The potential of Trace Amine-Associated Receptor Type 1 in ADHD-related compulsive behavior

Compulsive behavior is a common symptom in Attention Deficit Hyperactivity Disorder (ADHD) and is related to deficits in the cortico-striato-thalamo-cortical axis, mainly in monoaminergic pathways. Trace Amine-Associated Receptor Type 1 (TAAR1) maintains monoaminergic homeostasis in brain areas associated with compulsion and ADHD. This study aims to investigate the effects of TAAR1 on risk-taking and compulsive behaviors in an animal model of ADHD. 

Male (M) and female (F) WKY (W) and SHR (S) rats (p45–p55, n= 8-11) were treated with TAAR1 agonist (RO5166017, 10mg/kg), TAAR1 antagonist (EPPTB, 10mg/kg) or vehicle. After 20 min, an open field test was performed to evaluate locomotion and risk-taking behavior and a marble burying test to evaluate compulsive-like behavior. Western Blot analysis assessed the density of TAAR1. CEUA UFF: 9409171121.             

SHR exhibit higher risk-taking behavior compared to WKY (central area entries: WM:4.44±0.76; WF:6.14±1.71; SM:19.33±2.37;SF:22.70±1.36| central area  time: WM:45.52±8.48s; WF:33.43±8.30s; SM:75.85±5.37s; SF:77.26±10.12s| central area distance: WM:1.13±0.27m; WF:1.38±0.34m; SM:4.10±0.41m; SF:4.68±0.34m). SHR exhibits hyperactivity compared to WKY (WM:10.46±1.48m; WF:12.92±2.58m; SM:24.17±1.44m; SF: 29.30±1.12m). SHR exhibits a compulsive phenotype compared to WKY (W:4.87±0.94; S:9.42±0.82). Activation of TAAR1 reduced the compulsive phenotype in F SHR compared to vehicle-treated (SF vehicle-treated:11.20±1.22; RO5166017-treated:6.11±4.46). No significant differences were found in TAAR1 levels in the frontal cortex of M WKY and SHR, but there is a trend indicating a difference among F rats (normalized data %W: WM:99.94±39.01%; SM:63.21±20.23%| WF:128.60±15.57%; SF:78.52±15.18%).               

Different dimensions of inhibitory control seem to be affected in ADHD, resulting in hyperactivity, risk-taking and compulsive behavior. TAAR1 activation can reduce the compulsive phenotype in a sex-dependent manner.