Does mTOR play a role in the generation of levodopa-induced dyskinesias?

MARIANO SABORIDO; CELIA LARRAMENDY; GABRIEL NEIMAN; IRENE TARAVINI; GUSTAVO MURER; OSCAR GERSHANIK

Huerta Grande-Córdoba

Congreso; I Reunión Conjunta de Neurociencias (IRCN); 2009

Taller Argentino de Neurociencias y Sociedad Argentina de Investigación en Neurociencias

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Dyskinesias are one of the major limiting side effects encountered in the treatment of Parkinson’s disease. Increasing data suggest that the development of levodopa induced dyskinesias (LID) involves profound and persistent molecular changes in the striatum. However the intimate mechanisms that underlie LID are poorly understood. Strong evidence also suggests alterations in the induction phase of corticostriatal long term potentiation (LTP) and depotentiation in LID. It is known that LTP involves processes requiring protein synthesis. In view of this, it is tempting to speculate that molecular factors known to be involved in plastic changes such as LTP would also play a role in the development of LID. Mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that modulates cell growth, proliferation and synaptic plasticity via the regulation of protein synthesis. To understand some of the molecular factors and mechanisms involved in the development of LID we inhibited mTOR during sensitization to levodopa. To that effect, 22-gauge stainless steel cannulae were implanted hemilaterally in the striatum of 6-OHDA lesioned rats. Rats received 0.5 µl of vehicle or rapamycin (30, 60 and 120 nM) 15 min before levodopa (25 mg/kg), once every 48 h for a total of three times (sensitization). Two days after that, both groups received 25mg/kg levodopa. Contralateral rotations, dyskinesias and the use of the contralateral forelimb were tested. We found no significant differences in dyskinesia score between vehicle and rapamycin treated animals. This preliminary data suggests that mTOR is probably not involved in the molecular changes that lead to the development of LID in an animal model of parkinsonism.