Dopamine D2 receptors in nucleus accumbens cholinergic interneurons increase impulsive choice

Abstract

Impulsive choice, often characterized by excessive preference for small, short-term rewards over larger, long-term rewards, is a prominent feature of substance use and other neuropsychiatric disorders. The neural mechanisms underlying impulsive choice are not well understood, but growing evidence implicates nucleus accumbens (NAc) dopamine and its actions on dopamine D2 receptors (D2Rs). Because several NAc cell types and afferents express D2Rs, it has been difficult to determine the specific neural mechanisms linking NAc D2Rs to impulsive choice. Of these cell types, cholinergic interneurons (CINs) of the NAc, which express D2Rs, have emerged as key regulators of striatal output and local dopamine release. Despite these relevant functions, whether D2Rs expressed specifically in these neurons contribute to impulsive choice behavior is unknown. Here, we show that D2R upregulation in CINs of the mouse NAc increases impulsive choice as measured in a delay discounting task without affecting reward magnitude sensitivity or interval timing. Conversely, mice lacking D2Rs in CINs showed decreased delay discounting. Furthermore, CIN D2R manipulations did not affect probabilistic discounting, which measures a different form of impulsive choice. Together, these findings suggest that CIN D2Rs regulate impulsive decision-making involving delay costs, providing new insight into the mechanisms by which NAc dopamine influences impulsive behavior.

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

“…Previous studies have shown that the inactivation of the orbitofrontal cortex 28 and the nucleus accumbens 4 produces different effects on delay discounting depending on the basal levels of impulsivity, and suggested that low and high impulsivity have different neurobiological substrates 52 . In support of this idea, evidence shows that a higher number of D2 dopamine receptors in the mPFC 42 and the nucleus accumbens 45 is associated with low and high impulsivity, respectively. Furthermore, a very recent study shows that basal impulsivity is associated with the activity of mPFC-nucleus accumbens projections 32 .…”

“…Moreover, ISD did not change accuracy or choice latency, which indicates that ISD does not produce general alterations in cognitive (i.e., attention, working memory) or motor (i.e., motor impulsivity) behavior. The effects of ISD increasing delay discounting could be related to alterations in time processing (i.e., increase delay intolerance) or due to alterations in the subjective value of rewards, giving more value to immediate rewards in a context of higher uncertainty 43,[45][46][47] .…”