Role of nigral NFkappaB p50 and p65 subunit expression in haloperidol-induced neurotoxicity and stereotyped behavior in rats

Abstract

Long-term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia (TD) characterized by repetitive involuntary movements, involving the mouth, face and tongue. TD generally persists after haloperidol withdrawal indicating long lasting changes in brain function that are no longer related to the presence of the drug. The precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. Haloperidol has been shown to induce the expression of the transcription factor nuclear factor-kappaB (NFkappaB). NFkappaB resembles a heterodimer protein composed of a 50 and a 65 kDa subunits and the role of the NFkappaB subunits on haloperidol-induced toxicity remains still unknown. The aim of the present study is to investigate the role of the p65 and p50 subunits of NFkappaB on the toxicity induced by chronic haloperidol administration in an experimental model of TD. Rats were treated for 21 days with: haloperidol (1mg/kg), clozapine (1mg/kg) or saline. Apomorphine-induced stereotyped behavior was evaluated. Striatal expression of the dopamine transporter (DAT) and the nigral expression of the NFkappaB p65 and p50 subunits were measured by Western Blot. Haloperidol, but not clozapine, increased stereotyped behavior associated to a decreased striatal DAT expression (p<0.01). Haloperidol did not modify the nigral expression of the p65 subunit whereas clozapine decreased it (p<0.01). Both drugs induced a significant decrease in the nigral expression of the NFkappaB p50 (p<0.05 and p<0.01, respectively). The decrease in nigral expression of the p50 subunit may increase the vulnerability of the dopaminergic neurons to a possible neurotoxic effect of p65 subunits in the haloperidol-treated rats.