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Effects of Ca2+ channel blockers on physical dependence on diazepam in mice
H Mizoguchi1, M Yoshiike, T Suzuki
1Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Abstract:
The effects of Ca2+ channel blockers on the development of physical dependence on diazepam were examined in mice. Co-administration of flunarizine (T-type Ca2+ channel sensitive blocker), but not of either nifedipine or diltiazem (L-type Ca2+ channel sensitive blockers), with diazepam significantly suppressed the hypersensitivity to FG 7142 following chronic treatment with diazepam. The hypersensitivity to FG 7142 may reflect benzodiazepine withdrawal convulsions. These results suggest that flunarizine, but not nifedipine or diltiazem, may suppress the development of physical dependence on diazepam, and that T-type Ca2+ channels in the brain, rather than L-type Ca2+ channels, may be involved in the development of physical dependence on diazepam.
Insights
Flunarizine, a T-type calcium channel blocker, suppressed physical dependence on diazepam in mice, unlike L-type blockers. This suggests T-type channels are key in developing diazepam dependence.
Area of Science:
- Neuropharmacology
- Calcium Channel Blockers
- Drug Dependence
Background:
- Physical dependence on benzodiazepines like diazepam is a significant clinical concern.
- Calcium channels play a role in neuronal excitability and neurotransmitter release, potentially influencing drug dependence.
- T-type and L-type calcium channels have distinct roles in the central nervous system.
Purpose of the Study:
- To investigate the role of different calcium channel blockers in the development of physical dependence on diazepam.
- To determine if T-type or L-type calcium channels are more involved in diazepam dependence.
Main Methods:
- Mice were chronically treated with diazepam.
- Co-administration of diazepam with flunarizine (T-type blocker), nifedipine, or diltiazem (L-type blockers) was performed.
- Hypersensitivity to FG 7142, indicative of withdrawal, was assessed.
Main Results:
- Flunarizine significantly suppressed FG 7142-induced hypersensitivity in diazepam-treated mice.
- Nifedipine and diltiazem did not suppress this hypersensitivity.
- These findings suggest flunarizine mitigates diazepam withdrawal symptoms.
Conclusions:
- T-type calcium channels, targeted by flunarizine, appear to be involved in the development of physical dependence on diazepam.
- L-type calcium channels, targeted by nifedipine and diltiazem, do not seem to play a significant role in this process.
- Flunarizine may have therapeutic potential in managing benzodiazepine dependence.