Unveiling the Differences in Signaling and Regulatory Mechanisms between Dopamine D(2) and D(3) Receptors and Their Impact on Behavioral Sensitization

Dopamine receptors are classified into five subtypes, with D(2)R and D(3)R playing a crucial role in regulating mood, motivation, reward, and movement. Whereas D(2)R are distributed widely across the brain, including regions responsible for motor functions, D(3)R 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, D(2)R and D(3)R have distinct regulatory properties involving desensitization, endocytosis, posttranslational modification, and interactions with other cellular components. In vivo, D(3)R is closely associated with behavioral sensitization, which leads to increased dopaminergic responses. Behavioral sensitization is believed to result from D(3)R desensitization, which removes the inhibitory effect of D(3)R on related behaviors. Whereas D(2)R maintains continuous signal transduction through agonist-induced receptor phosphorylation, arrestin recruitment, and endocytosis, which recycle and resensitize desensitized receptors, D(3)R rarely undergoes agonist-induced endocytosis and instead is desensitized after repeated agonist exposure. In addition, D(3)R 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 D(3)R could be linked to D(3)R-mediated behavioral sensitization.