caa a22 4500 475792920 CHVBK 20180406123715.0 cr unu---uuuuu 170329e20001201xx s 000 0 eng 10.1023/A:1011171124603 doi (NATIONALLICENCE)springer-10.1023/A:1011171124603 Early Suppression of Striatal Cyclic GMP May Pre-Determine the Induction and Severity of Chronic Haloperidol-Induced Vacous Chewing Movements [Elektronische Daten] [Ans-Mari Bester, Brian Harvey] 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 (0.25mg/kg/d po) for 17 weeks, followed by 3 weeks withdrawal. Saline (ip) or the nNOS/guanylate cyclase inhibitor, methylene blue (5mg/kg/d ip), 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. Plenum Publishing Corporation, 2000 Haloperidol nationallicence extrapyramidal symptoms nationallicence tardive dyskinesia nationallicence nitric oxide nationallicence cGMP nationallicence methylene blue nationallicence Bester Ans-Mari School of Pharmacy (Pharmacology), Faculty of Health Sciences, University of Potchefstroom, Potchefstroom, 2520, North-West Province, South Africa aut Harvey Brian School of Pharmacy (Pharmacology), Faculty of Health Sciences, University of Potchefstroom, Potchefstroom, 2520, North-West Province, South Africa aut Metabolic Brain Disease Kluwer Academic Publishers-Plenum Publishers 15/4(2000-12-01), 275-285 0885-7490 15:4<275 2000 15 11011 https://doi.org/10.1023/A:1011171124603 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1011171124603 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bester Ans-Mari School of Pharmacy (Pharmacology), Faculty of Health Sciences, University of Potchefstroom, Potchefstroom, 2520, North-West Province, South Africa aut NATIONALLICENCE 700 1- Harvey Brian School of Pharmacy (Pharmacology), Faculty of Health Sciences, University of Potchefstroom, Potchefstroom, 2520, North-West Province, South Africa aut NATIONALLICENCE 773 0- Metabolic Brain Disease Kluwer Academic Publishers-Plenum Publishers 15/4(2000-12-01), 275-285 0885-7490 15:4<275 2000 15 11011 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer