Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible antioxidant mechanisms

1. Tardive dyskinesia (TD), a syndrome of potentially irreversible, involuntary hyperkinetic disorder occurring in 20 - 40% of the patient population undergoing chronic neuroleptic treatment is a major limitation of neuroleptic therapy. 2. Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. 3. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. 4. All the antipsychotics were administered i.p. once daily for 21 days, whereas carvedilol (also i.p.) was administered twice daily. Rats chronically treated with haloperidol (1.0 mg kg(-1)) or chlorpromazine (5 mg kg(-1)) but not clozapine (2 mg kg(-1)) significantly developed vacuous chewing movements and tongue protrusions. Carvedilol dose dependently (0.5 - 2 mg kg(-1)) reduced the haloperidol or chlorpromazine-induced vacuous chewing movements and tongue protrusions. 5. Biochemical analysis revealed that chronic haloperidol or chlorpromazine but not clozapine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the forebrains of rats. Chronic haloperidol or chlorpromazine but not clozapine treated rats showed decreased forebrain levels of antioxidant defence enzymes, superoxide dismutase (SOD) and catalase. 6. Co-administration of carvedilol (0.5-2 mg kg(-1)) significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic haloperidol or chlorpromazine treatment. Co-administration of carvedilol (1-2 mg kg(-1)) significantly reversed the haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels in rats. However, lower dose of carvedilol (0.5 mg kg(-1)) failed to reverse chronic haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels. 7. The major findings of the present study suggest that oxidative stress might play a significant role in neuroleptic-induced orofacial dyskinesia. In conclusion, carvedilol could be a useful drug for the treatment of neuroleptic-induced orofacial dyskinesia.