Nucleus accumbens fast-spiking interneurons in motivational and addictive behaviors

Abstract

The development of drug addiction is associated with functional adaptations within the reward circuitry, within which the nucleus accumbens (NAc) is anatomically positioned as an interface between motivational salience and behavioral output. The functional output of NAc is profoundly altered after exposure to drugs of abuse, and some of the functional changes continue to evolve during drug abstinence, contributing to numerous emotional and motivational alterations related drug taking, seeking, and relapse. As in most brain regions, the functional output of NAc is critically dependent on the dynamic interaction between excitation and inhibition. One of the most prominent sources of inhibition within the NAc arises from fast-spiking interneurons (FSIs). Each NAc FSI innervates hundreds of principal neurons, and orchestrates population activity through its powerful and sustained feedforward inhibition. While the role of NAc FSIs in the context of drug addiction remains poorly understood, emerging evidence suggests that FSIs and FSI-mediated local circuits are key targets for drugs of abuse to tilt the functional output of NAc toward a motivational state favoring drug seeking and relapse. In this review, we discuss recent findings and our conceptualization about NAc FSI-mediated regulation of motivated and cocaine-induced behaviors. We hope that the conceptual framework proposed in this review may provide a useful guidance for ongoing and future studies to determine how FSIs influence the function of NAc and related reward circuits, ultimately leading to addictive behaviors.

Calcium-Permeable AMPA Receptors Promote Endocannabinoid Signaling at Parvalbumin Interneuron Synapses in the Nucleus Accumbens Core

“…CP-AMPARs are glutamate-gated ion channels lacking the post-transcriptionally edited GluA2 subunit ( Lalanne et al, 2018 ). Although developmentally regulated, GluA2-lacking CP-AMPARs mediate fast excitatory transmission at privileged synaptic loci within IN-embedded microcircuits ( Hu et al, 2014 ; Schall et al, 2020 ). CP-AMPARs exhibit greater single-channel conductance, inward rectification, and sharp activation-deactivation kinetics that confer specialized synaptic properties ( Twomey et al, 2017 , 2018 ).…”

Potassium Channels and Their Potential Roles in Substance Use Disorders

“…We used the NAc because behavioral phenomena that occur METH self-administration (METH SA) are thought to be regulated by interconnections between distinct brain regions that include that structure [ 113 ]. Neuroplastic changes in the NAc are thought to participate in the development and maintenance of drug-taking behaviors [ 114 ]. We found, for the first time, that rats that continued to take METH compulsively exhibited differential DNA hydroxymethylation in comparison with both control and nonaddicted rats [ 55 ].…”

Parvalbumin interneurons in the nucleus accumbens regulate impairment of risk avoidance inDISC1transgenic mice

“…We found that FS-neurons in the NAc had reduced firing rates after tamoxifen administration and this correlated with a decrease in local theta power. In the NAc area, FS interneurons modulate principal neurons through its powerful and sustained feedforward inhibition [40,41]. PV expressing interneurons, which constitute 1-2% of NAc neurons, have particular firing properties and are classified as FS-neurons [40,42].…”

“…In the NAc area, FS interneurons modulate principal neurons through its powerful and sustained feedforward inhibition [40,41]. PV expressing interneurons, which constitute 1-2% of NAc neurons, have particular firing properties and are classified as FS-neurons [40,42]. Other interneurons in the NAc that express somatostatin, neuropeptide Y, and neuronal nitric oxide synthase are classified as persistently low-threshold spiking (PLTS) neurons [42].…”