Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia

Neuropharmacology. 2013 Mar;66:158-69. doi: 10.1016/j.neuropharm.2012.03.022. Epub 2012 Apr 3.

Abstract

Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naïve rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology*
  • Aminobutyrates / agonists
  • Aminobutyrates / pharmacology
  • Aminobutyrates / therapeutic use
  • Anilides / pharmacokinetics
  • Anilides / pharmacology*
  • Anilides / therapeutic use
  • Animals
  • Catalepsy / chemically induced
  • Catalepsy / drug therapy
  • Cyclohexanecarboxylic Acids / pharmacokinetics
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Cyclohexanecarboxylic Acids / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Dyskinesia, Drug-Induced / drug therapy*
  • Excitatory Amino Acid Agonists / pharmacokinetics
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Agonists / therapeutic use
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Haloperidol / antagonists & inhibitors
  • Haloperidol / pharmacology
  • Levodopa / adverse effects
  • Levodopa / pharmacology*
  • Levodopa / therapeutic use
  • Male
  • Oxidopamine
  • Parkinson Disease / drug therapy*
  • Phosphinic Acids / agonists
  • Phosphinic Acids / pharmacology
  • Phosphinic Acids / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Aminobutyrates
  • Anilides
  • Cyclohexanecarboxylic Acids
  • Excitatory Amino Acid Agonists
  • LSP1 2111
  • N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide
  • Phosphinic Acids
  • Receptors, Metabotropic Glutamate
  • Levodopa
  • Oxidopamine
  • Haloperidol
  • metabotropic glutamate receptor 4