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The Journal of Neuroscience, March 22, 2006, 26(12):3210-3219; doi:10.1523/JNEUROSCI.0170-06.2006

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Cellular/Molecular
Extracellular-Signal Regulated Kinase 1-Dependent Metabotropic Glutamate Receptor 5-Induced Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted by Cocaine Administration

Brad A. Grueter,¹ Heather B. Gosnell,¹ Christopher M. Olsen,^1,2 Nicole L. Schramm-Sapyta,¹ Tanya Nekrasova,³ Gary E. Landreth,³ and Danny G. Winder^1,2

¹Departments of Molecular Physiology and Biophysics and ²Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and ³Alzheimer's Research Laboratory, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

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

The bed nucleus of the stria terminalis (BNST) is a key component of the CNS stress and reward circuit. Synaptic plasticity in this region could in part underlie the persistent behavioral alterations in generalized anxiety and addiction. Group I metabotropic glutamate receptors (mGluRs) have been implicated in stress, addiction, and synaptic plasticity, but their roles in the BNST are unknown. We find that activation of group I mGluRs in the dorsal BNST induces depression of excitatory synaptic transmission through two distinct mechanisms. First, a combined activation of group I mGluRs (mGluR1 and mGluR5) induces a transient depression that is cannabinoid 1 receptor dependent. Second, as with endocannabinoid-independent group I mGluR long-term depression (LTD) in the adult hippocampus, we find that activation of mGluR5 induces an extracellular signal-regulated kinase (ERK)-dependent LTD. Surprisingly, our data demonstrate that this LTD requires the ERK1 rather than ERK2 isoform, establishing a key role for this isoform in the CNS. Finally, we find that this LTD is dramatically reduced after multiple exposures but not a single exposure to cocaine, suggesting a role for this form of plasticity in the actions of psychostimulants on anxiety and reward circuitries and their emergent control of animal behavior.

Key words: drug addiction; stress; anxiety; synaptic plasticity; extended amygdala; excitatory transmission

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Received Aug. 17, 2005; revised Feb. 9, 2006; accepted Feb. 9, 2006.

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

This article has been cited by other articles:

				L. Massi, I. Elezgarai, N. Puente, L. Reguero, P. Grandes, O. J. Manzoni, and F. Georges Cannabinoid Receptors in the Bed Nucleus of the Stria Terminalis Control Cortical Excitation of Midbrain Dopamine Cells In Vivo J. Neurosci., October 15, 2008; 28(42): 10496 - 10508. [Abstract] [Full Text] [PDF]

				B. A. Grueter, Z. A. McElligott, A. J. Robison, G. C. Mathews, and D. G. Winder In Vivo Metabotropic Glutamate Receptor 5 (mGluR5) Antagonism Prevents Cocaine-Induced Disruption of Postsynaptically Maintained mGluR5-Dependent Long-Term Depression J. Neurosci., September 10, 2008; 28(37): 9261 - 9270. [Abstract] [Full Text] [PDF]

				G. M. Drew, V. A. Mitchell, and C. W. Vaughan Glutamate Spillover Modulates GABAergic Synaptic Transmission in the Rat Midbrain Periaqueductal Grey via Metabotropic Glutamate Receptors and Endocannabinoid Signaling J. Neurosci., January 23, 2008; 28(4): 808 - 815. [Abstract] [Full Text] [PDF]

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