Dopaminergic Enhancement of Striatal Response to Reward in Major Depression

Am J Psychiatry. 2017 Apr 1;174(4):378-386. doi: 10.1176/appi.ajp.2016.16010111. Epub 2016 Oct 24.

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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Amisulpride
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Corpus Striatum / drug effects*
  • Corpus Striatum / physiopathology*
  • Cues
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology*
  • Depressive Disorder, Major / prevention & control
  • Dopamine / physiology*
  • Dopamine Antagonists / therapeutic use*
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / physiology*
  • Double-Blind Method
  • Female
  • Humans
  • Magnetic Resonance Imaging*
  • Male
  • Motivation / drug effects
  • Motivation / physiology
  • Reward*
  • Sulpiride / analogs & derivatives*
  • Sulpiride / therapeutic use
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology*

Substances

  • Dopamine Antagonists
  • Sulpiride
  • Amisulpride
  • Dopamine