Abstract
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.
Similar content being viewed by others
REFERENCES
APA Task Force on Tardive Dyskinesia (1992). Tardive dyskinesia-a task force report of the American Psychiatric Association. Washington, DC: APA Press.
Arancio, O., Kandel, E.R., and Hawkins, R.D. (1995). Activity-dependent long-term enhancement of transmitter release by synaptic 3′5′-cyclic GMP in cultured hippocampal neurons. Nature 376:74-80.
Avent, K.M. Usuki, E., Eyles, D.W., Keeve, R., Van der Schyf, C.J., Castagnoli, N, and Pond, S.M. (1996). Haloperidol and its tetrahydropyridine derivative (HPTP) are metabolized to potentially neurotoxic pyridium species in the baboon. Life Sci. 59:1473-1482; 1996.
Behl, C., Lezoualc'h, F., Widmann, M., Rupprecht, R., and Holsboer, F. (1996). Oxidative stress-resistant cells are protected against haloperidol toxicity. Brain Res. 717:193-195.
Borda, T., Genaro, A.M., and Cremaschi, G. (1999). Haloperidol effect on intracellular signals system coupled to alpha-1 adrenergic receptor in rat cerebral cortex. Cell Signal 11:293-300.
Calabresi, P., Gubellini, P., Centonze, D., Sancesario, G., Morello, M., and Giorgi M., Pisa (1999). A critical role for the nitric oxide/cGMP pathway in corticostriatal long-term depression. J. Neurosci. 19:2489-2499.
Cohen, B.M., Tsuneizumi, T., Balsessarini, R.J., Campbell, A., and Babb, S. (1992). Differences between antipsychotic drugs in persistence of brain levels and behavioral effects. Psychopharmacol 108:338-344.
Colasanti, M., and Suzuki, H. (2000). The dual personality of NO. Trends Pharmacol. Sci. 21:249-252.
Cortas, N.K., and Wakid, N.W. (1990). Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 36:1440-1443.
Del Bel, E.A., and Guimaraes, F.S. (2000). Sub-chronic inhibition of nitric oxide synthesis modifies haloperidol-induced catalepsy and the number of NADPH-diaphorase neurones in mice. Psychopharmacol 147:356-361.
Del-Bel, E.A., Da Silva, C.A., and Guimaraes, F.S. (1998). Catalepsy induced by nitric oxide synthase inhibitors. Gen Pharmacol 30:245-248.
Egan, M.F., Ferguson, J.N., and Hyde, T.M. (1995). Effects of chronic naloxone administration on vacous chewing movements and catalepsy in rats treated with long-term haloperidol decanoate. Brain Res. Bull. 38:355-363.
Eroglu, L., and Caglayan, B. (1997). Anxiolytic and antidepressant properties of methylene blue in animal models. Pharmacol. Res. 36:381-385.
Gibbon, C.J., and Swanepoel, C.R. (Eds) (1997). South African Medicines Formulary, 4th Edition, Medical Association of South Africa Publications, p371.
Gordge, M.P. (1998). How cytotoxic is nitric oxide? Exp. Nephrol. 6:12-16.
Grimm, J.W., Kruzich, P.J., and See, R.E. (1998). Emergence of oral and locomotor activity in chronic haloperidol-treated rats following cortical N-methyl-D aspartate stimulation. Pharmacol. Biochem. Behav. 60:67-173.
Guevara-Guzman, R., Emson, P.C., and Kendrick, K.M. (1994). Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J. Neurochem. 62:807-810.
Harvey, B.H., and Bester, A. (2000). Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment. Behav. Brain Res. 111:203-211.
Harvey, B.H., Carstens, M.E., and Taljaard, J.J.F. (1994). Evidence that lithium induces a glutamate-nitric oxide-mediated response in rat brain. Neurochem Res. 19:469-474.
Harvey,B.H., Stein, D.J., and Emsley, R.A. (1999). The new generation antipsychotics: Integrating the neuropathology and pharmacology of schizophrenia. S. Afr. Med. J. 89:661-672.
Harvey, B.H. (1996). Affective disorders and nitric oxide: A role in pathways to relapse and refractoriness? Hum. Psychopharmacol. 11:309-319.
