Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment

The irreversible nature of haloperidol-induced tardive dyskinesia suggests a neurotoxic etiology, although the causes are unknown. Since nitric oxide demonstrates neurotoxic as well as neuroprotectant properties, and antipsychotics can inhibit nitric oxide (NO) synthase in vitro, this study investigates the NO-cCMP pathway as a pre-determining factor in chronic haloperidol-associated dyskinesia in rats. Sprague-Dawley rats were administered either water, oral haloperidol (0.25 mg/kg per day po), the guanylyl cyclase-nNOS inhibitor, methylene blue (MB; 5 mg/kg per day ip) or haloperidol plus MB for 3 weeks. In a second protocol, rats received water or haloperidol orally for 17 weeks, followed by 3 weeks withdrawal. Either saline tip) or MB tip) was administered for 3 weeks prior to haloperidol withdrawal. Vacous chewing movements (VCMs) were continuously monitored, followed by the determination of serum nitrogen oxides (NOx) and striatal cGMP at week 20. Chronic haloperidol engendered significant VCMs, with acute withdrawal resulting in significantly reduced plasma NOx and striatal cGMP. Furthermore, NOx and cGMP suppression was amplified by pre-withdrawal MB administration. Sub-acute haloperidol similarly induced incremental VCMs, but without effect on NOx or cGMP. However, haloperidol plus MB also induced significantly greater VCMs with decreased cGMP compared to haloperidol alone. Thus, NOx-cGMP inhibition persists pronounced after long-term haloperidol treatment and withdrawal. MB potentiation of these effects suggests that haloperidol inhibits a NO-dependent neuro-protective response to oxidative stress in the striatum that may pre-determine TD development. (C) 2000 Elsevier Science B.V. All rights reserved.