Antipsychotic-like effects of TAAR1 agonists and D2 receptor blockers are mediated through distinct modulation of striatal neuronal dynamics.

Trace amine-associated receptor 1 (TAAR1) agonists are being investigated as potential new treatments for schizophrenia, a disorder characterized by striatal hyperdopaminergia and dysregulated cortical and hippocampal glutamatergic function. Current evidence suggests that TAAR1 agonists reduce elevated striatal dopamine synthesis capacity and release, likely through direct inhibition of presynaptic dopaminergic neurons and modulation of upstream glutamatergic signaling. However, their impact on postsynaptic striatal neuronal dynamics and associated behaviors remains largely unexplored. Here we investigated the effects of TAAR1 agonists, RO5166017 and clinical drug candidate ulotaront, on in vivo calcium dynamics of D1- and D2-receptor expressing medium spiny neurons (MSNs) in freely behaving mice, under normal and phencyclidine (PCP)-induced, psychosis-like conditions. Both ulotaront and RO5166017 mitigated PCP-induced alterations in locomotor behavior, MSN activity levels and spatiotemporal dynamics. Interestingly, the neural effects were dependent on both locomotor activity and the psychosis-like state. While ulotaront and RO5166017 differentially affected neuronal activity levels under normal conditions, they both produced a similar increase in the PCP state, specifically during movement, with comparable effects observed in D1 and D2 MSNs. Although the established antipsychotics haloperidol and clozapine produced similar behavioral effects, their impact on striatal MSNs was distinct and lacked prominent state dependence. These findings provide new insights into the distinct neurocircuit changes associated with the antipsychotic-like effects of TAAR1 agonists, distinguishing them from D2 receptor-targeting treatments.