Trace amine-associated receptor 1 modulates motor hyperactivity, cognition, and anxiety-like behavior in an animal model of ADHD

Abstract

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has recently been implicated in several psychiatric conditions related to monoaminergic dysfunction, such as schizophrenia, substance use disorders, and mood disorders. Although attention-deficit/hyperactivity disorder (ADHD) is also related to changes in monoaminergic neurotransmission, studies that assess whether TAAR1 participates in the neurobiology of ADHD are lacking. We hypothesized that TAAR1 plays an important role in ADHD and might represent a potential therapeutic target. Here, we investigate if TAAR1 modulates behavioral phenotypes in Spontaneously Hypertensive Rats (SHR), the most validated animal model of ADHD, and Wistar Kyoto rats (WKY, used as a control strain). Our results showed that TAAR1 is downregulated in ADHD-related brain regions in SHR compared with WKY. While intracerebroventricular (i.c.v.) administration of the selective TAAR1 antagonist EPPTB impaired cognitive performance in SHR, i.c.v. administration of highly selective TAAR1 full agonist RO5256390 decreased motor hyperactivity, novelty-induced locomotion, and induced an anxiolytic-like behavior. Overall, our findings show that changes in TAAR1 levels/activity underlie behavior in SHR, suggesting that TAAR1 plays a role in the neurobiology of ADHD. Although additional confirmatory studies are required, TAAR1 might be a potential pharmacological target for individuals with this disorder.