Haloperidol-induced immediate early genes in striatopallidal neurons requires the converging action of cAMP/PKA/DARPP-32 and mTOR pathways

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 drugs class. Pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-size...

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Bibliographic Details
Published inbioRxiv
Main Authors Onimus, Oriane, Valjent, Emmanuel, Fisone, Gilberto, Gangarossa, Giuseppe
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 18.09.2022
Subjects
Adaptation
Animal models
Antipsychotics
DARPP-32 protein
Dopamine D2 receptors
EGR-1 protein
Glutamic acid receptors (ionotropic)
Haloperidol
Immediate-early proteins
Immunofluorescence
Intracellular signalling
N-Methyl-D-aspartic acid receptors
Neostriatum
Protein kinase A
Psychotropic drugs
Spiny neurons
TOR protein
Transgenic mice
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Summary: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 drugs class. Pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-size 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. Competing Interest Statement The authors have declared no competing interest. Footnotes * Minor corrections to the main text. Changes in Fig. 3 and Fig. 4
DOI:10.1101/2022.09.10.507436