AI Article Synopsis
- The study investigates how varying doses of the mGlu antagonist LY341495 affect dyskinesia and psychosis-like behaviors in marmosets with Parkinson's disease after treatment with L-DOPA.
- Using different mGlu agonists and a serotonin antagonist, the researchers evaluated changes in dyskinesia and psychotic symptoms.
- Results indicated that higher doses of LY341495 reversed the benefits of the agonists on dyskinesia, suggesting that blocking mGlu receptors may not effectively counteract the negative impact of mGlu blockade on dyskinesia in Parkinson's disease.
Article Abstract
Background: We have previously demonstrated that the metabotropic glutamate 2 and 3 (mGlu) antagonist LY341495 reverses the anti-dyskinetic and anti-psychotic benefits conferred by mGlu activation and serotonin 2A (5-HT) antagonism. Here, we hypothesised that a higher dose of LY341495, associated with a higher antagonistic effect at mGlu receptors, would result in a reduction of the reversal of mGlu activation and 5-HT blockade on dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.
Methods: After induction of parkinsonism with MPTP, marmosets entered 3 streams of experiments, in which the following treatments were administered, in combination with l-3,4-dihydroxyphenylalanine (L-DOPA), after which dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were rated: 1. vehicle/vehicle, LY354740 (mGlu orthosteric agonist)/vehicle, LY354740/LY341495 1 mg/kg and LY354740/LY341495 3 mg/kg; 2. vehicle/vehicle, LY487379 (mGlu positive allosteric modulator)/vehicle, LY487379/LY341495 1 mg/kg and LY487379/LY341495 3 mg/kg; 3. vehicle/vehicle, EMD-281,014 (5-HT antagonist)/vehicle, EMD-281,014/LY341495 1 mg/kg and EMD-281,014/LY341495 3 mg/kg.
Results: Each of LY354740, LY487379 and EMD-281,014 reduced the severity of L-DOPA-induced dyskinesia, by 55%, 39% and 40%, respectively (all p < 0.001), as well as the severity of PLBs, by 48%, 36% and 41%, respectively (all p < 0.001). Adding LY341495 1 and 3 mg/kg to each of LY354740, LY487379 and EMD-281,014 resulted in a dose-dependent reversal of their anti-dyskinetic and anti-psychotic actions. No effect on the anti-parkinsonian action of L-DOPA was noted with any treatment combination.
Conclusion: These results suggest that an antagonistic effect at mGlu receptors may not be sufficient to overcome the deleterious effect of mGlu blockade on dyskinesia in PD. It remains to be seen whether similar effects would have been obtained with a selective mGlu antagonist.
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| http://dx.doi.org/10.1007/s43440-022-00378-9 | DOI Listing |
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