Chronic haloperidol-induced alterations in pallidal GABA and striatal D-1-mediated dopamine turnover as measured by dual probe microdialysis in rats

Using dual probe microdialysis, assessment of extracellular neurotransmitte r levels in the corpus striatum and globus pallidus was performed in ovarie ctomized and gonadally intact female, Sprague-Dawley rats following chronic (24 weeks) oral haloperidol administration. Vacuous chewing movements, an animal analog of orofacial dyskinesia, were also recorded at several time p oints during haloperidol administration and throughout the dialysis samplin g session. Basal GABA levels were significantly elevated in the globus pall idus of haloperidol-treated rats compared with vehicle animals. Injection o f the dopamine D-1 agonist dihydrexidine (3 mg/kg, s.c.) decreased striatal dopamine levels in both vehicle and haloperidol-treated rats, with a large r decrease seen in haloperidol-treated rats. Furthermore, dihydrexidine red uced striatal 3.4-dihydroxyphenylacetic acid and homovanillic acid levels o nly in haloperidol-treated rats. Gonadal status had no effect on any neuroc hemical measure. Vacuous chewing movements were significantly elevated in h aloperidol-treated groups by the sixth week of treatment, with higher count s seen in gonadally intact rats. Vacuous chewing movements were significant ly elevated above baseline in all groups following dihydrexidine, with no d ifferential effect of prior haloperidol treatment or gonadal status. These results indicate a tonic increase in pallidal GABA levels and a hyper sensitivity of D-1-mediated striatal dopamine and dopamine metabolite decre ases following chronic haloperidol treatment. While not found to be correla ted with neurochemical measures, the heightened vacuous chewing movements i n gonadally intact vs ovariectomized rats may serve as a model of hormone-m ediated differences in neuroleptic-induced oral dyskinesia. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.