Reward‐enhancing effect of methylphenidate is abolished in dopamine transporter knockout mice: A model of attention‐deficit/hyperactivity disorder

Abstract

Aim: Attention-deficit/hyperactivity disorder is a heterogeneous neurobiological disorder that is characterized by inattention, impulsivity, and an increase in motor activity. Although methylphenidate has been used as a medication for decades, unknown is whether methylphenidate treatment can cause drug dependence in patients with attention-deficit/hyperactivity disorder. This study investigated the reward-enhancing effects of methylphenidate using intracranial self-stimulation in an animal model of attention-deficit/hyperactivity disorder, dopamine transporter knockout mice. Methods:For the intracranial self-stimulation procedures, the mice were trained to nosepoke to receive direct electrical stimulation via an electrode that was implanted in the lateral hypothalamus. After the acquisition of nosepoke responding for intracranial self-stimulation, the effects of methylphenidate on intracranial self-stimulation were investigated. Results:In the progressive-ratio procedure, dopamine transporter knockout mice exhibited an increase in intracranial self-stimulation compared with wild-type mice.Treatment with 5 and 10 mg/kg methylphenidate increased intracranial self-stimulation responding in wild-type mice. Methylphenidate at the same doses did not affect intracranial self-stimulation responding in dopamine transporter knockout mice. We then investigated the effects of high-dose methylphenidate (60 mg/kg) in a rate-frequency procedure. High-dose methylphenidate significantly decreased intracranial self-stimulation responding in both wild-type and dopamine transporter knockout mice. Conclusions:These results suggest that low-dose methylphenidate alters the reward system (ie, increases intracranial self-stimulation responding) in wild-type mice via dopamine transporter inhibition, whereas dopamine transporter knockout mice do not exhibit such alterations. High-dose methylphenidate appears to suppress intracranial self-stimulation responding not through dopamine transporter inhibition but rather through other mechanisms. These results support the possibilityThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Animal Models of Depression: What Can They Teach Us about the Human Disease?

“…DAT-KO mice with dopamine transporter deletion developed depressive-like symptoms but have pronounced spontaneous hyperlocomotion [ 296 , 297 ] and mimic the effects of long-term exposure to psychostimulants. DAT-KO mice are, rather, a model of attention-deficit/hyperactivity disorder (ADHD), and their hyperlocomotion behavior was attenuated by treatment with Methylphenidate [ 298 , 299 ]. Increased expression of the 5-HT transporter in mice led to a low-anxiety phenotype [ 300 ].…”

The co-use of nicotine and prescription psychostimulants: A comprehensive review of their behavioral and neuropharmacological interactions

“…Such a gap may prompt ICSS studies to determine how prior or acute methylphenidate exposure alters the reward threshold decreasing effects of nicotine and vice versa. Like nicotine, methylphenidate also decreases ICSS reward-thresholds (Ide et al, 2018), so nicotine and methylphenidate likely interact to alter drug reward.…”

A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

“…Hyperactivity of DAT-KO rats and mice and perseverative pattern of motor activity was demonstrated in numerous investigations and are described as their distinctive traits ( Pogorelov et al, 2005 ; Vengeliene et al, 2017 ; Adinolfi et al, 2018 ; Cinque et al, 2018 ; Ide et al, 2018 ; Leo et al, 2018b ). DAT-KO rats spent much longer time and covered longer distances to perform a task, which might be due to their hyperactivity.…”

“…Dopamine transporter, by controlling re-uptake of released DA, plays a critical role in the regulation of both the intraneuronal and extracellular DA homeostasis ( Vaughan and Foster, 2013 ). Mice lacking the DAT (DAT-KO mice) were shown to have high extracellular DA levels, which results in spontaneous hyperlocomotion and certain cognitive dysfunctions ( Giros et al, 1996 ; Spielewoy et al, 2000 ; Gainetdinov et al, 2002 ; Efimova et al, 2016 ; Ide et al, 2018 ). In mutant mice, long-term alterations in DA signaling lead to profound disturbances in the cortico-striatal connections and functions ( Surmeier et al, 2007 ).…”