Frustrative nonreward and the basal ganglia: Chemogenetic inhibition and excitation of the nucleus accumbens and globus pallidus externus during reward downshift

Elsevier

Available online 21 February 2023, 107736

Neurobiology of Learning and MemoryAuthor links open overlay panel, , , Abstract

Frustrative nonreward induced by consummatory reward downshift (cRD) contributes to anxiety disorders and addiction, and is included in the Research Domain Criteria initiative as a relevant endophenotype. These experiments explored the role of the basal ganglia in cRD using inhibitory and excitatory DREADDs (designer receptors exclusively activated by designer drugs) infused in either the nucleus accumbens (NAc) or one of its downstream targets, the globus pallidus externus (GPe). NAc inhibition did not disrupt consummatory suppression during a 32-to-2% (Experiment 1) or 8-to-2% sucrose downshift (Experiment 2). However, NAc excitation enhanced consummatory suppression during a 32-to-2% sucrose downshift (Experiment 1). GPe inhibition caused a trend toward increased consummatory suppression after a 32-to-2% sucrose downshift, whereas GPe excitation eliminated consummatory suppression after an 8-to-2% sucrose downshift (Experiment 3). Chemogenetic manipulations of NAc and GPe had no detectable effects on open field activity. The effects of DREADD activation via clozapine N-oxide (CNO) administration were compared to controls that carried the DREADDs, but received vehicle injections. There was no evidence that CNO or vehicle injections in virus vector control (VVC) animals affected cRD or OF activity after either CNO or vehicle injections. NAc and GPe excitation led to opposite results in the cRD task, providing evidence that the basal ganglia circuit has a function in frustrative nonreward in the absence of motor effects.

Section snippetsintroduction

Frustrative nonreward is a negative emotional state induced by unexpected reductions or omissions of incentives (Amsel, 1992) that contributes to anxiety disorders and addiction (Ortega et al., 2017, Papini et al., 2015). Consummatory reward downshift (cRD) is an animal model used to induce frustrative nonreward, as shown by behavioral, pharmacological, and neurobiological evidence (Papini et al., 2015). Several techniques have been used to induce reward comparisons (e.g., DoMonte et al., 2017,

Experiment 1

Experiment 1 tested the effects of chemogenetic inhibition and excitation of the NAc on cRD. Evidence on the function of the NAc in cRD is ambiguous (see Introduction). A role of the NAc in cRD may be mediated by inputs from the BLA and/or the anterior paraventricular nucleus of the thalamus (aPVT). Inhibition of these inputs to the NAc increases behavioral responding during appetitive extinction, when behavior should be decreasing (e.g., DoMonte et al., 2017, Lafferty et al., 2020). This and

Subjects

The subjects were 58 male Wistar rats, experimentally naïve, and about 90 days old at the start of the experiment. These animals were bred in our colony from parents purchased from Charles River Laboratories. Pups were weaned at about 21 days of age and transferred to single-sex polycarbonate cages in groups of at least two animals. At around 40 days of age, they were transferred to wire-bottom cages, each containing a rodent retreat for enrichment, where they remained until the end of the

DREADD localization

Animals that lacked viral expression (n=3) or had viral expression significantly extended beyond the NAc (n=6) were excluded from all analyses. Thus, the sample was reduced from 58 to 49 animals after eliminating these 9 rats. The mean (±SEM) ad libitum weight of the 49 animals selected for analyses was 478.8 g (±6.0 g). Selected animals exhibited viral expression in the NAc and in both brain hemispheres. This final sample was distributed as follows: inhibitory DREADDs with CNO (n=9) and Veh (n

Experiment 2

Chemogenetic inhibition of the NAc caused a mild, albeit nonsignificant, enhancement of consummatory suppression in the cRD task (see Figure 3A). The possibility that a floor effect in the dependent measure prevented the emergence of the cRD effect was explored in Experiment 2. Chemogenetic excitation led to clear enhancement of consummatory suppression (see Figure 3B), so a similar suppressive effect of chemogenetic inhibition would be difficult to explain. In Experiment 2, chemogenetic

