Kappa opioid receptor modulation of nucleus accumbens feedforward inhibitory microcircuits

Abstract

The dynorphin/kappa opioid receptor (KOR) system within the nucleus accumbens (NAc) contributes to negative affective states following withdrawal from illicit drugs, pain, and stress. In the NAc, parvalbumin fast-spiking interneurons (PV-FSIs) receive similar excitatory input as neighboring medium spiny neurons (MSNs) and robustly inhibit MSN activity via feedforward inhibition. This critically regulates NAc circuit dynamics and has been implicated in impulsivity and psychostimulant induced associative learning. KORs have been shown to presynaptically inhibit glutamate, GABA, and dopamine release in the NAc. However, KOR regulation of feedforward inhibition remains untested. To address this gap, we first characterized KORs at glutamatergic synapses onto PV-FSIs in the NAc core (NAcc). We found that activation of KORs induced long-term depression (LTD) of excitatory drive onto PV-FSIs through postsynaptic PKA and calcium/calcineurin dependent endocytosis of AMPARs. We also report that KORs preferentially modulate midline nuclei of the thalamus (mThal) afferents and not prefrontal cortex (PFC) afferents onto NAcc PV-FSIs. We go on to show that KORs robustly decrease mThal driven feedforward inhibition onto both D1+ and D1- MSNs while only decreasing PFC driven feedforward inhibition onto D1- MSNs. As the NAc and dynorphin/KOR system are heavily recruited in stress-induced behavioral adaptations, we sought to determine the involvement of this mechanism in the response to stress. Mice subjected to restraint stress for one hour, a manipulation shown to increase NAc dynorphin, no longer expressed KOR dependent LTD. Importantly, LTD was rescued by administration of the KOR antagonist, nor-BNI, prior to restraint stress. This work identifies a novel synaptic mechanism by which KORs modulate NAc inhibitory microcircuits and for the recruitment and/or dysregulation of this mechanism following stress.