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Haloperidol-induced Nur77 expression in striatopallidal neurons is under the control of protein phosphatase 1 regulation by DARPP-32.
- Source :
-
Neuropharmacology [Neuropharmacology] 2014 Apr; Vol. 79, pp. 559-66. Date of Electronic Publication: 2014 Jan 15. - Publication Year :
- 2014
-
Abstract
- 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.<br /> (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Corpus Striatum metabolism
Cyclic AMP metabolism
Dopamine and cAMP-Regulated Phosphoprotein 32 genetics
Dopaminergic Neurons drug effects
Dopaminergic Neurons metabolism
Gene Knock-In Techniques
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Nucleus Accumbens drug effects
Nucleus Accumbens metabolism
Receptor, Adenosine A2A metabolism
Receptors, Dopamine D1 genetics
Receptors, Dopamine D1 metabolism
Receptors, Dopamine D2 metabolism
Up-Regulation drug effects
Antipsychotic Agents pharmacology
Corpus Striatum drug effects
Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism
Haloperidol pharmacology
Nuclear Receptor Subfamily 4, Group A, Member 1 metabolism
Protein Phosphatase 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 79
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24440754
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2014.01.008