Hirsch, E.C., and Hunot, S. (2000). Nitric oxide, glial cells and neuronal degeneration in parkinsonism. Trends Pharmacol. Sci. 21:163-165.
Hu, J., Lee, J.H., and El-Fakahany, E. (1994). Inhibition of neuronal nitric oxide synthase by antipsychotic drugs. Psychopharmacol 114:161-166.
Hubbard, J.W., Ganes, D., and Midha, K.K. (1987). Prolonger pharmacologic activity of neuroleptic drugs. Arch Gen. Psychiatry 44:99-100.
Kanner, J., Harel, S., and Granit, R. (1992). Nitric oxide, an inhibitor of lipid peroxidation by lipoxygenase, cyclooxygenase and hemoglobin. Lipids 27:46-49.
Kornhuber, J., Schultz, A., Wiltfang, J., Meineke, I., Gleiter, C.H., Zochling, R., Boissl, K.W., Leblhuber, F., and Riederer, P. (1999). Persistance of haloperidol in human brain tissue. Am. J. Psychiatry 156:885-890.
Lipton, S.A., Choi, Y.B., Pan, Z.H., Lei, S.Z., Chen, H.S.V., Sucher, N.J., Loscalzo, J., Singel, D.J., and Stamler, J.S. (1993). A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626-632.
Masaki, E., and Kondo, I. (1999). Methylene blue, a soluble guanylyl cyclase inhibitor reduces the sevoflurane minimal alveolar anaesthetic concentration and decreases brain cyclic GMP content in rats. Anaesthesia and Analgesia 89:484-489.
Moore, P.K., and Handy, R.L.C. (1997). Selective inhibitors of neuronal nitric oxide synthase — is no NOS really good NOS for the nervous system? Tr. Pharmacol. Sci. 18:204-211.
Nagase, S., Takemura, K., Ueda, A., Hirayama, A., Aoyagi, K., Kondoh, M., and Koyama, A. (1997). A novel non-enzymatic pathway for the generation of nitric oxide by reaction of hydrogen peroxide and D or L-arginine. Biochem. Biophys. Res. Comm. 233:150-153.
Rosengarten, H., Schweitzer, J.W., and Friedhoff, A.J. (1999). The effect of novel antipsychotics in rat oral dyskinesia. Prog. Neuro-Psychopharmacol Biol. Psychiatry 23:1389-1404.
SAS Institute (1988). SAS Procedures Guide Release, 6.03 Edition, SAS Institute Inc, NC, U.S.A.
Suto, T., Losonczy, G., Qiu, C., Hill, C., Samsell, L., Ruby,J., Charon, N., Venuto, R., and Baylis, C. (1995). Acute changes in urinary excretion of nitrite and nitrate do not necessarily predict renal vascular NO production. Kidney Int. 48:1272-1277.
Tsai, G., Goff, D.C., Chang, R.W., Flood, J., Baer, L., and Coyle, J.T. (1998). Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia. Am. J. Psychiatry 155:1207-1213.
Volke, V., Wegener, G., Vasar, E., and Rosenberg, R. (1999). Methylene blue inhibits hippocampal nitric oxide synthase in vivo. Brain Research 826:303-305
Wink, D.A., Vodovotz, Y., Grisham, M.B., DeGraff, W., Cook, J.C., Pacelli, R., Krishna, M., and Mitchell, J.B. (1999). Antioxidant effects of nitric oxide. In: Methods in Enzymlogy 301:413-424.
Yokoyama, H., Kasai, N., Ueda, Y., Niwa, R., Konaka, R., Mori, N., Tsuchihashi, N., Matsue, T., Ohya-Nishiguchi, H., and Kamada, H. (1998). In vivo analysis of hydrogen peroxide and lipid radicals in the striatum of rats under long-term administration of a neuroleptic. Free Rad. Biol. Med. 24:1056-1060.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bester, AM., Harvey, B.H. Early Suppression of Striatal Cyclic GMP May Pre-Determine the Induction and Severity of Chronic Haloperidol-Induced Vacous Chewing Movements. Metab Brain Dis 15, 275–285 (2000). https://doi.org/10.1023/A:1011171124603
Issue Date:
DOI: https://doi.org/10.1023/A:1011171124603