Haloperidol-induced Nur77 expression in striatopallidal neurons is under the control of protein phosphatase 1 regulation by DARPP-32.
Impaired dopaminergic signaling in the striatum is involved in diseases as diverse as Parkinson's disease, addiction, and schizophrenia. An important pathophysiological aspect is the loss of balance between striatopallidal and striatonigral pathways. Nur77 is an orphan nuclear receptor and dopamine-regulated immediate-early gene. Classical antipsychotic drugs widely used in the treatment of schizophrenia, such as haloperidol, increase Nur77 mRNA expression in the striatum. However, little is known about the intracellular signaling pathways involved in Nur77 induction. Here, using pharmacological approaches and transgenic mutant mice, we investigated the mechanisms underlying the up-regulation of Nur77 protein expression in the dorsal striatum after haloperidol injection. In drd1a::EGFP transgenic mice that express GFP in D1 neurons, Nur77 up-regulation induced by haloperidol occurred predominantly in GFP-negative neurons. In Gαolf heterozygous mutant mice, in which cAMP production in response to A2A stimulation is impaired in the striatum, haloperidol effect was not altered. In contrast, in DARPP-32 knock-in mutant mice bearing a T34A point mutation of the site responsible for cAMP-dependent phosphatase 1 inhibition, Nur77 up-regulation by haloperidol was prevented. Haloperidol also induced Nur77 protein in D2 neurons of the nucleus accumbens core of wild type but not T34A knock-in mice. Thus, our results show that expression of Nur77 is induced by haloperidol in D2 receptors-expressing medium-sized spiny neurons, through cAMP-dependent regulation of protein phosphatase 1, which is likely to modulate the effects of other protein kinases. Our results clarify the mechanisms of Nur77 induction by antipsychotic and its possible contribution to extrapyramidal effects.
Millennium Nucleus in Stress and Addiction (NEDA), Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Chile; Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France.
Natalia
N
Sánchez
Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France.
Renata
R
Coura
Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France.
Olivia
O
Engmann
Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France.
Lucile
L
Marion-Poll
Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France.
Sophie
S
Longueville
Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France.
Denis
D
Hervé
Millennium Nucleus in Stress and Addiction (NEDA), Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Chile. Electronic address: mandres@bio.puc.cl.
María E
ME
Andrés
Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France. Electronic address: jean-antoine.girault@inserm.fr.
Jean-Antoine
JA
Girault
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D014150:Antipsychotic Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C583261:Drd1 protein, mouse; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C497929:Ppp1r1b protein, mouse; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000242:Cyclic AMP; D054645:Protein Phosphatase 1; D006220:Haloperidol
Antipsychotics; Dopamine; Orphan nuclear receptors; Striatum