Differential striatal levels of TNF-alpha, NFkappaB p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment: role in orofacial dyskinesia

Abstract

Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-alpha and NFkappaB on the toxicity induced by chronic haloperidol administration in an animal model of tardive dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-alpha and NFkappaB p65 subunit were measured by ELISA technique. Haloperidol increased orofacial dyskinetic movements and total locomotor activity (on day 22) (P<or=0.05). Clozapine and risperidone also increased the orofacial dyskinetic movements but that significantly less than haloperidol (P<or=0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-alpha and NFkappaB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-alpha and NFkappaB p65 subunit (P<or=0.05). The present study suggests the impossible involvement of striatal TNF-alpha and NFkappaB p65 subunit in haloperidol-induced orofacial dyskinesia in rats, an animal model for human tardive dyskinesia.