Effect of the mGlu2 receptor positive allosteric modulator AZD8529 on L-DOPA-induced dyskinesia and psychosis-like behaviours in the parkinsonian marmoset

AZD8529 is a highly selective metabotropic glutamate 2 (mGlu₂) receptor positive allosteric modulator (PAM) that has undergone clinical trials for schizophrenia and smoking cessation. Previously, we demonstrated that the selective mGlu₂ receptor PAMs LY-487,379, CBiPES, and biphenylindanone A (BINA) alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease (PD). However, these drugs are not clinical candidates because of their pharmacological properties, contrary to AZD8529 which could be repurposed if pre-clinically efficacious. To assess the effect of AZD8529 on L-DOPA-induced dyskinesia and PLBs in the MPTP-lesioned marmoset, we first determined the pharmacokinetic (PK) profile of AZD8529 in this species to inform dose selection such that drug plasma levels were clinically relevant. Then, MPTP-lesioned animals were treated with L-DOPA with either vehicle or AZD8529 (0.1, 0.3, 1, and 10 mg/kg). The results showed a reduction in global dyskinesia severity (up to 70 %, P < 0.001), and in duration of on-time with disabling dyskinesia (up to 97 %, P < 0.001) when compared to L-DOPA/vehicle. Similarly, there was a reduction in global PLB severity (up to 64 %, P < 0.001), and in duration of on-time with disabling PLBs (up to 94 %, P < 0.001) when compared to L-DOPA/vehicle. Additionally, AZD8529 increased the duration of the anti-parkinsonian action of L-DOPA at doses of 0.3 mg/kg and above (up to 29 %, P < 0.05). Our results further demonstrate the potential of AZD8529 and mGlu₂ receptor positive allosteric modulation for alleviating L-DOPA-induced dyskinesia and PLBs while amplifying the therapeutic efficacy of L-DOPA.