Haloperidol-Induced Immediate Early Genes in Striatopallidal Neurons Requires the Converging Action of cAMP/PKA/DARPP-32 and mTOR Pathways

Oriane Onimus; Emmanuel Valjent; Gilberto Fisone; Giuseppe Gangarossa

doi:10.3390/ijms231911637

Haloperidol-Induced Immediate Early Genes in Striatopallidal Neurons Requires the Converging Action of cAMP/PKA/DARPP-32 and mTOR Pathways

Int J Mol Sci. 2022 Oct 1;23(19):11637. doi: 10.3390/ijms231911637.

Authors

Oriane Onimus¹, Emmanuel Valjent², Gilberto Fisone³, Giuseppe Gangarossa¹

Affiliations

¹ Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
² Institut de Génomique Fonctionnelle (IGF), Université de Montpellier, CNRS, Inserm, 34094 Montpellier, France.
³ Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.

Abstract

Antipsychotics share the common pharmacological feature of antagonizing the dopamine 2 receptor (D2R), which is abundant in the striatum and involved in both the therapeutic and side effects of this drug's class. The pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-sized spiny neurons (MSNs), leads to a plethora of molecular, cellular and behavioral adaptations, which are central in the action of antipsychotics. Here, we focused on the cell type-specific (D2R-MSNs) regulation of some striatal immediate early genes (IEGs), such as cFos, Arc and Zif268. Taking advantage of transgenic mouse models, pharmacological approaches and immunofluorescence analyses, we found that haloperidol-induced IEGs in the striatum required the synergistic activation of A2a (adenosine) and NMDA (glutamate) receptors. At the intracellular signaling level, we found that the PKA/DARPP-32 and mTOR pathways synergistically cooperate to control the induction of IEGs by haloperidol. By confirming and further expanding previous observations, our results provide novel insights into the regulatory mechanisms underlying the molecular/cellular action of antipsychotics in the striatum.

Keywords: D2R; PKA; dopamine; haloperidol; immediate early genes; mTOR; striatum.

MeSH terms

Adenosine / metabolism
Animals
Antipsychotic Agents* / metabolism
Antipsychotic Agents* / pharmacology
Corpus Striatum / metabolism
Dopamine / metabolism
Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics
Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
Genes, Immediate-Early
Glutamates / metabolism
Haloperidol* / pharmacology
Mice
Mice, Transgenic
N-Methylaspartate / metabolism
Neurons / metabolism
Receptors, Dopamine D1 / metabolism
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism

Substances

Antipsychotic Agents
Dopamine and cAMP-Regulated Phosphoprotein 32
Glutamates
Receptors, Dopamine D1
N-Methylaspartate
TOR Serine-Threonine Kinases
Haloperidol
Adenosine
Dopamine

Grants and funding

This work was supported by Agence Nationale de la Recherche (HERO, ANR-21-CE14-0021-01, G.G.), Fédération pour la Recherche sur le Cerveau and Association France Parkinson (G.G.), Université Paris Cité (G.G.), Inserm (E.V.), Fondation pour la Recherche Médicale (EQU202203014705, E.V.), Agence Nationale de la Recherche (DISCOMMODE, ANR-21-CE37-0013 and SubDOPA, ANR-21-CE16-0028, E.V.). Swedish Research Council (Grant 2019-01170, G.F.). O.O. was supported by a doctoral fellowship from the Fondation pour la Recherche Médicale.