Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation

Abstract

A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum--including the nucleus accumbens (NAc)--impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc.

Figure 1. Characterization of the D2R-mVenus overexpression

(A) Fusion of mVenus to the D2R receptor did not alter the ability of the agonist quinpirole to activate G protein as demonstrated in an aequorin-based assay. Quinpirole-induced luminescence was determined as described in Material and Methods and expressed as a percentage of the maximal response for each construct. Results of 3 independent experiments are represented as mean ± S.E.M fit to a sigmoidal dose response non-linear regression. (B) Representative examples of D2R-mVenus expression by AAV injection in NAc (top) and CPu (bottom). (C) Specificity of the anti-D2R antibody was determined by comparison of a wildtype and D2R KO stained sections (top row). D2R-mVenus expression highly overlaps with endogenous D2R expression (bottom row). (D) D2R-mVenus co-localized with MAP2, consistent with a dendritic/postsynaptic localization of the receptor. Scale bars: 30 μm. (E) Diagrammatic representation of the maximal (colors) and minimal (gray) extent of spread of D2R-mVenus (orange) and GFP (blue) for CPu (right diagram) and NAc (left diagram); numbers indicate distance from Bregma.

Figure 2. D2R overexpression in the NAc or the CPu does not alter operant learning

D2R overexpression in the NAc (A) or CPu (B) did not alter learning of the operant procedure in a continuous reinforcement schedule (CRF) or performance in fixed interval (FI) schedules.

Figure 3. D2R overexpression in the NAc, but not the CPu, increases effort in a progressive ratio task and a choice paradigm

D2R overexpression in the NAc (A) but not in the CPu (B) enhanced the average number of lever presses in a progressive ratio task. When tested in random ratio (RR) paradigms, D2R overexpression in the NAc (C) or the CPu (D) had no effect on operant response in any of the random ratios tested (number of sessions pooled for each ratios: RR5=13; RR10=4; RR20=7). However, when tested in a choice lever pressing/chow feeding procedure (number of sessions pooled for each ratios: RR5=9; RR10=8; RR20=12), mice overexpressing D2R in the NAc (E) showed an enhancement in their rate of lever press, whereas overexpression of D2R in the CPu (F) had no effect. (* statistically significant).

Figure 4. Animals that overexpress D2R in the NAc - but not the CPu – maintain their rate of lever presses in the choice procedure and eat less of the free chow

(A) Ratio (lever presses in choice)/(lever presses in no-choice) in the NAc and CPu (B) groups. Amount of chow consumed in the choice paradigm in the NAc group (C) and CPu (D) groups. (* statistically significant).

Figure 5. D2R overexpression does not affect representation of outcome or incentive value

D2R overexpression in the NAc (A, C) or the CPu (B, D) had no effect on satiety devaluation (A, B) by pre-feeding with either chow or evaporated milk, or on Pavlovian-to-instrumental transfer (C, D).