Haloperidol persists in brain tissue long after discontinuation while
haloperidol-induced
tardive dyskinesia often worsens after withdrawal of the
drug. The mechanism of
haloperidol-associated
tardive dyskinesia is unknown, although neurotoxic pathways are suspected.
Nitric oxide (
NO) synthase (NOS) inhibitors exacerbate
haloperidol-induced
catalepsy, while
haloperidol itself is a potent neuronal NOS inhibitor in vitro. Since NO and cGMP are involved in striatal neural plasticity, this study investigates a possible relation between cGMP and extrapyramidal symptoms as early predictors of
haloperidol-associated
tardive dyskinesia. Sprague-Dawley rats were administered either water or oral
haloperidol (0.25 mg/kg/d p.o.) for 17 weeks, followed by 3 weeks withdrawal. Saline (i.p.) or the nNOS/
guanylate cyclase inhibitor,
methylene blue (5 mg/kg/d i.p.), were co-administered with
haloperidol for the first three weeks of treatment. Vacous chewing movements (VCM's) were continuously monitored, followed by the determination of striatal cGMP and peripheral serum
nitrogen oxide (NOx) levels. Chronic
haloperidol engendered significant VCM's, with acute withdrawal associated with significantly reduced striatal cGMP levels as well as reduced serum NOx. Furthermore, suppressed cGMP levels were maintained and VCM's were significantly worse after early administration of
methylene blue to the chronic
haloperidol group. However, serum NOx was unchanged from control. We conclude that the central effects of chronic
haloperidol on striatal NO-cGMP function persist for up to 3 weeks post-withdrawal. Moreover, suppression of striatal cGMP constitutes an early neuronal insult that determines the presence and intensity of
haloperidol-associated motor dysfunction.