title: Characterisation of an mGlu8 receptor-selective agonist and antagonist in the lateral and medial perforant path inputs to the dentate gyrus.
abstract: Since its characterisation in 2001, the mGlu8-selective agonist DCPG has been widely used to explore the potential functional role of this group III mGlu receptor within the central nervous system. This research has implicated mGlu8 receptors in a number of disease states and conditions such as epilepsy and anxiety, suggesting that mGlu8-selective ligands may hold important therapeutic potential. However, there is evidence that DCPG exerts off-target effects at higher concentrations, limiting its use as an mGlu8-selective agonist. Here, we have used field recordings in rat hippocampal slices to investigate the effects of DCPG in the lateral perforant path (LPP), a pathway known to express high levels of mGlu8. We show that DCPG does inhibit excitatory transmission in this pathway, but produces a biphasic concentration-response curve suggesting activation of two distinct receptor types. The putative mGlu8-selective antagonist MDCPG antagonises the high, but not the low, potency component of this concentration-response curve. In addition, higher concentrations of DCPG also depress excitatory transmission in the medial perforant path (MPP), a pathway expressing very low levels of mGlu8 receptors. Experiments in slices from mice lacking mGlu8 receptors indicate that concentrations of DCPG >1 μM produce large non-selective effects in both the LPP and MPP. Further experiments in slices from mGlu2, 4 and 7 knock-out mice, as well as in an mGlu2-deficient substrain of Wistar rat, reveal that these non-selective effects are mediated primarily by mGlu2 receptors. Taken together, our results confirm the mGlu8-selectivity of DCPG at submicromolar concentrations, but suggest that care must be taken when employing higher concentrations of the agonist, which may additionally activate mGlu2 receptors, especially at synapses where their expression is high. MDCPG may be a useful tool in determining whether observable DCPG effects are attributable to mGlu8, versus mGlu2, receptor activation.
authors.affiliation: MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Dorothy Hodgkin Building, Bristol BS1 3NY, UK.
authors.forename: Marion S
authors.initials: MS
authors.lastname: Mercier
authors.forename: David
authors.initials: D
authors.lastname: Lodge
authors.forename: Guangyu
authors.initials: G
authors.lastname: Fang
authors.forename: Celine S
authors.initials: CS
authors.lastname: Nicolas
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Collett
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: Zuner A
authors.initials: ZA
authors.lastname: Bortolotto
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D019580:Perforant Pathway / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000172:deficiency; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C581970:2-amino-4-methylbicyclo(3.1.0)hexane2,6-dicarboxylic acid; D000596:Amino Acids; D000600:Amino Acids, Dicarboxylic; D001643:Bridged Bicyclo Compounds; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C111435:metabotropic glutamate receptor 8