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

J Neurosci. 2006 Mar 22;26(12):3210-9. doi: 10.1523/JNEUROSCI.0170-06.2006.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety Disorders / metabolism
  • Anxiety Disorders / physiopathology
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / metabolism*
  • Cocaine-Related Disorders / physiopathology
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / pharmacology
  • Long-Term Synaptic Depression / drug effects*
  • Long-Term Synaptic Depression / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 3 / drug effects*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Organ Culture Techniques
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / drug effects*
  • Receptors, Metabotropic Glutamate / metabolism
  • Reward
  • Septal Nuclei / drug effects*
  • Septal Nuclei / metabolism
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Dopamine Uptake Inhibitors
  • Grm5 protein, mouse
  • Receptor, Cannabinoid, CB1
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Mitogen-Activated Protein Kinase 3
  • Cocaine