The <scp>TAAR1</scp> Agonist <scp>PCC0105004</scp> Regulates Amygdala Synaptic Plasticity to Alleviate Anxiety‐Like Behaviors in Rats

Anxiety disorder is a persistent, widespread, and intractable mood disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of CUMS-induced anxiety-like behavior. The elevated zero maze and open field tests test were employed to evaluate the anti-anxiety-like activity of PCC0105004. PCC0105004 dose-dependently attenuated anxiety-like behaviors in rats without affecting spontaneous activity. Morphologically, PCC0104005 decreased the density of dendritic spines in the amygdala. For the mechanistic studies, whole-genome transcriptomic analysis revealed significant differences in the patterns of amygdala gene expression in the CUMS-induced anxiety rat model. These transcriptomic data were further confirmed by using RT-qPCR and western blotting, further revealing alterations associated with genes (Col1a1, DCN, Ewsr1) known to regulate synaptic plasticity, and PCC0105004 was able to reverse these changes. These results suggest that PCC0105004 is a promising anxiolytic candidate for pharmacotherapy of anxiety and warrants further examination and development.