Differential nigral expression of Bcl-2 protein family in chronically haloperidol and clozapine-treated rats:: Role in neurotoxicity and stereotyped behavior

Tardive dyskinesia (TD) is a syndrome characterized by repetitive involuntary movements induced by the administration of typical neuroleptics such as haloperidol. TD generally persists after haloperidol withdrawal indicating that haloperidol produces long-lasting changes in brain function. In contrast to the typicals, atypical medications, such as clozapine, have very low rates of TD. The mechanisms underlying drug-induced TD are poorly understood. We have investigated the role of nigral expression of the bcl-2 family of proteins on haloperidol-induced neurotoxicity. Rats were treated for 21 days with the following drugs: haloperidol (1 mg/kg), clozapine (1 mg/kg) or saline. After a 3-day washout period, apomorphine-induced stereotyped behavior was scored. Western blotting was performed to evaluate the nigral expression of the dopamine transporter (DAT), bax, bcl-X-L and bcl-2 proteins. Haloperidol administration, but not clozapine, increased stereotyped behavior (p < 0.01) in association with a decrease in striatal DAT expression (p < 0.05). Haloperidol and clozapine treatment significantly decreased the nigral expression of bax (p < 0.05, p < 0.0 1, respectively). Neither treatment modified bCXL expression. Haloperidol increased (p < 0.05), whereas clozapine did not significantly modify the nigral expression of bcl-2. Our results suggest that the increase in bcl-2 expression in the haloperidol-treated animals might be a compensatory mechanism that may reflect cellular damage induced by haloperidol in the dopaminergic neurons in the pars compacta of the substantia nigra. (c) 2006 Published by Elsevier Inc.