Pharmacological Modulation of Dopamine Receptors Reveals Distinct Brain-Wide Networks Associated with Learning and Motivation in Nonhuman Primates

The neurotransmitter dopamine (DA) has a multifaceted role in healthy and disordered brains through its action on multiple subtypes of dopaminergic receptors. How the modulation of these receptors influences learning and motivation by altering intrinsic brain-wide networks remains unclear. Here, we performed parallel behavioral and resting-state functional MRI experiments after administration of two different DA receptor antagonists in male and female macaque monkeys. Systemic administration of SCH-23390 (D1 antagonist) slowed probabilistic learning when subjects had to learn new stimulus-reward associations and diminished functional connectivity (FC) in corticocortical and frontostriatal connections. In contrast, haloperidol (D2 antagonist) improved learning and broadly enhanced FC in cortical connections. Further comparisons between the effect of SCH-23390/haloperidol on behavioral and resting-state FC revealed specific cortical and subcortical networks associated with the cognitive and motivational effects of DA manipulation, respectively. Thus, we reveal distinct brain-wide networks that are associated with the dopaminergic control of learning and motivation via DA receptors.