Accumbens dopamine D2 receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum

Abstract

Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons. In vivo physiology confirms the reduction in indirect pathway inhibitory transmission to the VP, and inhibition of indirect pathway terminals to VP is sufficient to enhance motivation. In contrast, D2R upregulation in the indirect pathway does not disinhibit neuronal activity of the direct pathway in vivo. These data suggest that D2Rs in ventral striatal projection neurons promote motivation by weakening the canonical output to the ventral pallidum.

Modulating Dopamine Signaling and Behavior with Chemogenetics: Concepts, Progress, and Challenges

“…This is further supported by a study by Gallo et al substantiating a role of the ventral pallidum. It was shown in this study that activation of hM4Di expressed in NAc iMSNs projecting to the ventral pallidum increased motivation to work for a salient reward in a lever-pressing task with progressive ratio schedule (Gallo et al, 2018). Of additional interest, selective hM3Dq-stimulation of NAc interneurons expressing nitric oxide synthase was demonstrated to increase sucrose seeking after extinction and cue-induced reinstatement .…”

Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders

“…D2R‐OE NacInd mice also showed an increased rate of lever pressing for a preferred food (milk) when less preferred home cage chow was available for no effort. Combined, these results indicate that increased D2Rs in NAc indirect MSNs increase locomotor activity, including in situations incentivized by preferred food . Motivation for all types of reinforcement was not altered as alcohol consumption and cocaine place preference were not affected by this intervention …”

“…To determine the consequences of D2R up‐regulation when restricted to the indirect pathway, a virus containing a Cre‐dependent form of Drd2 was injected into the NAc of adult D2‐Cre mice (D2R‐OE NacInd mice) . This technique resulted in a 3‐fold increase in D2Rs and avoided the expression of D2Rs in direct MSNs that occurred in the D2R‐OE dev mice and other non–cell‐type‐specific virus‐mediated up‐regulation .…”

“…In line with this, the selective up‐regulation of D2Rs in indirect MSNs by Gallo and colleagues had two main circuit‐level effects. While it decreased synaptic transmission at indirect‐to‐direct MSN collaterals, it also decreased baseline transmission to the ventral pallidum (VP) . Therefore, the motivational enhancement could be explained by disinhibition of the direct pathway via collaterals, or by inhibition of indirect pathway transmission to the VP.…”

A new GABAergic projection from the BNST onto accumbal parvalbumin neurons controls anxiety

“…Regarding anxiety regulation, it is accepted that D1-MSNs are not involved in anxiety-related behavior, but play roles in modulating reward-related responses 14, 15 whereas D2-MSNs may regulate anxiety-related aversion or avoidance behavior 16 . However, the role of D2-MSNs are not entirely clear because other work points to a role in reward seeking, but not anxiety-related behavior 17, 18 . Based on these very different findings, we predicted that there is another neuronal type within the NAc that contributes to anxiety-related behavior.…”