Allosteric Dopamine transporter modulator inhibits cocaine‐induced behavior

Abstract

The dopamine transporter (DAT) is a transmembrane protein responsible for reuptake the neurotransmitter dopamine back into the presynaptic neurons. Dopamine (DA) is involved in driving motivation, it is increased when people expect a reward, and it is also involved in many central nervous systems (CNS) disorders. The inhibition of the reuptake process prevents dopamine in the synaptic cleft from getting back into the presynaptic neuron. Cocaine and amphetamine both inhibit DA reuptake by binding to the orthosteric site but through different mechanisms. Cocaine is a classical inhibitor that blocks the transporter through competitive inhibition. On the other hand, amphetamine is a substrate of DAT and causes competitive inhibition of DA reuptake and reversal of the transporter leading to the release of DA. As a result of the DA reuptake inhibition, the DA in the synaptic cleft increases, leading to amplified downstream dopaminergic signaling primarily in the mesolimbic pathway. Because DAT is a primary target of psychostimulants, compounds acting on the DAT in novel ways could potentially treat psychostimulant use disorders. We previously found a novel compound—KM822 and characterized it as an allosteric modulator of DAT function that significantly decreases cocaine‐induced locomotive response in planarians. To test if KM822 has similar effects in mammals, we administered KM822 and cocaine through intracranial infusions into Long Evans rats' nucleus accumbens (NAc) and measured locomotion. 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 increase in locomotion by itself. KM822's ability to block hyper‐locomotion induced by amphetamine, another psychostimulant with a different mechanism of action, was also examined. Finally, we examined KM822's ability to interfere with cocaine's rewarding effect using the conditioned place preference (CPP) assay. In this assay, animals are tested for their preference for a cocaine‐associated environment. Unlike locomotion assay, this assay is more relevant to behaviors associated with cocaine addiction and therefore has high translational value. Overall, these studies demonstrated KM822's ability to block DAT inhibitor‐induced behaviors in rats and provided strong evidence that the novel allosteric DAT modulator KM822 has significant potential for treating psychostimulant addiction.