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The Journal of Neuroscience, September 10, 2008, 28(37):9261-9270; doi:10.1523/JNEUROSCI.2886-08.2008

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Behavioral/Systems/Cognitive
In Vivo Metabotropic Glutamate Receptor 5 (mGluR5) Antagonism Prevents Cocaine-Induced Disruption of Postsynaptically Maintained mGluR5-Dependent Long-Term Depression

Brad A. Grueter,¹ Zoe A. McElligott,⁴ Alfred J. Robison,¹ Gregory C. Mathews,² and Danny G. Winder^1,2,3

¹Department of Molecular Physiology and Biophysics, ²Center for Molecular Neuroscience, ³J. F. Kennedy Center for Research on Human Development, and ⁴Neuroscience Graduate Program, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615

Correspondence should be addressed to Dr. Danny G. Winder, Department of Molecular Physiology and Biophysics, 23rd and Pierce Avenue South, Room 724B, RRB, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Email: danny.winder{at}vanderbilt.edu

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.

Key words: addiction; synaptic plasticity; mGluR5; LTD; cocaine; glutamate

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Received June 23, 2008; revised Aug. 3, 2008; accepted Aug. 10, 2008.

Correspondence should be addressed to Dr. Danny G. Winder, Department of Molecular Physiology and Biophysics, 23rd and Pierce Avenue South, Room 724B, RRB, Vanderbilt University School of Medicine, Nashville, TN 37232-0615. Email: danny.winder{at}vanderbilt.edu

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