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Elevated neuronal nitric oxide synthase expression in chronic haloperidol-treated rats.
Yuen-Sum Lau1, Elizabeth Petroske, Gloria E Meredith
1Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes St. (M3-111), Kansas City, MO, USA. lauy@umkc.edu
Neuropharmacology
|October 24, 2003
Summary
Long-term haloperidol use increases nitric oxide synthase (NOS) in rat brains, potentially contributing to tardive dyskinesia. This neuroleptic effect involves dopamine D2 receptors and behavioral changes.
Area of Science:
- Neuroscience
- Pharmacology
- Neurobiology
Background:
- Long-term neuroleptic drug use, like haloperidol, can cause tardive dyskinesia, linked to dopamine D2 receptor supersensitivity.
- Emerging evidence suggests nitric oxide synthase (NOS) involvement in dopaminergic supersensitivity, but its role in neuroleptic-induced changes in the basal ganglia is unclear.
Purpose of the Study:
- To investigate the chronic effects of haloperidol on neuronal nitric oxide synthase (nNOS) expression in the rat basal ganglia.
- To explore the relationship between nNOS, dopamine D2 receptors, and behavioral changes following chronic haloperidol administration.
Main Methods:
- Rats were administered haloperidol (1 mg/kg) or saline daily for 21 days.
- Post-treatment, NOS activity, nNOS mRNA and protein expression were assessed in striatum and nucleus accumbens using in situ hybridization, Western blot, and immunohistochemistry.
- Dopamine D2 receptor density, calmodulin kinase II activity, and behavioral changes (locomotor activity, stereotypy) were evaluated.
Main Results:
- Haloperidol treatment significantly increased NOS activity, nNOS mRNA, and protein levels in the striatum but not the nucleus accumbens.
- These changes correlated with increased striatal dopamine D2 receptor sites, elevated calmodulin kinase II activity, and enhanced locomotor and stereotypy behaviors.
- The effects of haloperidol on the NOS system were selective to the neostriatum.
Conclusions:
- Chronic haloperidol administration impacts the nNOS system in the rat striatum, suggesting its involvement in neuroleptic-induced dopaminergic supersensitivity.
- A significant interplay exists between nNOS, dopamine D2 receptors, and the calmodulin system in mediating the behavioral effects of chronic neuroleptic treatment.
- This study highlights a potential toxic effect of chronic haloperidol on the NOS system, specifically within the neostriatum.