Haloperidol-induced dyskinesia is associated with striatal NO synthase suppression: reversal with olanzapine.
The underlying pathophysiological basis of tardive dyskinesia (TD) remains speculative. Haloperidol (HP) inhibits neuronal nitric oxide (NO) synthase (NOS) activity in vitro, but has not to date been studied in an intact animal model. Recent animal studies have found that extrapyramidal dysfunction evoked by chronic HP is associated with suppression of striatal cyclic guanosine monophosphate (cGMP), as well as plasma nitrogen oxides. Striatal dopamine (DA) is central to motor control, while NO plays an important neuroregulatory role in striatal DA function. Recent case reports suggest that atypical antipsychotics, such as olanzapine (OLZ), may be effective in reversing TD. Here, rats treated with HP (1.5 mg/kg per day p.o.) for 28 days developed significant vacuous chewing movements (VCMs) together with significant suppression of striatal NOS activity. Acute challenge with OLZ (1 and 2 mg/kg i.p.) significantly reversed both HP-induced VCMs and suppression of striatal NOS activity. Therefore TD may involve attenuation of NO-mediated neuromodulation in the striatum. Reversal of VCMs and NOS suppression with OLZ suggests that disinhibition of striatal NOS activity may underlie the clinical benefit of OLZ in TD.
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School of Pharmacy (Pharmacology), Faculty of Health Sciences, University of Potchefstroom, North West Province, South Africa 2520.
Harvey
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D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000523:psychology; D006220:Haloperidol / Q000009:adverse effects*; D008297:Male; D008409:Mastication; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077152:Olanzapine; D010890:Pirenzepine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D009569:Nitric Oxide; D010890:Pirenzepine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D006220:Haloperidol; D000077152:Olanzapine