Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD).

Juhee Han,Su Jin Moon,Chang Ju Kim,Minha Hong,Efthimios M C Skoulakis,Geon Ho Bahn,Yeon Jung Lee

doi:10.1371/journal.pone.0108918

Abstract

BackgroundHyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD).PurposeTo investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus.MethodsYoung male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined.ResultsThe motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner.ConclusionHyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway.

Highlights

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood and adolescent disorder that affects 5–10% of schoolaged children worldwide [1] and can affect 3–5% of the adult population [2]
The ‘‘dopaminergic hypothesis’’ is the most widely accepted hypothesis by researchers for understanding the attention-deficit/hyperactivity disorder (ADHD) pathophysiology [3]. It is based on dysregulation in dopaminergic neurotransmission causing behavioral alterations in both ADHD and in the spontaneously hypertensive rat (SHR), which has been used as an ADHD animal model [4]
We investigated the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the DA D2 receptor in the SHR animal model of ADHD based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions such as prefrontal cortex (PFC), striatum, and hypothalamus

Summary

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood and adolescent disorder that affects 5–10% of schoolaged children worldwide [1] and can affect 3–5% of the adult population [2]. The ‘‘dopaminergic hypothesis’’ is the most widely accepted hypothesis by researchers for understanding the ADHD pathophysiology [3] It is based on dysregulation in dopaminergic neurotransmission causing behavioral alterations in both ADHD and in the spontaneously hypertensive rat (SHR), which has been used as an ADHD animal model [4]. Initial functional MRI studies showed decreased activation of the dopamine (DA) pathway [5] and the DA hypothesis suggested that DA deficits in specific brain regions, such as cortical areas and/or the striatum, could produce ADHD symptoms [6]. Purpose: To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus

Methods

Results

Conclusion