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Detection of dopaminergic supersensitivity induced by neuroleptic drugs in mice
Abstract:
We investigated the sensitivity of dopaminergic receptors in mice fed neuroleptic drugs. Groups of mice were fed daily doses of approximately 10% of the LD50 of haloperidol, clozapine, chlorpromazine, trifluoperazine, or thioridazine for 2, 4, or 8 weeks. Four days after withdrawal of the neuroleptics, thozalinone, a dopaminergic stimulant, was given ip at 50 mg/kg to elicit gnawing behavior. Increased gnawing behavior was seen in mice after 4 weeks of administration of haloperidol (80%), chlorpromazine (80%), trifluoperazine (100%), and thioridazine (100%) compared with control values (50%). The gnawing behavior in mice treated with clozapine was the same as that for control mice. Levels of gnawing behavior after 2 or 8 weeks of administration of the same drugs were lower than those reported above. Alcohol increased the thozalinone-elicited gnawing behavior 2 weeks after dosing with haloperidol and trifluoperazine. After 4 and 8 weeks of administration of the drugs, the locomotor activity of mice was increased from 29-113% (4 weeks) to 37-110% (8 weeks) compared with controls. The study of neuroleptic drug-induced dopaminergic supersensitivity may serve as a method for detection of tardive dyskinesia-inducing effects.
Insights
Neuroleptic drugs like haloperidol and trifluoperazine increased dopaminergic receptor sensitivity in mice, leading to heightened gnawing behavior. This finding may help detect tardive dyskinesia risks.
Area of Science:
- Neuropharmacology
- Behavioral Neuroscience
Background:
- Neuroleptic drugs are widely used antipsychotics that target dopamine receptors.
- Understanding drug-induced changes in dopaminergic system sensitivity is crucial for predicting side effects.
- Tardive dyskinesia is a serious neurological disorder associated with long-term neuroleptic use.
Purpose of the Study:
- To investigate the impact of chronic neuroleptic administration on dopaminergic receptor sensitivity in mice.
- To evaluate the potential of neuroleptic-induced behaviors as a biomarker for tardive dyskinesia.
Main Methods:
- Mice were administered daily doses of haloperidol, clozapine, chlorpromazine, trifluoperazine, or thioridazine (10% LD50) for 2, 4, or 8 weeks.
- After drug withdrawal, thozalinone (a dopaminergic stimulant) was administered to induce gnawing behavior.
- Locomotor activity was measured after 4 and 8 weeks of drug administration.
Main Results:
- Significant increases in thozalinone-elicited gnawing behavior were observed after 4 weeks of haloperidol, chlorpromazine, trifluoperazine, and thioridazine treatment.
- Clozapine did not alter gnawing behavior compared to controls.
- Locomotor activity was significantly increased after 4 and 8 weeks of drug administration.
Conclusions:
- Chronic administration of certain neuroleptics induces dopaminergic supersensitivity in mice, evidenced by increased gnawing behavior.
- This animal model may serve as a valuable tool for predicting the tardive dyskinesia-inducing potential of neuroleptic medications.