title: In vivo metabotropic glutamate receptor 5 (mGluR5) antagonism prevents cocaine-induced disruption of postsynaptically maintained mGluR5-dependent long-term depression.
abstract: Metabotropic glutamate receptor 5 (mGluR5) plays a critical role in psychostimulant-induced behavior, yet it is unclear whether mGluR5 is activated by psychostimulant administration, or whether its role is constitutive. We previously reported that activation of mGluR5 with the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) can induce a long-term depression (DHPG-LTD) of glutamatergic transmission in the bed nucleus of the stria terminalis (BNST), and that ex vivo induction of this LTD is disrupted by repeated in vivo administration of cocaine. Here we demonstrate that DHPG-LTD is not maintained by alterations in glutamate release, and that postsynaptic endocytosis is necessary. Furthermore, we find that a single administration of cocaine produces a transient disruption of DHPG-LTD, and the duration of this disruption was increased by repeated days of cocaine administration. The disruption produced by cocaine was not permanent, because DHPG-LTD could be induced 10 d after cocaine administration. To test the role of mGluR5 in vivo in the cocaine-induced disruption of DHPG-LTD, we injected mice with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine before cocaine. mGluR5 antagonism during in vivo cocaine administration rescued subsequent ex vivo induction of DHPG-LTD. The effects of in vivo cocaine could be mimicked by application of cocaine to BNST-containing slices, suggesting that the actions of cocaine are local. Thus, using a novel strategy of in vivo antagonist-induced rescue of ex vivo agonist effects for the same receptor, we provide evidence suggesting that mGluR5 activation is actively recruited by in vivo cocaine.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Grueter
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: McElligott
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Mathews
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D012686:Septal Nuclei / Q000187:drug effects / Q000502:physiology
chemical_list: D018765:Dopamine Uptake Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D008734:Methoxyhydroxyphenylglycol; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D003042:Cocaine; C010117:3,4-dihydroxyphenylglycol
references.citation: Curr Opin Pharmacol. 2006 Feb;6(1):98-102
references.pmid: 16368268
references.citation: J Neurosci. 2005 Mar 16;25(11):2992-3001
references.pmid: 15772359
references.citation: Trends Pharmacol Sci. 2001 Jul;22(7):331-7
references.pmid: 11431019
references.citation: J Neurophysiol. 2002 Mar;87(3):1395-403
references.pmid: 11877514
references.citation: Neuropsychopharmacology. 2008 May;33(6):1379-90
references.pmid: 17625498
references.citation: Psychopharmacology (Berl). 2001 Dec;158(4):360-5
references.pmid: 11797056
references.citation: Pharmacol Ther. 2006 Sep;111(3):855-76
references.pmid: 16545872
references.citation: J Neurosci. 2001 Aug 15;21(16):RC160
references.pmid: 11473131
references.citation: Neuropsychopharmacology. 2005 Apr;30(4):657-68
references.pmid: 15602500
references.citation: Nat Rev Neurosci. 2007 Nov;8(11):844-58
references.pmid: 17948030
references.citation: Nature. 2001 May 31;411(6837):583-7
references.pmid: 11385572
references.citation: J Neurosci. 2000 Oct 15;20(20):RC102
references.pmid: 11027253
references.citation: Nat Neurosci. 1999 May;2(5):454-60
references.pmid: 10321250
references.citation: Nat Neurosci. 2001 Dec;4(12):1217-23
references.pmid: 11694884
references.citation: J Neurosci. 1997 Nov 1;17(21):8613-20
references.pmid: 9334432
references.citation: Nat Rev Neurosci. 2007 Feb;8(2):101-13
references.pmid: 17237803
references.citation: Neuropharmacology. 2001 Nov;41(6):664-71
references.pmid: 11640920
references.citation: Neuron. 1999 Nov;24(3):649-58
references.pmid: 10595516
references.citation: J Neurosci. 1999 Oct 15;19(20):RC35
references.pmid: 10516337
references.citation: Annu Rev Pharmacol Toxicol. 1997;37:205-37
references.pmid: 9131252
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8384-8
references.pmid: 12060781
references.citation: Nat Neurosci. 2005 Aug;8(8):1043-50
references.pmid: 16025109
references.citation: Neuropsychopharmacology. 2005 Jul;30(7):1302-11
references.pmid: 15812571
references.citation: J Comp Neurol. 2007 Dec 20;505(6):682-700
references.pmid: 17948876
references.citation: Nat Neurosci. 2001 Nov;4(11):1079-85
references.pmid: 11687813
references.citation: J Neurosci. 2004 Aug 25;24(34):7482-90
references.pmid: 15329395
references.citation: J Neurosci. 2006 Mar 22;26(12):3210-9
references.pmid: 16554472
references.citation: J Neurosci. 2004 Aug 4;24(31):6939-45
references.pmid: 15295029
references.citation: Mol Pharmacol. 2005 Feb;67(2):349-55
references.pmid: 15548766
references.citation: J Neurosci. 2005 Nov 9;25(45):10537-45
references.pmid: 16280591
references.citation: J Neurosci Res. 2004 Feb 15;75(4):472-9
references.pmid: 14743430
references.citation: J Neurosci. 2006 Jun 7;26(23):6337-45
references.pmid: 16763042
references.citation: Mol Neurobiol. 2007 Dec;36(3):232-44
references.pmid: 17955198
references.citation: J Neurosci. 2002 Mar 15;22(6):2165-73
references.pmid: 11896156
references.citation: J Neurosci. 2002 Jul 1;22(13):5713-8
references.pmid: 12097523
references.citation: Nat Neurosci. 2001 Sep;4(9):873-4
references.pmid: 11528416
references.citation: Brain Res. 1998 Feb 16;784(1-2):105-15
references.pmid: 9518570
references.citation: Neuron. 1997 Jun;18(6):969-82
references.pmid: 9208864
references.citation: J Neurosci. 2002 Jun 15;22(12):5173-87
references.pmid: 12077212