ADDRESSING THE MECHANISM OF PRIMING OF DOPAMINE RECEPTORS AND ITS EFFECT ON DRUGINDUCED DYSKINESIA

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

Mar del Plata

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

SAFE-SAIC-SAI

Parkinson?s disease (PD) is characterized by dopamine (DA)depletion in the striatum and the gold standard treatment is stillthe use of 3,4-dihydroxyphenyl-l-alanine (L-DOPA), despite itsprolonged use induces severe motor complications, known asL-DOPA-induced dyskinesia (LID). Not all dopaminergic agonistsshare the same capacity to induce dyskinesia, and D2 agonistsare frequently used in clinical practice because its low dyskinetogenicprofile. Priming is defined as the behavioral and molecularsensitization occurring after the first exposure to L-DOPA or fullDA agonist. Priming is not necessarily associated with dyskinesiabut once it has occurred, lower doses of L-DOPA or dopamineagonists are enough to induce dyskinesia. Priming has beenextensively studied by pharmacological approaches but themolecular mechanism underlying is not well understood. The aimof this work is to understand the mechanisms of priming and toevaluate the effect of selective D1 or D2 receptor stimulation onsubsequent DA agonist responses. This knowledge will contributeto elucidate the mechanisms underlying dyskinesia. To reach thisgoal, we developed a mice model of PD. C57 mice were injectedwith 6-OHDA and received dyskinetogenic doses of L-DOPA orsaline for 3, 5 or 7 days to induce priming. We tested the effect ofdifferent days of priming to induce Quinpirole-induced dyskinesia.Using a 3 day priming protocol, a group of mice was tested withdifferent doses of the D2 agonist Quinpirole or L-DOPA. We determinedthe score of dyskinesia and analyzed striatal molecularchanges by immunohistochemistry, including TH (to determinedopaminergic loss), pERK, FosB and cFos (molecules related toLID). We compared dyskinetic potentials of L-DOPA or Quinpiroletreatment, as well as their ability to induce expression of markersthat have been already related to dyskinesia.Our results represent the first step to explore the molecularmechanisms of priming and the differential induction of dyskinesiaby selective or full dopaminergic agonist.