Our laboratory focuses on identification and validation of the therapeutic targets for alcoholism and drug addiction using genetically engineered mice models such as knockout, knockin, and transgenic mice. To understand the roles of genetic components in alcoholism and drug addiction, we use various approaches in the areas of molecular biology, biochemistry, neuroanatomy, behavior, electrophysiology, and pharmacology. Currently, we are interested in the role of adenosine in the brain. We found that glutamate-driven CREB activation was increased in the striatum of type 1 adenosine transporter (ENT1) null mice. Since striatal CREB activation is associated with reduced drug reward, we will determine whether alterations in signaling pathways that account for increased striatal pCREB contribute to tolerance, rewarding effects of ethanol, and increased ethanol consumption in ENT1 null mice. We plan to study other adenosine transporter genes and generate appropriate rodent models to identify therapeutic targets as well as to develop effective clinical paradigms in rodent models.