Dopaminergic Enhancement of Striatal Response to Reward in Major Depression

Abstract

Objective: Major depressive disorder is characterized by reduced reward-related striatal activation and dysfunctional reward learning, putatively reflecting decreased dopaminergic signaling. The goal of this study was to test whether a pharmacological challenge designed to facilitate dopaminergic transmission can enhance striatal responses to reward and improve reward learning in depressed individuals.

Method: In a double-blind placebo-controlled design, 46 unmedicated depressed participants and 43 healthy control participants were randomly assigned to receive either placebo or a single low dose (50 mg) of the D₂/D₃ receptor antagonist amisulpride, which is believed to increase dopamine signaling through presynaptic autoreceptor blockade. To investigate the effects of increased dopaminergic transmission on reward-related striatal function and behavior, a monetary incentive delay task (in conjunction with functional MRI) and a probabilistic reward learning task were administered at absorption peaks of amisulpride.

Results: Depressed participants selected previously rewarded stimuli less frequently than did control participants, indicating reduced reward learning, but this effect was not modulated by amisulpride. Relative to depressed participants receiving placebo (and control participants receiving amisulpride), depressed participants receiving amisulpride exhibited increased striatal activation and potentiated corticostriatal functional connectivity between the nucleus accumbens and the midcingulate cortex in response to monetary rewards. Stronger corticostriatal connectivity in response to rewards predicted better reward learning among depressed individuals receiving amisulpride as well as among control participants receiving placebo.

Conclusions: Acute enhancement of dopaminergic transmission potentiated reward-related striatal activation and corticostriatal functional connectivity in depressed individuals but had no behavioral effects. Taken together, the results suggest that targeted pharmacological treatments may normalize neural correlates of reward processing in depression; despite such acute effects on neural function, behavioral modification may require more chronic exposure. This is consistent with previous reports that antidepressant effects of amisulpride in depression emerged after sustained administration.

Keywords: Antidepressants; Biological Markers; Brain Imaging Techniques; Dopamine; Mood Disorders-Unipolar; Reward.

Figure 1

Procedure and timeline. Upon arrival to the scanning session participants completed a pre-MRI safety screening form and provided a urine sample for drug and pregnancy (if applicable) testing. Participants’ heart rate and blood pressure were then examined by the study physician. Next, the study physician administered a capsule of either amisulpride or placebo to participants. Participants were randomly selected to receive amisulpride or placebo, and the study physician and members of the research team were blind to the assignment of participants to active or placebo conditions. Participants then waited for one hour in a quiet room to allow amisulpride plasma concentration to peak (18, 19). During the waiting period participants practiced the Monetary Incentive Delay Task. Forty-five minutes post-drug administration, the study physician measured participants’ heart rate and blood pressure for the second time, and participants were asked to complete a drug side-effects questionnaire. Next, participants completed an (approximately 1.5 hour long) MRI scan that included structural scans and a functional scan while completing the Monetary Incentive Delay Task. Following the scan, and approximately 2.5 hours post-drug administration, participants completed the Probabilistic Selection Task (administered to coincide with the second peak in amisulpride plasma concentration (18, 19)). After completing the Probabilistic Selection Task, participants’ heart rate, blood pressure and side-effects were reexamined by the study physician and then, upon the physician’s approval, participants were debriefed, paid, and discharged. BP - Blood Pressure; MID - Monetary Incentive Delay; PST - Probabilistic Selection Task.

Figure 2

Striatal response to cues and outcomes. (A) Striatal response to cues, across all type, was greater in depressed participants receiving amisulpride compared to depressed participants receiving placebo (Caudate: p = 0.022; Nacc: p = 0.036; Putamen: p = 0.049), as well as compared to healthy control participants receiving amisulpride (Caudate: p = 0.017; Nacc (trend): p = 0.063). (B) Striatal response to reward outcomes was greater in depressed participants receiving amisulpride compared to depressed participants receiving placebo (Nacc, p = 0.007; Putamen, p = 0.050), as well as compared to control participants receiving amisulpride (Caudate, p = 0.044; Putamen, p = 0.003). Nacc activation in response to reward outcome was also higher in controls receiving placebo relative to depressed participants receiving placebo (p = 0.026). (C) Striatal response to penalty outcomes did not differ across groups and there was no consistent pattern across regions in the penalty condition.

Figure 3

Striatal connectivity in response to reward outcomes. (A) Whole-brain psychophysiological interaction (PPI) analyses revealed increased functional connectivity between the bilateral caudate and regions of the dorsal anterior cingulate cortex (dACC) (yellow), and between the bilateral nucleus accumbens (Nacc) and regions of the midcingulate cortex (MCC) (green) in response to reward outcomes across the entire sample at peak p<0.001, FWE p<0.05. No changes in striatal connectivity were found in response to penalty outcomes. (B) Caudate-dACC functional connectivity was significantly higher in control participants receiving placebo relative to all other groups (all p’s < 0.033). (C) Nacc-MCC functional connectivity was significantly higher in both controls receiving placebo and depressed participants receiving amisulpride than in depressed participants receiving placebo (p = 0.037; p = 0.022, respectively).

Figure 4

Reward learning and Nacc-MCC functional connectivity. Regression analyses revealed positive relationships between reward learning and reward-related nucleus accumbens to midcingulate (Nacc-MCC) functional connectivity in depressed participants receiving amisulpride (β = 0.65, p = 0.003) and healthy control participants receiving placebo (β = 0.54, p = 0.029), but not in depressed participants receiving placebo (β = −0.24, p = 0.354) or controls participants receiving amisulpride (β = 0.08, p = 0.740). Reward learning - “Choose A” accuracy from the Probabilistic Selection Task.