Method

The subjects were 25 male Wistar rats, experimentally naïve, and about 90 days old at the start of the experiment. The mean (±SEM) ad libitum weight of the 21 animals selected for analyses was 512.4 g (±12.9 g). Animals were randomly assigned to four groups: Inh/CNO, Inh/Veh, VVC/CNO, and VVC/Veh. In the cRD task, training conditions were as described in Experiment 1, except that these animals were exposed to an 8-to-2% sucrose downshift. All animals were perfused on the same day of exposure to

DREADDs localization

Animals that lacked viral expression in the NAc in both hemispheres (n=2), or expression of the viral construct extended beyond the target region (n=2) were excluded from all further analyses. Thus, the sample was reduced from 25 to 21 animals after eliminating these 4 rats. Animals selected for the final sample were distributed as follows: Inh/CNO (n=8), Inh/Veh (n=7), VVC/CNO (n=3), and VVC/Veh (n=3). Figure 4 shows the area of maximal fluorescence mapped on the Paxinos and Watson (2013)

Experiment 3

DREADD excitation, but not inhibition, of the NAc reduced licking in the aversive context of a sucrose downshift. Of the several efferent pathways from the NAc, its influence on the direct and indirect pathways of the BG was our primary focus (see Introduction). Based on the results of Experiment 1, it was hypothesized that chemogenetic excitation of the NAc activated the indirect pathway connecting the NAc with the GPe and the GPi (Conrad and Pfaff, 1976, Heimer et al., 1991, Williams et al.,

Method

The subjects were 60 male Wistar rats, experimentally naïve, and about 90 days old at the start of the experiment. The mean (±SEM) ad libitum weight of the 40 animals selected for analyses was 496.1 g (±7.9 g). Maintenance conditions, experimental procedures, and statistical analyses were as described in Experiment 1. The coordinates for infusion in the GPe were: AP: -2.2, ML: ±4.3, and DV: -7.95.

The cRD task involved access to sucrose solutions of different concentrations prepared as described

DREADDs localization

Animals that lacked viral expression in both hemispheres (n=5) or had viral expression significantly extending beyond the GPe (n=15) were excluded from all analyses. Thus, the sample was reduced from 60 to 40 animals after eliminating these 20 rats. Using the same infusion rate as in Experiment 1 in the NAc combined with the narrower shape of the GPe might have caused extended expression outside the target area. Animals included in the final sample (n=40) exhibited viral expression in the GPe

General discussion

This article focused on the role of the NAc and GPe in frustrative nonreward triggered by a high-to-low sucrose downshift in the cRD task (Ortega et al., 2017, Papini et al., 2015). In cRD experiments, preshift-to-postshift reward disparity can be adjusted to minimize floor or ceiling effects. The preshift sucrose concentrations used in these experiments (32% and 8% sucrose) were used to minimize floor or ceiling effects on licking that could obscure chemogenetic effects. For example,

CRediT authorship contribution statement

Sara Guarino: Conceptualization, Methodology, Writing – review & editing. Christopher Hagen: Conceptualization, Methodology, Writing – review & editing. Quynh Nguyen: Conceptualization, Writing – review & editing. Mauricio R. Papini: Conceptualization, Data curation, Writing – original draft, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The National Institute on Drug Abuse Drug Supply Program provided the clozapine N-oxide (CNO) used in these studies. This research was partially funded by TCU/SERC grants G-180614 (SG), G-200408 (SG), G-200409 (CH), UG-180534 (QN), UG-200736 (QN), and UG-190630 (to A. DeMarco); Psi Chi grant 23728PS (QN, MRP); and by grants from the TCU Honors College (QN). The authors thank A. F. Clark and Y. Liu for providing access to the fluorescence microscope for processing images at the University of

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