| Abstract No.: | B-B2058 |
| Country: | Canada |
| | |
| Title: | EXTRACELLULAR SIGNAL-REGULATED KINASES (ERK) AND PROTEIN KINASE C (PKC) ACTIVITIES ARE INVOLVED IN THE MODULATION OF NUR77 AND NOR-1 EXPRESSION BY DOPAMINERGIC DRUGS |
| | |
| Authors/Affiliations: | 2 Emmanuelle Bourhis*; 2 Jérôme Maheux; 1 Claude Rouillard; 2 Daniel Lévesque;
1 Laval University, CRCHUL, Neuroscience Unit, Québec, QC, Canada; 2 University of Montreal, Faculty of Pharmacy, QC, Canada
|
| | |
| Content: | Introduction: The dopamine system is the main target of antipsychotic and psychostimulant drugs. These drugs mainly target dopamine receptors and induce the transcription of several immediate early genes (IEG), including orphan nuclear receptors of the Nur family (Nurr1, Nur77 and Nor-1). However, intracellular signalling cascades triggered by dopamine receptor drugs and leading to modulation of the expression of these transcription factors remain unknown.
Objective: The objective of the study was to investigate the effect of selective kinase inhibitors on the modulation of Nur transcripts in vivo.
Methods: Groups of wild type mice received a systemic injection of the D2 antagonist eticlopride or its vehicle, with or without SL327, a MAPK- and ERK-related Kinase (MEK) inhibitor, or NPC-15437, a PKC inhibitor, two kinase inhibitors that can cross the blood brain barrier. A similar paradigm was performed with a combination of the D1 and D2 receptor agonists SKF82958 and quinpirole, respectively. The locomotor activity induced by dopamine receptor drugs (catalepsy for the D2 antagonist and ambulatory activity for the dopamine agonists) alone or in combination with kinase inhibitors was measured. Nurr1, Nur77 and Nor-1 mRNA levels were evaluated in various brain regions (striatum, accumbens, cortex and midbrain) by in situ hybridization using specific radiolabeled complementary RNA probes, whereas pERK1/2 and total ERK1/2 activities were measured by immunohistochemistry.
Results: Modulation of striatal Nur77 expression by the dopamine D2 receptor antagonist was mainly associated with an increase in ERK1/2 activity, whereas modulation of Nor-1 expression mainly depended on PKC activation. Modulation of striatal Nur77 mRNA levels by the combination of dopamine receptor agonists involved both ERK and PKC activities, whereas a selective ERK activity was associated with the modulation of Nor-1 mRNA levels by dopamine agonists. Kinase inhibitors also modulated Nurr1 mRNA levels in substantia nigra.
Conclusion: Our results demonstrate that signalling pathways leading to the modulation of Nur77 and Nor-1 expression following dopamine receptor drug administration involved different kinases. In addition, the modulation of dopamine drug-induced locomotor activity by kinase inhibitors suggests that locomotor activity is dependent on Nur77, but not Nor-1, expression. This work was supported by Canadian Institutes for Health Research (CIHR) and National Alliance for Research on Schizophrenia and Depression (NARSAD) of United States. |
| | |
| Back |
|
