title: mGlu5 and adenosine A2A receptor interactions regulate the conditioned effects of cocaine.
abstract: Adenosine A2A receptors and metabotropic glutamate type 5 (mGlu5) receptors are co-localized in the striatum and can functionally interact to regulate drug-seeking. We further explored this interaction using antagonism of mGlu5 receptors with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) in combination with genetic deletion of A2A receptors. The conditioned rewarding and locomotor-activating properties of cocaine were evaluated via conditioned place preference (CPP). Vehicle-treated mice of both genotypes expressed a CPP to cocaine while MTEP abolished cocaine CPP in wild-type, but not A2A knockout, mice. These results were mirrored when conditioned hyperactivity was assessed. In contrast, MTEP attenuated the acute locomotor-activating properties of cocaine similarly in both genotypes. These data provide evidence for a functional interaction between adenosine A2A and mGlu5 receptors in mediating the conditioned effects of cocaine but not direct cocaine-induced hyperactivity. This functional interaction is supported by modulation of 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol ([125I]ZM241385) binding to the A2A receptor by MTEP.
authors.affiliation: Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Brown
authors.forename: Jhodie R
authors.initials: JR
authors.lastname: Duncan
authors.forename: Monique R
authors.initials: MR
authors.lastname: Stagnitti
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011877:Radionuclide Imaging; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014227:Triazines / Q000493:pharmacokinetics; D014230:Triazoles / Q000493:pharmacokinetics
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007456:Iodine Isotopes; D011725:Pyridines; D043705:Receptor, Adenosine A2A; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D003042:Cocaine