Allosteric Dopamine transporter modulator inhibits cocaine-induced behaviors

Abstract

<b>Abstract ID 52443</b> <b>Poster Board 211</b> The neurotransmitter dopamine (DA) is involved in motivation, reward mechanisms, and many central nervous system diseases. DA is transported into the presynaptic neurons by a protein called dopamine transporter (DAT). The psychostimulant cocaine is an inhibitor of DAT. When DAT is inhibited by cocaine, the DA in the synaptic cleft increases and this leads to amplified downstream dopaminergic signaling primarily in the mesolimbic pathway. This increase in cocaine-induced DA signaling is responsible for the addictive properties of cocaine. Because DAT is the primary target of cocaine, compounds acting on the DAT in novel ways could potentially treat cocaine use disorders. We previously found a novel compound—KM822 and characterized it as an allosteric modulator of DAT function. KM822 significantly decreases cocaine-induced locomotive response in planarians. To test if KM822 has similar effects in mammals, we administered KM822 and cocaine intracranially into nucleus accumbens (NAc) area in Long Evans rats and measured the locomotion changes. We targeted the NAc as it is a part of the brain that plays a crucial role in the mesolimbic dopaminergic pathway and has been recognized by its high density of DAT. Our results showed that KM822 significantly decreased hyper-locomotion induced by cocaine and notably did not cause any locomotion changes by itself. We also examined KM8229s ability to interfere with cocaine9s rewarding effect using the conditioned place preference (CPP) assay. In this assay, animals are tested for their preference for a cocaine-associated environment as a model of cocaine seeking. Unlike the locomotion assay, this assay is more relevant to behaviors associated with cocaine addiction and therefore has higher translational value. CPP is also utilized to determine the addictive liability of KM822. c-Fos expression is frequently utilized as a functional marker to investigate neuronal processes in response to a stimuli. To determine how KM822 affects neuronal activity in the NAc, c-Fos staining was conducted, and the expression of c-Fos was compared between animals pre-treated with KM822 and those pre-treated with vehicle before cocaine infusion. In the future, we plan to further assess the impact of KM822 in extinction and relapse utilizing CPP. Overall, these studies demonstrate the ability of KM822 to block DAT inhibitor-induced behaviors in rats and provide strong evidence that the novel allosteric DAT modulator KM822 has significant potential for treating cocaine addiction. Support/Funding Information: NIH R01- MH121453