Cocaine increases the stimulation of dopamine release, at variance with atypical dopamine uptake inhibitors. New clues for the abuse liability of psychostimulants?

Abstract

Dopamine uptake inhibitors (DUIs), such as cocaine and methylphenidate, are characterized by their ability to bind to the dopamine transporter (DAT) and prevent dopamine (DA) from being transported from the extracellular to the intracellular side of a neuronal terminal. It was originally posited that all DUIs would have the same effect on behavior, neurochemistry, and abuse liability in animal models as well as humans. However, a subset of these drugs, atypical DUIs (e.g. JHW007), have shown dissimilar profiles. While these DUIs have the same target and similar binding affinities to typical DUIs, their effects on behavior and neurochemistry are markedly different and predict little to no abuse liability in animal models.The goal of the present study was to determine how the neurochemistry of this atypical subset of DUIs differs from typical DUIs in mice. A pharmacological approach was taken utilizing Fast Scan Cyclic Voltammetry (FSCV), for real time monitoring of DA release and reuptake from the terminal; Fiber Photometry (FP), for real time monitoring of Ca2+ fluctuations in the terminal; and Electrophysiological (Ephys) ligand displacement experiments, to characterize the interactions between DUIs and the DAT.FSCV data indicate that cocaine and other abused DUIs have effects on both DA reuptake (by binding to the DAT and blocking DA transport) and stimulated release (causing an increase in mobilization of DA vesicles). In contrast the atypical DUIs, such as JHW007, have similar effects on DA reuptake, but do not cause a significant increase in stimulated DA release. FP experiments show how this difference influences Ca2+ fluctuations. JHW007 has a greater dose‐dependent impact on the influx of Ca2+ following stimulation than cocaine. Further Ephys experiments indicate a correlation between DA release and the off‐rate for each DUI, while no significant correlation was found for DA release and DAT affinity. Our data suggest 1) the dopaminergic effects of cocaine and other typical DUIs are not solely related to their ability to block the DAT; 2) DAT affinity alone is not an indicator for abuse liability; 3) the effect of the DUIs on the quaternary structure of the DAT and its downstream interactions may play an important role in the effects of typical DUIs related to abuse. Our preclinical results suggest that atypical DUIs can mitigate the effects of cocaine, leading to possible treatment candidates for psychostimulant use disorders in humans.Support or Funding InformationThis research was funded in part by the Medication Development Program, National Institute on Drug Abuse, IRP, NIH/DHHSThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.