Role of Serotonin in the Paradoxical Calming Effect of Psychostimulants on Hyperactivity

Abstract

The mechanism by which psychostimulants act as calming agents in humans with attention-deficit hyperactivity disorder (ADHD) or hyperkinetic disorder is currently unknown. Mice lacking the gene encoding the plasma membrane dopamine transporter (DAT) have elevated dopaminergic tone and are hyperactive. This activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission. The parallels between the DAT knockout mice and individuals with ADHD suggest that common mechanisms may underlie some of their behaviors and responses to psychostimulants.

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB

“…87,88 The serotonergic modulation of dopaminergic function is also supported by the analysis of DAT-KO mice, in which hyperlocomotion is reversed by selective 5HT2A antagonists and the effects of psychostimulant treatments depend on the serotonin system. 34,88 Therefore, our results contribute to growing evidence, suggesting that the serotoninergic system may indirectly affect ADHD by modulating dopamine neurotransmission. 16 …”

“…Once administered, serotonin agonists, which include 5-hydroxytryptophan, L-tryptophan and selective serotonin reuptake inhibitors, markedly attenuate hyperactivity in the DAT-KO mice. 34 In addition, mice lacking the 5HT1B receptor show hyperactivity, increased aggression and behavioral deinhibition [35][36][37][38][39] and 5HT4 receptor knockout mice show attenuated novelty-induced exploratory activity. 40 Finally, 5HT2 receptor agonists modulate hyperlocomotor activity in rats, and monoamine oxidase inhibitors reduce impulsiveness in animal models of ADHD.…”

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…Mice lacking the DAT gene display markedly increased levels of DA in the mesolimbic system and striatum [373], that results in hyperlocomoter behaviors [373,374] and also deficits in PPI [375,376]. The DAT knockout mice phenotypes resemble amphetamine-like effects, and both hyperlocomotion and PPI deficits can be reversed with either D 1 or D 2 receptor antagonists [376], the atypical antipsychotics clozapine and quetiapine [377], various antidepressant drugs, and monoamine transporter inhibitors [378].…”

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

“…This article will focus mainly on its role in the etiology of ADHD. Evidence to support dopaminergic dysfunction in ADHD derives from three research areas: the neuropharmacology of stimulant medication (Zametkin and Rapoport 1987; Amara and Kuhar 1993), the behavior and biochemistry of animal models (Giros et al 1996;Gainetdinov et al 1999, Russell 2000, and neuroimaging studies in ADHD adults (Dougherty et al 1999, Krause et al 2000, and Faraone and Biederman 2002. For this reason, many molecular genetic studies have focused on dopamine system genes.…”

“…Animal studies have shown that DAT1 knockout mice have increased extracellular dopamine but reduced striatal dopamine and tyrosine hydroxylase activity and may suggest that feedback mechanisms lead to reduced striatal dopamine. This is particularly interesting as DAT1 knockout mice have hyperactivity as part of their phenotype (Giros et al 1996;Gainetdinov et al 1999), and neuroimaging studies suggest frontostriatal dysfunction in ADHD patients (reviewed by Tannock 1998). Overall, the evidence for DAT1 suggests relative hypodopaminergic transmission in critical areas such as the striatum and the possible influence of excess dopamine neurotransmission from higher cortical areas.…”