Activation of D1 receptors affects human reactivity and flexibility to valued cues

Abstract

Reward-predicting cues motivate goal-directed behavior, but in unstable environments humans must also be able to flexibly update cue-reward associations. While the capacity of reward cues to trigger motivation ('reactivity') as well as flexibility in cue-reward associations have been linked to the neurotransmitter dopamine in humans, the specific contribution of the dopamine D1 receptor family to these behaviors remained elusive. To fill this gap, we conducted a randomized, placebo-controlled, double-blind pharmacological study testing the impact of three different doses of a novel D1 agonist (relative to placebo) on reactivity to reward-predicting cues (Pavlovian-to-instrumental transfer) and flexibility of cue-outcome associations (reversal learning). We observed that the impact of the D1 agonist crucially depended on baseline working memory functioning, which has been identified as a proxy for baseline dopamine synthesis capacity. Specifically, increasing D1 receptor stimulation strengthened Pavlovian-to-instrumental transfer in individuals with high baseline working memory capacity. In contrast, higher doses of the D1 agonist improved reversal learning only in individuals with low baseline working memory functioning. Our findings suggest a crucial and baseline-dependent role of D1 receptor activation in controlling both cue reactivity and the flexibility of cue-reward associations.

Figures

Fig. 1. Task design and results for Pavlovian-to-instrumental transfer (PIT) task.

a In the initial instrumental conditioning phase, participants learned to associate distinct behavioral responses (key presses) with distinct primary reinforcers (popcorn and smarties). b During Pavlovian conditioning, participants associated four different predictive cues with one of four outcome types (popcorn, smarties, cashew nuts, and nothing). c In the final transfer-test PIT phase, we measured key presses to the Pavlovian cues. d In individuals with high baseline WMC, stronger D1R stimulation increased PIT (independently of PIT type), indicating enhanced cue reactivity. No significant drug effects occurred in low WMC individuals.

Fig. 2. Task design and results for the reversal learning task.

a In each trial, one of two stimuli (a house and a landscape) was selected by the computer (indicated by a white frame) and participants had to predict whether the selected stimulus was associated with a reward (a happy smiley) or with punishment (a sad smiley). After participants’ prediction, the outcome was presented. Stimulus–outcome associations reversed after variable numbers of correct predictions. b D1R stimulation had no impact on predictions of the correct outcome following reversal trials with unexpected rewards. c Following unexpected punishment, increasing D1R activation improved behavior selectively in individuals with low baseline WMC.