Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist

Abstract

Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the ‘indirect pathway’ of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a sub-threshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.

Imaging metabotropic glutamate receptor system: Application of positron emission tomography technology in drug development

“…In addition, diverse chemotypes of both mGlu 5 and mGlu 2 PAMs show robust activity in the preclinical models of schizophrenia and cognition. Selective high‐affinity mGlu 4 PAMs demonstrate efficacy in several different rodent models for both pain and Parkinson's disease (PD) . Based on the existing chemical scaffolds, several successful PET tracers for imaging mGlu receptors have been developed (Figure ).…”

Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability

“…6,14,15 Figure 1 shows some representative mGlu 4 PAMs. 6,14,16,17,18,19,20 Subsequent results with PAMs of mGlu 4 have further validated the antiparkinsonian activity in animal models of PD, 11,17,21,22,23,24 in which this approach has opened a new avenue for developing nondopaminergic treatments for PD and for identifying a novel disease modifying therapeutics.…”

Ceftriaxone reduces L‐dopa–induced dyskinesia severity in 6‐hydroxydopamine parkinson's disease model

“…Recent work has focused on the pharmacological blockade of glutamate receptors directed at alternate subtypes. However, it is not resolved as to whether an antidyskinetic effect, similar or superior to that of amantadine, may be achieved by other glutamate receptor drugs, such as metabotropic glutamate receptor modulators …”

“…However, it is not resolved as to whether an antidyskinetic effect, similar or superior to that of amantadine, may be achieved by other glutamate receptor drugs, such as metabotropic glutamate receptor modulators. 35,47,48 The pharmacological-based reduction of striatal or nigral glutamate efflux may reduce LID severity. [49][50][51] GLT-1 is a primary glial glutamate transporter responsible for clearing synaptic glutamate 52 and may be involved in neurodegenerative processes.…”