Functional studies of a dopamine transporter allosteric modulator and its effect on cocaine-induced behavior
Year: 2020
Type: dissertation
Abstract: Cocaine is one of the oldest, strongest, and most dangerous psychostimulants isolated from natural products. It works by blocking the dopamine transporter (DAT), a transmembrane protein that pumps dopamine out of the synaptic cleft back into the cytosol, thereby raising the extracellular dopamine level resulting in euphoria. Although cocaine is an ancient drug that became popular in the 1880s and officially was banned by the United States government in 1922, there are no Food and Drug Administration-approved therapies for cocaine addiction. Numerous attempts have been made to find treatments for cocaine abuse. However, most of them failed due to the potential abuse liability, lack of efficacy, or severe side effects. Our lab has previously identified a novel allosteric site in the human serotonin transporter (hSERT). To find an allosteric modulator of DAT, we have developed a compound-KM822 that target the same allosteric domain in human DAT. KM822 pretreatment can increase the IC50 of DAT inhibition by cocaine in in vitro studies, indicating that it might have therapeutic effects for treating cocaine addiction. However, whether KM822 has an effect in vivo and its binding mechanism remains unclear. To obtain a better understanding of the KM822 binding mechanism, we tested several KM822 analogs. Analogs with different chemical moiety substitution showed different potency towards different amino acids forming the allosteric binding site. Among all the analogs, NP-1-152 displayed a pharmacology similar to KM822, suggesting that the combination of the chemical moiety substitution in NP-1-152 created an interaction with DAT similar to KM822. In Long-Evans rats, KM822 microinjected directly into the nucleus accumbens didn't affect the regular locomotion activity on rats during their active cycle, indicating that it doesn't cause hyperlocomotion or sedation. Preliminary data on the therapeutic effect of KM822 on cocaine-induced behavior will also be presented.
DOI: 10.17918/00001267
Authors: Yibin Xu, Ole V. Mortensen, Joanne R. Mathiasen
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4387735487