Dopamine D4 receptor deficiency alters behavioral responsiveness of mice to methylphenidate

The DRD4 gene’s seven‑repeat allele (DRD4.7) is linked to novelty seeking, substance abuse, and ADHD, but its physiological effects remain unclear. To model reduced D4 receptor signaling, we compared wild‑type and D4 receptor knockout (D4R KO) mice. D4R KO mice showed normal exploratory responses to novelty but increased anxiety-like behavior. They displayed heightened locomotor activation to high-dose methylphenidate (MP) and greater behavioral sensitization to chronic MP. Prefrontal cortex gene expression analysis identified transcripts regulated by D4R signaling that may contribute to MP‑induced plasticity. These findings clarify D4R’s role in cortical function and its relevance to ADHD and stimulant response.