title: Distinct effects of mGlu4 receptor positive allosteric modulators at corticostriatal vs. striatopallidal synapses may differentially contribute to their antiparkinsonian action.
abstract: Metabotropic glutamate 4 (mGlu4) receptor is a promising target for the treatment of motor deficits in Parkinson's disease (PD). This is due in part to its localization at key basal ganglia (BG) synapses that become hyperactive in this pathology, particularly striatopallidal synapses. In this context, mGlu4 receptor activation using either orthosteric agonists or positive allosteric modulators (PAMs) improves motor symptoms in rodent PD models in certain conditions. However, literature data show that mGlu4 receptor PAMs have no effect at striatopallidal GABAergic synapses (unless combined with an orthosteric agonist) and on the firing activity of pallidal neurons, and fail to provide significant motor improvement in relevant PD models. This questions the mechanistic hypothesis that mGlu4 receptor PAMs should act at striatopallidal synapses to alleviate PD motor symptoms. To shed light on this issue, we performed brain slice electrophysiology experiments. We show that Lu AF21934, an mGlu4 PAM small-molecule probe-compound, was ineffective at striatopallidal synapses at all concentrations tested, while it significantly inhibited corticostriatal synaptic transmission. Similarly, Lu AF21934 did not affect electrophysiology readouts at striatopallidal synapses in the presence of haloperidol or in 6-hydroxydopamine-lesioned rats. Interestingly, co-application of Lu AF21934 with a glutamate transporter inhibitor revealed a significant inhibitory action at striatopallidal synapses. Possibly, this effect could rely on increased level/permanence of glutamate in the synaptic cleft. Such differential efficacy of mGlu4 receptor PAMs at corticostriatal vs. striatopallidal synapses raises several issues regarding the synaptic target(s) of these drugs in the BG, and challenges the mechanisms by which they alleviate motor deficits in experimental PD models.
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR7288, 13009 Marseille, France. Electronic address: paolo.gubellini@univ-amu.fr.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gubellini
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR7288, 13009 Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Melon
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Dale
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, USA.
authors.forename: Dario
authors.initials: D
authors.lastname: Doller
authors.affiliation: Aix-Marseille Université, CNRS, IBDM UMR7288, 13009 Marseille, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kerkerian-Le Goff
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005917:Globus Pallidus / Q000187:drug effects / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D027322:Amino Acid Transport System X-AG; D000813:Anilides; D000978:Antiparkinson Agents; D003509:Cyclohexanecarboxylic Acids; D018492:Dopamine Antagonists; D018683:Excitatory Amino Acid Agents; C581971:N1-(3,4-dichlorophenyl)-cyclohexane-1,2-dicarboxamide; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D016627:Oxidopamine; D006220:Haloperidol; C108823:metabotropic glutamate receptor 4
keywords: Basal ganglia; Electrophysiology; Globus pallidus; Lu AF21934; Rat; Striatum