Cocaine addiction is a psychiatric disorder that remains a serious public health problem worldwide. Because effective pharmacological drugs have not been identified, further understanding of molecular mechanisms behind the development of cocaine addiction is important to find novel targets for the pharmacological treatment. In our previous study, we succeeded in ensuring daily 24-hr access to cocaine for mice by employing an intracranial drug delivery system with reverse microdialysis technique. Using this novel system, we screened for several knockout mice available at our university, and found that functional deficit of major histocompatibility complex class 1 (MHCI), a major player in the adaptive immune system, exaggerated cocaine-seeking behavior. It has been recently discovered that MHCI is expressed in the brain that has long been designated as an immune privilege region and plays an important role in the modulation of synaptic plasticity such as elimination of long-term depression and enhanced long-term potentiation, resulting in the enhanced synaptic connections. We sought to evaluate the possibility whether modulation of MHCI expression in the brain is involved in the process of persistent cocaine-seeking behavior of wild type mice. After subjecting wild-type mice to cocaine self-administration paradigm, we discovered that expression of MHCI was reduced only in the VTA, implying a possibility that MHCI expressed in the VTA is important in the development of cocaine self-administration. In consistent with this idea, cocaine-induced enhancement of synaptic inputs into dopaminergic neurons of the VTA was significantly larger in functional MHCI knockout mice than in wild-type mice. These results indicate that cocaine self-administration leads to reduction of MHCI expression and enhances inputs into dopaminergic neurons in the VTA, resulting in the development of cocaine self-administration.