Striatal dopamine D2/D3 receptor regulation of human reward processing and behaviour

Abstract

Signalling at dopamine D2/D3 receptors is thought to underlie motivated behaviour, pleasure experiences and emotional expression based on animal studies, but it is unclear if this is the case in humans or how this relates to neural processing of reward stimuli. Using a randomised, double-blind, placebo-controlled, crossover neuroimaging study, we show in healthy humans that sustained dopamine D2/D3 receptor antagonism for 7 days results in negative symptoms (impairments in motivated behaviour, hedonic experience, verbal and emotional expression) and that this is related to blunted striatal response to reward stimuli. In contrast, 7 days of partial D2/D3 agonism does not disrupt reward signalling, motivated behaviour or hedonic experience. Both D2/D3 antagonism and partial agonism induce motor impairments, which are not related to striatal reward response. These findings identify a central role for D2/D3 signalling and reward processing in the mechanism underlying motivated behaviour and emotional responses in humans, with implications for understanding neuropsychiatric disorders such as schizophrenia and Parkinson's disease.

Fig. 1. Study design.

The order of study interventions and measures for the two arms of the study is shown. The arms were conducted sequentially, with arm 1 completed prior to arm 2 commencing. The order of treatments within each arm (active drug or placebo first) was randomised and counter-balanced to ensure approximately equal numbers of subjects receiving drug or placebo first. Subjects and investigators were blind to the treatment allocation. The washout period was a minimum of 10 days for amisulpride, and a minimum of 28 days for aripiprazole. The monetary incentive delay (MID) task, Brief Negative Symptom Scale (BNSS), Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) were performed at baseline, follow up (FU) 1 and FU 2 visits, to measure the neural response during reward processing and behavioural, hedonic, and motor effects.

Fig. 2. Effects of the D2/D3 antagonist amisulpride on human-motivated behaviour, hedonic and emotional responses, motor function and reward processing.

A Effect of amisulpride vs placebo on negative symptoms (Brief Negative Symptom Scale, individual values with mean ± SE). n = 29, linear mixed-effects model: b = 4.62, t(49) = 2.51, 95% CI = 0.92:8.32, two-sided p = 0.015. B Effect of amisulpride vs placebo on akathisia (Barnes Akathisia Rating Scale, individual values with mean ± SE). n = 29, linear mixed effects model: b = 1.48, t(50) = 4.53, 95% CI = 0.83:2.14, two-sided p = 3.63 × 10⁻⁵. C Effect of amisulpride vs placebo on parkinsonism (Simpson Angus Scale, individual values with mean ± SE). n = 29, linear mixed effects model: b = 1.03, t(50) = 3.12, 95% CI =  0.37:1.69, two-sided p = 0.0030. D Effect of amisulpride vs placebo on caudate activation during reward outcome in monetary incentive delay (MID) task (individual values with mean ± SE of beta values). n = 21, paired sample t-test: mean difference = −146.2, t(20) = 3.17, 95% CI = −50.0:−242.4, FDR corrected two-sided p = 0.014. E Relationship between change in caudate BOLD signal during reward outcome on amisulpride and plasma amisulpride levels (μg/L). n = 22, Pearson’s r = −0.44, FDR corrected p-value = 0.041. F Relationship between reduction in caudate reward outcome activation and ranked increase in negative symptoms on amisulpride (BNSS). n = 21, Spearman’s rho = −0.49, FDR corrected p-value = 0.041. G Whole-brain statistical maps showing areas of reduced BOLD signal on amisulpride vs placebo during reward outcome. n = 21. Colour bar indicates z-statistic. Source data are provided as a Source data file.

Fig. 3. Effects of the D2/D3 partial agonist aripiprazole on human-motivated behaviour, hedonic and emotional responses, motor function and reward processing.

A Effect of aripiprazole vs placebo on negative symptoms (Brief Negative Symptom Scale, individual values with mean ± SE). n = 27, linear mixed effects model: BNSS: b = 1.24, t(48) = 1.69, 95% CI = −0.24:2.72, two-sided p = 0.10. B Effect of aripiprazole vs placebo on akathisia (Barnes Akathisia Rating Scale, individual values with mean ± SE). n = 27, linear mixed effects model: b = 1.04, t(49) = 3.31, 95% CI  = 0.41:1.67, two-sided p = 0.0017. C Effect of aripiprazole vs placebo on parkinsonism (Simpson Angus Scale, individual values with mean ± SE). n = 27, linear mixed effects model: b = 1.19, t(48) = 3.61, 95% CI = 0.53:1.85, two-sided p = 0.00073. D Effect of aripiprazole vs placebo on caudate activation during reward outcome in monetary incentive delay (MID) task (individual values with mean ± SE of beta values). n = 22, paired sample t-test: mean difference = 26.8, t(21) = 0.62, 95% CI = −116.4:62.7, FDR corrected two-sided p = 0.54. Source data are provided as a Source data file.

Fig. 4. Comparison between the effects of the D2/D3 antagonist amisulpride and the D2/D3 partial agonist aripiprazole on human-motivated behaviour, hedonic and emotional responses, motor function and reward processing.

A Comparison of amisulpride–placebo (AMI–PLAC) differences to aripiprazole–placebo (ARI–PLAC) differences on negative symptoms (Brief Negative Symptom Scale, individual values with mean ± SE). n = 56, Student’s t-test: t(54) = −1.71, two-sided p = 0.094. B Comparison of AMI–PLAC differences to ARI–PLAC differences on akathisia (Barnes Akathisia Rating Scale, individual values with mean ± SE). n = 56, Student’s t-test: t(54) = 0.97, two-sided p = 0.33. C Comparison of AMI–PLAC differences to ARI–PLAC differences on Parkinsonism (Simpson Angus Scale, individual value with mean ± SE). n = 56, Student’s t-test: t(54) = 0.33, two-sided p = 0.74. D Comparison of AMI–PLAC differences to ARI–PLAC differences on reward outcome activation in caudate from monetary incentive delay (MID) task (individual values with mean ± SE of beta values). n = 43, independent sample t-test: mean difference = =173.0, t(41) = −2.75, 95% CI: −300.3:−45.7, FDR corrected two-sided p-value = 0.027, Cohen’s d = 0.84. E Statistical map for brain regions where the reduction in neural response during reward outcome  on AMI is greater than that on ARI, relative to placebo. n = 43. Colour bar indicates z-statistic. Source data are provided as a Source data file.