Differential D1 and D2 receptor internalization and recycling induced by amphetamine in vivo

The dopamine system plays a significant role in drug reward and the pathogenesis of addiction. Psychostimulant drugs acutely increase dopamine levels, triggering receptor internalization. In vitro data suggest that dopamine D1 receptors (D1R) recycle, whereas D2 receptors (D2R) degrade in response to activation. Yet, receptor fates in vivo remain unclear. This study bridges in vitro mechanisms and in vivo measurements of stimulant-induced modulation of receptor states using longitudinal multi-modal imaging combined with neuropharmacology. We demonstrate how repeated amphetamine administration differentially modulates D1R vs. D2R signaling in nonhuman primates over 24 hours using simultaneous positron emission tomography and functional magnetic resonance imaging. In contrast to predominantly inhibitory D2R signaling due to an initial amphetamine challenge, excitatory D1R functional signaling prevails three hours later, while D2Rs stay internalized. These results demonstrate differential externalization mechanisms of the D1R and D2R in vivo and a shift in receptor subtype activation after a dopamine surge. ### Competing Interest Statement The authors have declared no competing interest.