The nucleus accumbens, the brain’s “pleasure center” or “reward pathway”, is especially rich in dopamine neurons. Psychostimulants such as cocaine increase synaptic dopamine levels in this region, resulting in feelings of euphoria and the ”high” associated with such drugs. It has been postulated that the abusable psychostimulants stabilize the outward-facing (extracellular-facing) conformation of the dopamine transporter (DAT), whereas high affinity but non-abusable DAT inhibitors stabilize the inward-facing conformation. This work applies computational methods to evaluate the molecular interactions between DAT inhibitors with either the inward- or outward-facing DAT conformation. Cocaine and benztropine have been docked into the inward- and outward-facing DAT molecular models. Molecular dynamic simulations of DAT binding cocaine and benztropine reveal key interactions in the molecular mechanism of ligand-induced DAT conformations. The resulting poses for the inhibitors are consistent with the present observation that cocaine prefers an outward-open DAT conformation whereas benztropine prefers an inward-open DAT conformation.

Dopamine transporter conformations induced by cocaine and atypical DAT inhibitors

251st National Meeting (2016)

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