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

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