BACKGROUND: Treatment of schizophrenia's symptoms with typical antipsychotic drugs shows some efficacy, but the induction of extrapyramidal symptoms represents a serious handicap, which considerably limits their usefulness. Recent evidence suggests that Nur77 (nerve growth factor-induced B) and retinoids are involved in biochemical and behavioral effects of antipsychotic drugs associated with striatal functions. METHODS: We evaluated the effect of retinoid ligands on oral dyskinesias (vacuous chewing movements) induced by haloperidol in wild-type and Nur77-deficient mice. RESULTS: Nur77 gene ablation (knockout) or administration of a retinoid antagonist induced vacuous chewing movements and exacerbated those induced by haloperidol, whereas the retinoid agonist docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) reduced them. Both the prodyskinetic effect of the retinoid antagonist and the antidyskinetic effect of docosahexaenoic acid are dependent on the presence of Nur77, since these drugs remained inactive in Nur77 knockout mice. CONCLUSION: These results suggest that nuclear receptors Nur77 and retinoid X receptor are involved in haloperidol-induced dyskinesias and that retinoid agonists may represent a new way to improve typical antipsychotic drug therapy.
BACKGROUND: Treatment of schizophrenia's symptoms with typical antipsychotic drugs shows some efficacy, but the induction of extrapyramidal symptoms represents a serious handicap, which considerably limits their usefulness. Recent evidence suggests that Nur77 (nerve growth factor-induced B) and retinoids are involved in biochemical and behavioral effects of antipsychotic drugs associated with striatal functions. METHODS: We evaluated the effect of retinoid ligands on oral dyskinesias (vacuous chewing movements) induced by haloperidol in wild-type and Nur77-deficient mice. RESULTS:Nur77 gene ablation (knockout) or administration of a retinoid antagonist induced vacuous chewing movements and exacerbated those induced by haloperidol, whereas the retinoid agonist docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) reduced them. Both the prodyskinetic effect of the retinoid antagonist and the antidyskinetic effect of docosahexaenoic acid are dependent on the presence of Nur77, since these drugs remained inactive in Nur77 knockout mice. CONCLUSION: These results suggest that nuclear receptors Nur77 and retinoid X receptor are involved in haloperidol-induced dyskinesias and that retinoid agonists may represent a new way to improve typical antipsychotic drug therapy.
Authors: François Gilbert; Marc Morissette; Michel St-Hilaire; Brigitte Paquet; Claude Rouillard; Thérèse Di Paolo; Daniel Lévesque Journal: Biol Psychiatry Date: 2006-08-07 Impact factor: 13.382