Stress- and Drug-Dependent Regulation of Metabotropic Glutamate Receptors in the Bed Nucleus of the Stria Terminalis

Abstract

Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory transmission throughout the central nervous system, and have been implicated in a variety of neurological disorders. This work focuses primarily on two mGluR subtypes, mGluR5 and mGluR8, both of which act to depress excitatory transmission in the bed nucleus of the stria terminalis (BNST). The BNST is an integral component of the brain’s stress/anxiety and addiction circuitry, and excitatory transmission in this region is thought to be recruited by both in vivo stress and in vivo drug exposure. The first part of this thesis focuses on mGluR5, the function of which is altered by in vivo cocaine. Using biochemical techniques, I characterized mGluR5 activation of the ERK/MAPK cascade and examined several potential mechanisms by which cocaine could regulate mGluR5 function in vivo. I found no change in gross surface levels of mGluR5 in the BNST after in vivo cocaine and that mGluR5 antagonism failed to block cocaine-induced ERK activation. This suggests cocaine-induced disruption of mGluR5 function is not targeting the receptor itself, but rather occurs upstream of mGluR5-induced ERK activation. Thus, the mechanism of cocaine-induced disruption of mGluR5 function remains unknown. The second half of this thesis focuses on mGluR8, unique among mGluR subtypes for its distinct expression patterns. Mice lacking mGluR8 exhibit a naïve anxiety phenotype, suggesting this receptor may function as a brake to prevent activation of anxiety circuitry. Using electrophysiology, I utilized converging pharmacological and genetic approaches to identify an important role for mGluR8 in regulating excitatory transmission in the BNST. Furthermore, I found that mGluR8 function is regulated by adrenergic receptor signaling in the BNST, and is disrupted by in vivo stress exposure. Overall, this thesis highlights the importance of the BNST in stress and addiction circuitry, and identifies mGluR8 as a critical regulator of excitatory transmission in this region that is selectively disrupted by noradrenergic signaling and in vivo stress.