazolam's anxiolytic effects.
- A significant reduction in benzodiazepine binding was observed in the hippocampus after nicotine treatment.
- No changes in benzodiazepine binding were found in the midbrain.
Conclusions:
- Rapid cross-tolerance to midazolam's anxiolytic effects develops with short-term nicotine treatment.
- Reduced hippocampal benzodiazepine binding may explain tolerance to midazolam in this region.
- Alternative mechanisms, potentially involving the serotonergic system, might contribute to tolerance at the dorsal raphe nucleus.