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

• DOI: 10.1523/jneurosci.0170-06.2006
• Publication Date: 2006-03-22T20:18:20Z
• Authors: Brad A. Grueter; Heather B. Gosnell; Christopher M. Olsen; Nicole L. Schramm...; Tanya Nekrasova; Gary E. Landreth; Danny G. Winder
• Keywords: Male; Mice, Knockout; Mitogen-Activated Protein Kinase 3; Long-Term Synaptic Depression; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Anxiety Disorders; Synaptic Transmission; Mice, Inbred C57BL; Cocaine-Related Disorders; Disease Models, Animal; Mice; 03 medical and health sciences; Organ Culture Techniques; 0302 clinical medicine; Cocaine; Dopamine Uptake Inhibitors; Receptor, Cannabinoid, CB1; Reward; Animals; Septal Nuclei; Stress, Psychological

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.