Additive effects of mGluR2 positive allosteric modulation, mGluR2 orthosteric stimulation and 5-HT2AR antagonism on dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset

Abstract

Purpose Antagonising serotonin (5-HT) type 2A receptors (5-HT_2AR) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson’s disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR₂), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT_2AR antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT_2AR antagonism with concurrent mGluR₂ orthosteric stimulation and mGluR₂ positive allosteric modulation. Methods Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered l-3,4-dihydroxyphenylalanine (l-DOPA) in combination with vehicle or the 5-HT_2AR antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR₂ orthosteric agonist (OA) LY-354,740, the mGluR₂ positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated. Results EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on l-DOPA anti-parkinsonian action were observed. Conclusion Our results suggest that combining 5-HT_2AR antagonism with mGluR₂ activation results in greater reduction of l-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR₂ OA and a mGluR₂ PAM are combined with a 5-HT_2AR antagonist than when a mGluR₂ OA or a mGluR₂ PAM are added to a 5-HT_2AR antagonist.