Addressing the mechanism of priming of dopamine receptors and its effect on drug induced dyskinesia.

GOMEZ G; BALLESTERO P; SANZ BLASCO S; BERNARDI MA; GERSHANIK OS; TARAVINI IR; FERRARIO JE

Mar del Plata

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Farmacología Experimental; 2016

Sociedad Argentina de Farmacología Experimental

Parkinson?s disease (PD) is characterized by dopamine (DA) depletion in the striatum and the gold standard treatment is still the use of 3,4-dihydroxyphenyl-l-alanine (L-DOPA), despite its prolonged use induces severe motor complications, known as L-DOPA-induced dyskinesia (LID). Not all dopaminergic agonists share the same capacity to induce dyskinesia, and D2 agonists are frequently used in clinical practice because its low dyskinetogenic profile. Priming is defined as the behavioral and molecular sensitization occurring after the first exposure to L-DOPA or full DA agonist. Priming is not necessarily associated with dyskinesia but once it has occurred, lower doses of L-DOPA or dopamine agonists are enough to induce dyskinesia. Priming has been extensively studied by pharmacological approaches but the molecular mechanism underlying is not well understood. The aim of this work is to understand the mechanisms of priming and to evaluate the effect of selective D1 or D2 receptor stimulation on subsequent DA agonist responses. This knowledge will contribute to elucidate the mechanisms underlying dyskinesia. To reach this goal, we developed a mice model of PD. C57 mice were injectedwith 6-OHDA and received dyskinetogenic doses of L-DOPA or saline for 3, 5 or 7 days to induce priming. We tested the effect of different days of priming to induce Quinpirole-induced dyskinesia. Using a 3 day priming protocol, a group of mice was tested with different doses of the D2 agonist Quinpirole or L-DOPA. We determined the score of dyskinesia and analyzed striatal molecular changes by immunohistochemistry, including TH (to determine dopaminergic loss), pERK, FosB and cFos (molecules related to LID). We compared dyskinetic potentials of L-DOPA or Quinpirole treatment, as well as their ability to induce expression of markers that have been already related to dyskinesia. Our results represent the first step to explore the molecular mechanisms of priming and the differential induction of dyskinesia by selective or full dopaminergic agonist.