Adenosine A2A receptors and metabotropic glutamate 5 receptors are co-localized and functionally interact in the hippocampus: a possible key mechanism in the modulation of N-methyl-D-aspartate effects.
Hippocampal metabotropic glutamate 5 receptors (mGlu5Rs) regulate both physiological and pathological responses to glutamate. Because mGlu5R activation enhances NMDA-mediated effects, and given the role played by NMDA receptors in synaptic plasticity and excitotoxicity, modulating mGlu5R may influence both the physiological and the pathological effects elicited by NMDA receptor stimulation. We evaluated whether adenosine A2A receptors (A(2A)Rs) modulated mGlu5R-dependent effects in the hippocampus, as they do in the striatum. Co-application of the A(2A)R agonist CGS 21680 with the mGlu5R agonist (RS)-2-chloro-s-hydroxyphenylglycine(CHPG) synergistically reduced field excitatory postsynaptic potentials in the CA1 area of rat hippocampal slices. Endogenous tone at A(2A)Rs seemed to be required to enable mGlu5R-mediated effects, as the ability of CHPG to potentiate NMDA effects was antagonized by the selective A(2A)R antagonist ZM 241385 in rat hippocampal slices and cultured hippocampal neurons, and abolished in the hippocampus of A(2A)R knockout mice. Evidence for the interaction between A(2A)Rs and mGlu5Rs was further strengthened by demonstrating their co-localization in hippocampal synapses. This is the first evidence showing that hippocampal A(2A)Rs and mGlu5Rs are co-located and act synergistically, and that A(2A)Rs play a permissive role in mGlu5R receptor-mediated potentiation of NMDA effects in the hippocampus.
Tebano
M T
MT
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Martire
A
A
Rebola
N
N
Pepponi
R
R
Domenici
M R
MR
Grò
M C
MC
Schwarzschild
M A
MA
Chen
J F
JF
Cunha
R A
RA
Popoli
P
P
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D005576:Colforsin / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D010627:Phenethylamines / Q000494:pharmacology; D010648:Phenylacetates / Q000494:pharmacology; D011247:Pregnancy; D017729:Presynaptic Terminals / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D050765:Qa-SNARE Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D043683:Receptors, Adenosine A2 / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
C107349:2-chloro-5-hydroxyphenylglycine; D058908:Adenosine A2 Receptor Agonists; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010627:Phenethylamines; D010648:Phenylacetates; D011725:Pyridines; D050765:Qa-SNARE Proteins; D064529:Receptor, Metabotropic Glutamate 5; D043683:Receptors, Adenosine A2; D018094:Receptors, Metabotropic Glutamate; D016708:Synaptophysin; D050598:Vesicular Glutamate Transport Protein 1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D005576:Colforsin; D016202:N-Methylaspartate; C121465:6-methyl-2-(phenylethynyl)pyridine; D000241:Adenosine; D005998:Glycine; D001640:Bicuculline