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Identifier

000373407

Title

Συμπεριφορικές και μοριακές συνιστώσες της δράσης του αγωνιστή των D3/D2 υποδοχέων ροπινιρόλη

Alternative Title

Behavioral and molecular effects of the D3/D2 receptor agonist ropinirole

Author

Μαυρικάκη, Μαρία-Υπακοή

Thesis advisor

Παναγής, Γεώργιος

Reviewer

Svenningsson per

Abstract

Ropinirole is a selective D3/D2 receptor agonist clinically used in the treatment of Parkinson Disease. The aim of the present study was to examine the multiple behavioural and molecular aspects of ropinirole’s effects. Specifically, we investigated the effects of ropinirole on locomotor activity, brain stimulation reward, anxiety-related behavior, depressive-like behaviour and spatial reference and working memory. Considering the molecular studies, we examined weather ropinirole can act as a «biased» ligand in one of the two dopaminergic intracellular signaling pathways as well as the effects of ropinirole on both pathways. To assess these hypotheses, we performed immunoblotting to evaluate PKA’s activity by measuring the phosphorylation on GluR1 subunit on Ser845, a specific PKA phosphorylation site as well as GSK-3β activation by evaluating the phosphorylation of GSK-3β on Ser9 residue. In addition, we investigated the effects of ropinirole on brain’s general plasticity utilizing phosphorylation studies to study intracellular signaling of MAPK kinase pathway. Furthermore, we measured the effects of ropinirole on Immediate Early Genes (IEGs) expression including c-fos and arc. Our data indicate that ropinirole does not affect locomotor activity while it increased the reinforcing efficacy of brain stimulation only in the highest dose. In the 102 dose of 1mg/kg, ropinirole demonstrated anxiolytic and antidepressive-like effects, possibly by interacting with the serotoninergic system. In the dose of 10mg/kg, ropinirole demonstrated the same profile but in addition to the possible interaction with the serotoninergic system, we speculate an interaction with the noradrenergic system. Finally, in both doses, ropinirole improved spatial reference memory, although this effect did not reach statistical significance. In contrast, ropinirole did not affect spatial working memory performance. The molecular findings of our study indicate that ropinirole did not affect the intracellular signaling pathways of PKA, GSK-3β and MAPK. However, ropinirole demonstrated a tendency to decrease p-Ser845-GluR1 so as p-Ser9-GSK-3β in the ventral striatum, indicating that it exerts mild effects on both dopaminergic intracellular signaling pathways. In addition, ropinirole induced the expression of c-fos mRNA in the prefrontal cortex, in the dose of 10mg/kg, while decreased the expression of arc mRNA in the dorsal striatum in the dose of 1mg/kg. Our data demonstrate that ropinirole exerts antidepressant, anxiolytic and reinforcing properties via mild regulation of both dopaminergic signaling pathways in the ventral striatum. In addition, prefrontal cortex activation is related to these effects and possibly also regulates other neurotransmitter systems including the serotoninergic and the noradrenergic. To conclude, the present study supports the involvement of D3 receptors on emotional processes and supports the “dopaminergic hypothesis of affective disorders”.

Language

Greek

Subject

D3/D2 agonist

Elevated plus maze

Forced swim test

Immediate early genes

Intracellular signaling

Intracranial self -stimulation (ICSS)

Nervous system

Radial arm maze

Ropinorole