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 D 1 receptors (D 1 R) recycle, whereas D 2 receptors (D 2 R) 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 D 1 R vs. D 2 R signaling in nonhuman primates over 24 hours using simultaneous positron emission tomography and functional magnetic resonance imaging. In contrast to predominantly inhibitory D 2 R signaling due to an initial amphetamine challenge, excitatory D 1 R functional signaling prevails three hours later, while D 2 Rs stay internalized. These results demonstrate differential externalization mechanisms of the D 1 R and D 2 R in vivo and a shift in receptor subtype activation after a dopamine surge.