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 neurotransmitter levels in the corpus striatum and globus pallidus was performed in ovariectomized 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 points during haloperidol administration and throughout the dialysis sampling session. Basal GABA levels were significantly elevated in the globus pallidus of haloperidol-treated rats compared with vehicle animals. Injection of the dopamine D(1) agonist dihydrexidine (3mg/kg, s.c.) decreased striatal dopamine levels in both vehicle and haloperidol-treated rats, with a larger decrease seen in haloperidol-treated rats. Furthermore, dihydrexidine reduced striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid levels only in haloperidol-treated rats. Gonadal status had no effect on any neurochemical measure. Vacuous chewing movements were significantly elevated in haloperidol-treated groups by the sixth week of treatment, with higher counts seen in gonadally intact rats. Vacuous chewing movements were significantly elevated above baseline in all groups following dihydrexidine, with no differential effect of prior haloperidol treatment or gonadal status. These results indicate a tonic increase in pallidal GABA levels and a hypersensitivity of D(1)-mediated striatal dopamine and dopamine metabolite decreases following chronic haloperidol treatment. While not found to be correlated with neurochemical measures, the heightened vacuous chewing movements in gonadally intact vs ovariectomized rats may serve as a model of hormone-mediated differences in neuroleptic-induced oral dyskinesia.