Objective: To assess the effects of concurrent metabotropic glutamate type 2 (mGlu₂) positive allosteric modulation and orthosteric stimulation combined with serotonin type 2A (5-HT_2A) antagonism.

Background: In recent work we have discovered that there may be a ceiling to the anti-psychotic and anti-dyskinetic action of 5-HT_2A blockade. We have shown that adding a mGlu₂ positive allosteric modulator (PAM) or orthosteric agonist (OA) to a 5-HT_2A antagonist results in additive effects. Whether greater benefits would be achieved upon combining a mGlu₂ PAM and a mGlu₂ OA while also antagonising 5-HT_2A receptors has not been determined. Here, we seek to provide an answer to this question. To this end, we have used the mGlu₂ PAM LY-487,379, the mGlu_2/3 OA LY-354,740 and the 5-HT_2A antagonist EMD-281,014, based upon previous studies we conducted in the marmoset.

Method: Six marmosets of either sex were rendered parkinsonian by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after which psychosis-like behaviours (PLBs) and dyskinesia were induced by administration of L-3,4-dihydroxyphenylalanine (L-DOPA). Animals were then administered the following treatments, in combination with L-DOPA, in a randomised fashion: vehicle/vehicle/vehicle, EMD-281,014/vehicle/vehicle, EMD-281,014/LY-487,379/vehicle, EMD-281,014/vehicle/LY-354,740 and EMD-281,014/LY-487,379/LY-354,740, after which PLBs, dyskinesia and parkinsonism were rated.

Results: As previously demonstrated, EMD-281,014 reduced both PLBs and dyskinesia. In addition, as previously shown, adding either LY-487,379 or LY-354,740 to EMD-281,014 led to further anti-psychotic and anti-dyskinetic effects, compared to EMD-281,014 alone. Moreover, the EMD-281,014/LY-487,379/LY-354,740 treatment conferred greater anti-psychotic and anti-dyskinetic effects than the EMD-281,014/LY-487,379/vehicle (by 22% and 34%, P < 0.05 and P < 0.01, respectively) and the EMD-281,014/vehicle/LY-354,740 (by 37% and 47%, both P < 0.001) treatments.

Conclusion: These results suggest that activation of mGlu₂ receptors through concurrent positive allosteric modulation and orthosteric stimulation may provide greater reduction of L-DOPA-induced psychosis and dyskinesia than selective positive allosteric modulation or orthosteric stimulation, when combined to a 5-HT_2A antagonist.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-simultaneous-mglu2-positive-allosteric-modulation-and-orthosteric-stimulation-combined-with-5-ht2a-antagonism-on-psychosis-like-behaviours-dyskinesia-and-parkinsonism-in-the-mptp-lesioned-m/