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 antipsyc hotics can inhibit nitric oxide (NO) synthase in vitro, this study investig ates the NO-cCMP pathway as a pre-determining factor in chronic haloperidol -associated dyskinesia in rats. Sprague-Dawley rats were administered eithe r water, oral haloperidol (0.25 mg/kg per day po), the guanylyl cyclase-nNO S 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 oral ly for 17 weeks, followed by 3 weeks withdrawal. Either saline tip) or MB t ip) was administered for 3 weeks prior to haloperidol withdrawal. Vacous ch ewing movements (VCMs) were continuously monitored, followed by the determi nation of serum nitrogen oxides (NOx) and striatal cGMP at week 20. Chronic haloperidol engendered significant VCMs, with acute withdrawal resulting i n significantly reduced plasma NOx and striatal cGMP. Furthermore, NOx and cGMP suppression was amplified by pre-withdrawal MB administration. Sub-acu te haloperidol similarly induced incremental VCMs, but without effect on NO x or cGMP. However, haloperidol plus MB also induced significantly greater VCMs with decreased cGMP compared to haloperidol alone. Thus, NOx-cGMP inhi bition persists pronounced after long-term haloperidol treatment and withdr awal. 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.