Abstract by Alexandra Larson
Chemistry and Biochemistry
Synthetic Process and Application of AP20187
Drugs of abuse, including alcohol consumption, increase dopamine levels in the nucleus accumbens of the brain. This increase in dopamine levels is thought to underlie the rewarding aspects of these drugs and lead to addiction. The mechanisms, however, underlying alcohol's effects on dopamine release remain unclear. In this study, the Michaelis laboratory completed a total synthesis of a chemical dimerizer (AP20187). This molecule triggers cell death in macrophages expressing a specific protein. Transgenic mice using macrophage Fas-induced apoptosis (mafia mice) express this protein that recognizes AP20187, which enables selective depletion of macrophages in the brain. AP20187, was then used to study the role of the immune system in addiction. These studies, enabled by our synthesis, shed light on the mechanisms underlying alcohol’s effects on dopamine release in the brain. AP20187 allows us to better understand the mechanisms of addiction and potentially provide new strategies to address addiction in abused substances.