Trace amine-associated receptor 1 (TAAR1) activation reduced mania-relevant hyperexploration and risky decision-making in dopamine transporter knockdown mice

Abstract

Background:

Risky decision-making is a cardinal feature of bipolar disorder (BD), yet no targeted pharmacotherapies exist for this behavioral deficit. Dopamine transporter knockdown (DAT KD) mice reproduce the DAT hypoexpression profile of BD and demonstrate pharmacologically sensitive, BD-relevant patterns of risky decision-making and hyperexploration in the cross-species translatable Iowa Gambling Task (IGT) and Behavioral Pattern Monitor (BPM), respectively. Agonists of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor that presynaptically modulates dopamine transmission, may normalize these deficits and thereby represent a novel therapeutic avenue for the management of BD.

Aims:

Assessment of the impact of TAAR1 activation on BD-relevant behaviors in a mouse model of mania.

Methods:

The effects of the TAAR1 agonist R05256390 (0, 0.3, and 1.0 mg/kg, i.p.; within-subjects) were first determined on unconditioned exploration in male and female DAT KD and wildtype (WT) littermate mice in the BPM and then on risky decision-making in the IGT (1.0 mg/kg).

Results:

Consistent with people with BD, DAT KD mice exhibited hyperlocomotion, elevated specific exploration, and more linear movement in the BPM, plus elevated risk preference in the IGT. R05256390 (0.3 and 1 mg/kg) reduced locomotion in DAT KD males and WT females, respectively, as well as specific and diversive exploration across genotypes. TAAR1 activation also reduced risky choice in DAT KD mice while elevating this behavior in WTs.

Conclusions:

These findings support the potential for TAAR1 agonists as novel treatments for hyperactivity and risky decision-making in BD, and suggest an inverted U-shaped relationship between dopamine tone and decision-making optimization.