Allosteric modulator of dopamine transporter inhibits cocaine-induced behaviors in rats

Yibin Xu

doi:10.17918/00011127

Psychostimulant use disorder (PUD) is a serious disease marked by uncontrollable drug seeking behaviors. Cocaine is one psychostimulant that has been misused for centuries. It is hard for individuals to stop cocaine use as cues like surrounding environment can easily trigger their cocaine associated memory leading to relapse. The dose needed to generate the rewarding feeling also escalate with repeated cocaine use and can eventually cause overdose death. Cocaine blocks the function of the dopamine transporter (DAT), that regulates the homeostasis of dopamine (DA) by transporting excessive DA back to the presynaptic neuron. As a result, cocaine leads to a significant increase in DA levels, which then amplifies downstream dopaminergic transmission and DA signaling. This increase in DA signaling is responsible for the addictive properties of cocaine. Behavioral interventions have been used to help individuals to stop the use of psychostimulants, however, most of the patients relapse after leaving rehabilitation. Yet, no FDA approved pharmacological therapy for psychostimulant use disorders is approved. Here, we propose that compounds that bind to DAT in a newly discovered allosteric site might impact cocaine-DAT interaction and therefore may inhibit cocaine induced behaviors and neuronal activities. KM822 is a novel allosteric modulator we recently discovered that binds to DAT in a more extracellular site compared to the site where DA and cocaine binds. Nucleus accumbens (NAc) that is known for its high DAT level, therefore, we first examined the impact of infusing KM822 into NAc on cocaine induced hyperlocomotion. We find that KM822 successfully inhibits cocaine induced hyperlocomotion when infused in NAc?. Second, we examined the impact of KM822 on the rewarding property of cocaine using the conditioned place preference (CPP) test. CPP closely models behaviors such as cocaine seeking that is relevant to cocaine dependence and therefore has higher translational value compared to the locomotion test. The result shows when KM822 is given prior to cocaine infusion on the conditioning days, it successfully ameliorates the development of cocaine induced CPP. To test if allosteric DAT modulators can have a therapeutic effect on a model of relapse, we find that KM822 pretreatment successfully inhibits cocaine-primed reinstatement in rats. We also find that KM822 does not have any addictive liability as repeated KM822 infusion does not induce any preference change in the CPP test. c-Fos is an immediate early gene that is expressed when neurons are activated. As a result, the changes in c-Fos expression are frequently utilized as a functional marker to investigate neuronal response to stimuli. We find that KM822 does not lead to significant change in c-Fos expression by itself in NAc. but inhibits c-Fos expression when infused prior to cocaine. Examining the effect of repeated KM822 on DAT expression, we find no significant change in total DAT expression. To conclude, these studies provide valuable information on how a DAT allosteric modulator affects neuronal activities in vivo. Moreover, findings from these studies demonstrate the ability of KM822 to block cocaine-induced behaviors in rats and provide strong evidence of the novel allosteric DAT modulator KM822 as a proof of concept in treating PUD, especially cocaine use disorders.

Allosteric modulator of dopamine transporter inhibits cocaine-induced behaviors in rats

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Allosteric modulator of dopamine transporter inhibits cocaine-induced behaviors in rats

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