Role of the phosphodiesterase 10A in the activity of medium spiny striatal neurons during the occurrence of L-DOPA induced dyskinesias

Author(s)

Rayanne Poletti Guimarães

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
• Defense date: 2021-03-15

Examining board members

Fernando Eduardo Padovan Neto; Cleiton Lopes Aguiar; Rafael Naime Ruggiero

• Advisor: Fernando Eduardo Padovan Neto

Abstract

Long-term treatment of Parkinson\'s disease (PD) with L-DOPA is associated with side effects called L-DOPA-induced dyskinesias (LIDs). The striatum is a key structure of the striatum related to the LIDs. The medium spiny neurons (MSNs) constitute approximately 95% of the striatal neurons and comprise the direct and indirect motor control pathways. Chronic treatment with L-DOPA is able to modulate these pathways. Much evidence suggests that LIDs would emerge as a result of an imbalance between direct and indirect pathways. The enzyme phosphodiesterase 10A (PDE10A) is expressed mainly in MSNs in the striatum and metabolizes the second messengers (cAMP and cGMP), thus exercising a strong modulation of the activity of MSNs. Thus, our hypothesis is that the inhibition of phosphodiesterase 10A would have an antidiscinetic effect by modulating the activity of MSNs. All procedures were approved by the local ethics committee (CEUA-FFCLRP/USP (18.5.35.59.5). Rats injured by 6-OHDA were treated chronically with L-DOPA (5 mg/kg/day plus benserazide 12.5 mg/kg/day, subcutaneously) once a day for a week, after this period the dyskinetic rats received vehicle (n = 9) or PDE10A inhibitor ME3398 (1 mg/kg/day, n=6; 3 mg / kg, n=4; gavage) one hour before L-DOPA, once a day for two additional weeks. Behavioral analyzes were performed to quantify limb, axial and orofacial LIDs that affect parkinsonian animals. The walking test was performed once a week, 1 hour after levodopa administration to monitor the effect of L-DOPA antiparkinsonian activity in animals. After treatment, extracellular electrophysiology was performed in vivo in the parkinsonian striatum to characterize the activities evoked by stimulation cortical and spontaneous activities of MSNs. ME3398 (1 mg/kg) decreased axial, forelimb and orofacial dyskinesias 90 minutes after L-DOPA administration in the third week of treatment (p <0.05 vs. 6-OHDA - vehicle + L-DOPA). ME3398 (3 mg/kg) prolonged axial, forelimb and orofacial dyskinesias up to 150 minutes after L-DOPA administration at the third week of treatment (p < 0.05 vs. 6-OHDA - vehicle + LDOPA). Electrophysiological analysis revealed that ME3398 (3 mg/kg) increased the probability of firing of MSNs evoked by cortex stimulation (p = 0.001 vs. SHAM - vehicle 1 + vehicle 2 and p = 0.001 vs 6-OHDA - ME3398 (1 mg/kg) + L-DOPA). There were no statistically significant differences between groups in the spontaneous activity of MSNs. These data reinforce the discussion that PDE10A inhibitors can increase or decrease dyskinesias, depending on the dose used. Furthermore, electrophysiological recordings suggest that dyskinesias may increase due to facilitated cortico-striatal pathway transmission. (AU)

• FAPESP's process: 18/12956-5 - Role of phosphodiesterase 10A in striatal medium spiny neuron activity during L-DOPA-induced dyskinesia
• Grantee: Rayanne Poletti Guimarães
• Support Opportunities: Scholarships in Brazil - Master