Dopamine D2 Receptors, D1/D2 Receptor Heteromers and CaMKII Signaling in the Neurobiology of Drug Addiction

Drug addiction is a serious brain disorder with widespread somatic, psychological, psychiatric, and legal consequences, characterized by compulsive drug seeking, craving, withdrawal, and relapse, particularly with psychostimulants. A key feature of drugs commonly abused by humans is their ability to enhance dopamine (DA) neurotransmission in mesolimbic circuits, thereby activating DA receptors and altering emotional and motivational behaviors. Recent studies have demonstrated that dopamine D2 receptors (D2Rs), existing both as monomers and as D1/D2 receptor heteromers with dopamine D1 receptors (D1Rs), are critically involved in the neurobiological mechanisms underlying drug addiction. Furthermore, Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα), which interacts with D2Rs and associates with D1/D2 receptor heteromers, plays a pivotal role in regulating the molecular mechanisms of the reward system, primarily through its phosphorylation. In addition, fatty acid-binding protein 3 (FABP3), by forming a complex with the long isoform of the D2 receptor (D2LR), has been shown to contribute significantly to the development of drug addiction. This article first reviews the roles of D2Rs and D1/D2 receptor heteromers in addiction, followed by a discussion of the underlying mechanisms of CaMKII signaling. We further highlight recent advances identifying FABP3 as a potential pharmacological target to mitigate addiction and prevent relapse, offering new avenues for therapeutic development and future clinical interventions.