Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice

Abstract

Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT 2C receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT 2C signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.

Case-Control Study of the Effects of Gut Microbiota Composition on Neurotransmitter Metabolic Pathways in Children With Attention Deficit Hyperactivity Disorder

“…Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder that occurs most frequently in school-age children and is characterized as inattention with or without excessive impulsivity and hyperactivity (Abramov et al, 2019). Previous studies have reported that ADHD pathogenesis may be associated with dysregulation of neurotransmitters such as dopamine, serotonin (5-hydroxytryptamine, 5-HT), and norepinephrine (Magula et al, 2019;Stewart et al, 2019;Suzuki et al, 2019). Others have shown that the incidence of ADHD may have a certain degree of heritability, and genes related to dopamine, norepinephrine, and 5-HT transmission have been found to be abnormally expressed in children with ADHD (Banerjee and Nandagopal, 2015;Karmakar et al, 2017;Kim et al, 2018).…”

Effects of Jian-Pi-Zhi-Dong Decoction on the Expression of 5-HT and Its Receptor in a Rat Model of Tourette Syndrome and Comorbid Anxiety

“…Metabolism of 5-HT in the brain directly affects or is related to human mental activity. A large number of studies have shown that 5-HT metabolic abnormalities play important role in the pathophysiological mechanism of TS [ 26 ], anxiety disorders [ 27 ], ADHD [ 28 ], OCD [ 29 , 30 ] and other mental behavior disorders. Fluoxetine, a selective serotonin reuptake inhibitor, as the first-line psychological treatment to counter TS and comorbid anxiety also supports the association of 5-HT dysfunction with TS and comorbid anxiety [ 11 ].…”

A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease

“…Rather, it reflects the absence of common risk variants. Several rare coding DAT variants with functional deficits both in vitro and in vivo have been identified in patients with psychiatric disorders (Bowton et al, 2014;Campbell et al, 2019;Cartier et al, 2015;Davis et al, 2018;DiCarlo et al, 2019;Gowrishankar et al, 2018;Grunhage et al, 2000;Hamilton et al, 2013;Hansen et al, 2014;Herborg et al, 2018;Mazei-Robison et al, 2005;Sakrikar et al, 2012;Stewart et al, 2019;Wu et al, 2015) but the causal link between these putative risk alleles and disease is still elusive as the family trees and cohort sizes have been too small for meaningful linkage or association analysis. We have, to the best or our knowledge, carried out the first association analysis of a coding DAT variant using large-scale exome data, and demonstrate a nominally significant association to bipolar disease.…”