Kappa opioid receptor modulation of excitatory drive onto nucleus accumbens fast-spiking interneurons

Abstract

The dynorphin/kappa opioid receptor (KOR) system within the nucleus accumbens (NAc) contributes to affective states. Parvalbumin fast-spiking interneurons (PV-FSIs), a key component of feedforward inhibition, participate in integration of excitatory inputs to the NAc by robustly inhibiting select populations of medium spiny output neurons, therefore greatly influencing NAc dependent behavior. How the dynorphin/KOR system regulates feedforward inhibition in the NAc remains unknown. Here, we elucidate the molecular mechanisms of KOR inhibition of excitatory transmission onto NAc PV-FSIs using a combination of wholecell patch-clamp electrophysiology, optogenetics, pharmacology, and a parvalbumin reporter mouse. We find that postsynaptic KOR stimulation induces long-term depression (LTD) of excitatory synapses onto PV-FSI by stimulating the endocytosis of AMPARs via a PKA and calcineurin-dependent mechanism. Furthermore, KOR regulation of PV-FSI synapses are input specific, inhibiting thalamic but not cortical inputs. Finally, following acute stress, a protocol known to elevate dynorphin/KOR signaling in the NAc, KOR agonists no longer inhibit excitatory transmission onto PV-FSI. In conclusion, we delineate pathway-specific mechanisms mediating KOR control of feedforward inhibitory circuits in the NAc and provide evidence for the recruitment of this system in response to stress.

Opioid Receptor-Mediated Regulation of Neurotransmission in the Brain

“…KOR inhibition of glutamate transmission in NAc MSNs is lost in animals with 5 days of repeated cocaine exposure with at least up to 2 weeks of withdrawal ( Mu et al, 2011 ). KORs also regulate glutamatergic input to PV-expressing FSIs in NAc, however, this is specific to thalamic, but not cortical inputs ( Coleman et al, 2021 ). In addition, activation of KORs produces a postsynaptic LTD plasticity, wherein AMPARs are internalized via a PKA-calcineurin signaling pathway.…”

Cocaine self-administration augments kappa opioid receptor system-mediated inhibition of dopamine activity in the mesolimbic dopamine system

“…While we were able to show augmented KOR-induced inhibition of DA release after cocaine self-administration, as well as elevated Pdyn and Oprk mRNA levels in the NAc, we do not know the location of the increased KORs in the NAc. KORs are located not only on the axonal DA projections from the VTA to the NAc ( Svingos et al, 1999 ), but also on various pre-and post-synaptic sites, including but not limited to cholinergic interneurons as well as serotonergic ( Fontaine et al, 2022 ) and glutamatergic ( Svingos et al, 1999 , Coleman et al, 2021 ) afferents.…”

Dichotomic Regulation of Striatal Plasticity by Dynorphin

“…KORs are expressed in both pre- and postsynaptic sites (Svingos et al, 2001). In addition to its prominent presynaptic actions on glutamatergic and dopaminergic inputs to SPNs (Nestler, 2004), postsynaptic KOR activation can also lead to AMPARs endocytosis via protein kinase A (PKA)/calcineurin-dependent mechanisms in interneurons (Coleman et al, 2021). Because LTP expression in dSPN requires postsynaptic activation of D1R, which subsequently upregulates the adenylate cyclase (AC)/protein kinase A (PKA) cascade pathway (Surmeier et al, 2014), and KOR can downregulate AC/PKA signaling through Gi/o-coupled mechanism (Bruchas and Chavkin, 2010; Gentleman et al, 1983), it is likely that Dyn/KOR signaling directly interacts with D1R signaling to bi-directionally regulate LTP expression in dSPNs through a postsynaptic mechanism.…”

“…KORs are expressed in both pre-and postsynaptic sites (Svingos et al, 2001). In addition to its prominent presynaptic actions on glutamatergic and dopaminergic inputs to SPNs (Nestler, 2004), postsynaptic KOR activation can also lead to AMPARs endocytosis via protein kinase A (PKA)/calcineurin-dependent mechanisms in interneurons (Coleman et al, 2021).…”

“…For example, activation of KOR by Dyn can suppress dopamine (DA) release in the striatum (Di Chiara and Imperato, 1988; Spanagel et al, 1992) and the effect is short-term and can be reverted after washout (Ehrich et al, 2015). In addition, acute KOR activation can also suppress glutamatergic synaptic transmission (Coleman et al, 2021; Mu et al, 2011) or prolonged activation of KOR causes long-term depression (LTD) (Atwood et al, 2014) through pre-synaptic mechanisms.…”