The SERT Met172 Mouse: An Engineered Model To Elucidate the Contributions of Serotonin Signaling to Cocaine Action

Cocaine abuse and addiction remain highly prevalent and, unfortunately, poorly treated. It is well-known that essential aspects of cocaine’s addictive actions involve the drug’s ability to block the presynaptic dopamine (DA) transporter (DAT), thereby elevating extracellular levels of DA in brain circuits that subserve reward, reinforcement, and habit. Less well appreciated are the multiple DA-independent actions of cocaine, activities that we and others believe contribute key pieces to the puzzle of cocaine addiction, treatment, and relapse. In particular, a significant body of work points to altered serotonin (5-HT) signaling as one such component, not surprising given that, relative to DAT, cocaine acts as potently to block the 5-HT transporter (SERT) as to block DAT, and thereby elevates extracellular 5-HT levels throughout the brain when reward-eliciting DA elevations occur. To elucidate the contribution of SERT antagonism to the actions of cocaine, we engineered a mouse model that significantly redu...