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

Abstract

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 GABAergic 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. Futhermore, we examined the signal transduction pathways that mediate this inhibition, and provide the first functional information implicating ERK 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 provide important inhibitory control over presynaptic GABAergic signaling within the BNST, and provide the first direct functional demonstration of KOR sensitive long-range GABAergic connections between the CeA and the BNST.

κ-Opioid Receptors in the Central Amygdala Regulate Ethanol Actions at Presynaptic GABAergic Sites

“…*P , 0.05; **P # 0.01. mediated by presynaptic mechanisms. Similar presynaptic actions of KOR activation have been recently demonstrated in the locus coeruleus (Kreibich et al, 2008) and bed nucleus of the stria terminalis (Li et al, 2012).…”

“…KORs are localized on axon terminals as well as on neuronal cell bodies, and they may act through two mechanisms: by inhibition of neurotransmission directly at terminal release sites (Svingos et al, 1999;Li et al, 2012) as well as by direct hyperpolarization of cell bodies (Margolis et al, 2003). An example of such modulation of neurotransmission, a decrease in dopamine release by the dynorphin/ KOR system in the nucleus accumbens (NAcc), was proposed as one mechanism underlying the effect on alcohol consumption (Lindholm et al, 2007).…”

Hypotheses Relating to the Function of the Claustrum

“…This may be interpreted as an inhibition of sensory binding. In our present context it is interesting that activation of the kappa opioid receptor has been shown to inhibit the release of GABA in the bed nucleus of the stria terminalis by a pre-synaptic mechanism (Li et al, 2012a). If the same holds in the claustrum, this would provide direct evidence that the GABAergic system in the claustrum may be related to sensory binding.…”

The role of the dynorphin/κ opioid receptor system in anxiety

“…Both stress and CRF cause dynorphin-dependent κ opioid receptor activation in the BLA, nucleus accumbens, dorsal raphe and hippocampus [30] . Recent evidence indicates that κ opioid receptors are expressed on the terminal of amygdala inputs to BNST [89] , a brain region strongly involved in fear and anxiety [90] . Thus, there is a considerable possibility that the dynorphin/κ opioid receptor system within these regions may play a role in anxiety.…”