Development of a peptide targeting dopamine transporter to improve ADHD-like deficits

Terence K Y Lai,Fang Liu,Ping Su,Hailong Zhang

doi:10.1186/s13041-018-0409-0

Terence K Y Lai, Fang Liu + Show 2 more

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https://doi.org/10.1186/s13041-018-0409-0

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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a neurocognitive disorder characterized by hyperactivity, inattention, working memory deficits and impulsivity. Its worldwide prevalence is estimated to be 3–5% in children and adolescents. The mainstay treatment for ADHD is stimulant medications (e.g. methylphenidate), which increase synaptic dopamine by directly blocking dopamine transporter (DAT). Although these pharmacological agents are effective, they are often associated with various side effects including risks for future substance use disorders in ADHD patients. Here, we investigated an interaction between DAT and dopamine D2 receptor (D2R) as a novel target to develop potential therapeutics for the treatment of ADHD by using an interfering peptide (TAT-DATNT) to dissociate this protein complex. We found that TAT-DATNT promotes locomotor behavior in Sprague-Dawley rats. Furthermore, using in vivo microdialysis and high-performance liquid chromatography, we found that the disruption of D2R-DAT elevates extracellular dopamine level. More importantly, the interfering peptide, TAT-DATNT, attenuates hyperactivity and improves spontaneous alternation behavior in spontaneously hypertensive rats (SHR) ------ a common animal model of ADHD. This work presents a different means (i.e. other than direct blockade by a DAT inhibitor) to regulate the activity of DAT and dopaminergic neurotransmission, and a potential target site for future development of ADHD treatments.

Highlights

Attention-deficit hyperactivity disorder (ADHD), characterized by hyperactivity and inattention, affects between 3 and 5% in children and adolescents worldwide [1, 2]
Before we investigated the effects of TAT-DATNT in spontaneously hypertensive rats (SHR) rats, we hoped to rule out the possibility that TAT-DATNT may act differently in rats compare to mice
Since the current stimulant treatments for ADHD all strengthen synaptic dopamine signaling [39], we examined the effects of the TAT-DATNT on the hyperactivity of SHR rats and we hypothesized that this peptide will reverse such hyperactivity by disrupting the D2 receptor (D2R)-dopamine transporter (DAT) interaction

Summary

Introduction

Attention-deficit hyperactivity disorder (ADHD), characterized by hyperactivity and inattention, affects between 3 and 5% in children and adolescents worldwide [1, 2]. The exact etiology of ADHD remains elusive, dysregulation of the dopaminergic system is heavily implicated due to the actions of the current ADHD treatments [3]. These pharmacological agents are stimulants such as methylphenidate [4], and they enhance dopaminergic neurotransmission by directly blocking dopamine transporters (DAT) [5]. They are effective clinically, there are concerns about potential drug abuse and risks for future substance use disorders [6,7,8]. With its localization on the presynaptic membrane of dopaminergic nerve terminals [17, 18], DAT utilizes the Na+ gradient created by the plasma membrane Na+/K+ ATPase as the driving force to transport synaptic dopamine across cellular

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