Presynaptic Inhibition of Gamma-Aminobutyric Acid Release in the Bed Nucleus of the Stria Terminalis by Kappa Opioid Receptor Signaling

Background: The kappa opioid receptor (KOR) and its endogenous agonist, the neuropeptide dynorphin, are a critical component of the central stress system. Both dynorphin and KOR are expressed in the bed nucleus of the stria terminalis (BNST), a brain region associated with anxiety and stress. This suggests that KOR activation in this region may play a role in the regulation of emotional behaviors. To date, however, there has been no investigation of the ability of KOR to modulate synaptic transmission in the BNST. Methods: We used whole-cell patch-clamp recordings from acutely prepared mouse brain slices to examine the actions of KOR on inhibitory transmission in the BNST. Additionally, we used neurochemical and pathway-specific optogenetic manipulations to selectively stimulate gamma-aminobutyric acid (GABA)ergic fibers from the central nucleus of the amygdala (CeA) to the BNST. Results: We found that activation of KOR reduced GABAergic transmission through a presynaptic mechanism. Furthermore, we examined the signal transduction pathways that mediate this inhibition and provide the first functional information implicating extracellular signal-regulated kinase in KOR-mediated presynaptic modulation. Moreover, we found that at KOR signaling robustly reduced inhibitory synaptic transmission in the CeA to BNST pathway. Conclusions: Together, these results demonstrate that KOR provides important inhibitory control over presynaptic GABAergic signaling within the BNST and provides the first direct functional demonstration of KOR-sensitive long-range GABAergic connections between the CeA and the BNST.