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Midazolam withdrawal and discriminative motor control: effects of FG 7142 and Ro 15-1788
1Department of Psychology-Busch, Rutgers University, New Brunswick, NJ 08903.
Abstract:
Rats chronically drank either water or midazolam solution (0.1 mg/ml) in daily, 3-h schedule-induced polydipsia sessions and were evaluated in daily motor control sessions after polydipsia when midazolam metabolite levels had fallen to zero (withdrawal). Under midazolam polydipsia, animals orally self-administered between 21 and 38 mg/kg daily. The effect of acute drug administration [midazolam (0.75-3 mg/kg, SC), FG 7142 (1-8 mg/kg, IP), Ro 15-1788 (10-20 mg/kg, IP)] on motor control performance was similar after either chronic water or midazolam polydipsia. Thus chronic, oral midazolam self-administration did not lead to tolerance to the motor impairment produced by SC midazolam, nor did the daily discontinuation lead to impaired motor performance, nor had these performances, which occurred after daily elevated midazolam metabolite levels had reached zero (withdrawal), become sensitized to the effects of either the benzodiazepine inverse agonist FG 7142 or the agonist Ro 15-1788.
Insights
Chronic oral midazolam self-administration in rats did not cause tolerance to its motor impairment effects. Withdrawal from daily midazolam did not impair motor control or sensitize rats to other benzodiazepine-related drugs.
Area of Science:
- Neuropharmacology
- Behavioral Neuroscience
- Drug Addiction Research
Background:
- Benzodiazepines, like midazolam, are commonly used for sedation and anxiety.
- Understanding tolerance and withdrawal effects is crucial for managing drug dependence.
- Schedule-induced polydipsia is a model to study chronic drug self-administration.
Purpose of the Study:
- To investigate tolerance to midazolam's motor impairment after chronic oral self-administration.
- To assess motor control performance during withdrawal from daily midazolam.
- To examine sensitization to benzodiazepine agonists and inverse agonists after chronic midazolam exposure.
Main Methods:
- Rats underwent daily schedule-induced polydipsia sessions, self-administering midazolam orally.
- Motor control was assessed after drug administration and during withdrawal periods.
- Acute administration of midazolam, FG 7142 (inverse agonist), and Ro 15-1788 (agonist) was tested.
Main Results:
- Chronic midazolam self-administration did not induce tolerance to acute midazolam-induced motor impairment.
- Motor performance was not impaired during withdrawal (when metabolite levels were zero).
- Withdrawal did not lead to sensitization to the effects of FG 7142 or Ro 15-1788.
Conclusions:
- Oral midazolam self-administration in rats does not lead to tolerance in motor control.
- Daily midazolam discontinuation does not result in motor deficits or altered sensitivity to benzodiazepine receptor ligands.