Metabotropic glutamate receptor mediated synaptic plasticity in the bed nucleus of the stria terminalis as a target for stress, anxiety and addiction disorders

Abstract

The importance of integration of information from neurocircuits innervating the reward circuitry is becoming increasingly recognized. For instance, the roles of stress/anxiety pathways in modulating specific effects of the reward system are becoming more apparent. Behavioral data suggest the bed nucleus of the stria terminalis (BNST) is involved in integrating stress information and relaying this information to the stress and reward pathways. Moreover, behavioral data suggest glutamatergic transmission in the BNST as well as other regions in the stress/reward pathways plays an integral role in regulating stress and drug addiction behaviors. Changes in synaptic physiology in the BNST could in part underlie the persistent behavioral alterations in generalized anxiety, addiction and post-traumatic stress disorder. Metabotropic glutamate receptors (mGluRs) have been implicated in stress, addiction and synaptic plasticity, but their roles in the BNST are currently unknown. Field recordings and whole-cell patch clamp analysis in an in vitro slice preparation of C57/Bl6j adult male mouse dorsolateral BNST were utilized. Activation of either group I, group II or group III mGluRs in the dBNST causes a depression of excitatory synaptic transmission. Further characterization of mGluR5-dependent long-term depression (LTD) of excitatory synaptic transmission indicates this LTD is associated with a decrease in miniature EPSC frequency but not a change in paired pulse ratios of evoked responses. This suggests a novel maintenance mechanism for this form of LTD. Potential downstream effectors of group I mGluRs that have also been implicated in stress, addiction and synaptic plasticity are the cannabinoid system and extracellular signal regulated kinase (ERK). mGluR5-mediated LTD in the BNST is G-protein dependent, and persists in the cannabinoid receptor 1 knockout mouse. Further, converging pharmacological and genetic approaches suggest the mGluR5-mediated LTD in the BNST is ERK dependent. Consistent with an emerging role for group I mGluRs in drug addiction, mGluR5-mediated LTD in the BNST is attenuated in mice trained to self-administer cocaine.