Unveiling the Differences in Signaling and Regulatory Mechanisms between Dopamine D₂ and D₃ Receptors and Their Impact on Behavioral Sensitization

Dopamine receptors are classified into five subtypes, with D₂R and D₃R playing a crucial role in regulating mood, motivation, reward, and movement. Whereas D₂R are distributed widely across the brain, including regions responsible for motor functions, D₃R are primarily found in specific areas related to cognitive and emotional functions, such as the nucleus accumbens, limbic system, and prefrontal cortex. Despite their high sequence homology and similar signaling pathways, D₂R and D₃R have distinct regulatory properties involving desensitization, endocytosis, posttranslational modification, and interactions with other cellular components. In vivo, D₃R is closely associated with behavioral sensitization, which leads to increased dopaminergic responses. Behavioral sensitization is believed to result from D₃R desensitization, which removes the inhibitory effect of D₃R on related behaviors. Whereas D₂R maintains continuous signal transduction through agonist-induced receptor phosphorylation, arrestin recruitment, and endocytosis, which recycle and resensitize desensitized receptors, D₃R rarely undergoes agonist-induced endocytosis and instead is desensitized after repeated agonist exposure. In addition, D₃R undergoes more extensive posttranslational modifications, such as glycosylation and palmitoylation, which are needed for its desensitization. Overall, a series of biochemical settings more closely related to D₃R could be linked to D₃R-mediated behavioral sensitization.