title: Differential nigral expression of Bcl-2 protein family in chronically haloperidol and clozapine-treated rats: role in neurotoxicity and stereotyped behavior.
abstract: 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<0.01, respectively). Neither treatment modified bcx(L) 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.
authors.affiliation: Laboratori de Neurologia Experimental, Fundació Clínic-Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Saldaña
authors.forename: M
authors.initials: M
authors.lastname: Bonastre
authors.forename: E
authors.initials: E
authors.lastname: Aguilar
authors.forename: C
authors.initials: C
authors.lastname: Marin
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D015153:Blotting, Western; D003024:Clozapine / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006220:Haloperidol / Q000633:toxicity*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000523:psychology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D014150:Antipsychotic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003024:Clozapine; D006220:Haloperidol