Antioxidant strategy to counteract the side effects of antipsychotic therapy: an in vivo study in rats

The effects of long-term administration of the dopamine D-2 receptor antagonist haloperidol on Parkinsonian symptoms have been shown to persist after cessation of the drug treatment. In order to determine whether the level of tyrosine hydroxylase could be affected by subchronic administration of haloperidol, we examined tyrosine hydroxylase-positive immunoreactive cells in the substantia nigra after blockade of dopaminergic receptors with this antipsychotic. Three weeks of injections with haloperidol (1.5 mg/kg, i.p.) caused a significant decrease in tyrosine hydroxylase-positive cell counts at 24 h (27%), 5 days (21%) and 2 weeks (10%) after the last administration, an effect that was blocked by concurrent administration of the antioxidant, vitamin C. The level of tyrosine hydroxylase returned to baseline after 4 weeks withdrawal, no change being observed at later time-points. Nissl staining demonstrated that no damage to the cell bodies was observed, suggesting that the decrease in tyrosine hydroxylase-positive cells was not due to dopaminergic cell loss. These results demonstrate a depleting action of a short course of haloperidol on nigral tyrosine hydroxylase that outlasts the period of application by 2-4 weeks. Moreover, the current study has shown the effect of the antioxidant vitamin C in protecting haloperidol effects on tyrosine hydroxylase-immunostaining. (C) 2000 Elsevier Science B.V. All rights reserved.