The anti-dyskinetic effect of the clinic-ready mGluRpositive allosteric modulator AZD8529 in the 6-OHDA-lesioned rat.

L-3,4-dihydroxyphenylalanine (L-DOPA) remains the main treatment for motor symptoms of Parkinson's disease (PD). However, chronic use is associated with the development of complications such as L-DOPA-induced dyskinesia. We previously demonstrated that LY-487,379, a highly selective metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM), reduces the severity of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, without interfering with the anti-parkinsonian action of L-DOPA. Here, we seek to determine the effect of AZD8529, another highly selective mGluR2 PAM, on L-DOPA-induced AIMs in the 6-OHDA-lesioned rat. Unlike LY-487,379, AZD8529 has previously undergone clinical trials and could therefore be repurposed if proven efficacious in pre-clinical studies. We first determined the pharmacokinetic (PK) profile of AZD8529 to administer doses leading to clinically relevant plasma levels in the behavioural studies. Then, dyskinetic 6-OHDAlesioned rats were administered AZD8529 (0.1, 0.3, and 1 mg/kg) or vehicle in combination with L-DOPA followed by assessment of AIMs severity. The cylinder test was then used to evaluate the effect of AZD8529 on the anti-parkinsonian action of L-DOPA. We found that AZD8529 (0.1, 0.3 and 1 mg/kg) in combination with L-DOPA significantly reduced the severity of AIMs duration (P < 0.05), but not amplitude, when compared to L-DOPA/vehicle. AZD8529 administration did not interfere with L-DOPA anti-parkinsonian action. Our results provide evidence that mGluR2 positive allosteric modulation with AZD8529 may be a viable, yet relatively modest, treatment strategy to alleviate L-DOPA-induced.