The Trace Amine-Associated Receptor 1 (TAAR1) is one of the six functional receptors belonging to the family of monoamine-related G protein-coupled receptors (TAAR1-TAAR9) found in humans. However, the exact biological mechanisms of TAAR1 central and peripheral action remain to be fully understood. TAAR1 is widely expressed in the prefrontal cortex and several limbic regions, interplaying with the dopamine system to modulate the reward circuitry. Recent clinical trials suggest the efficacy of TAAR1 agonists as potential novel antipsychotic agents. Here, we characterize behavioral and neurochemical phenotypes of TAAR1 knockout mice, focusing on aggression and self-grooming behavior that both strongly depend on the monoaminergic signaling and cortico-striatal and cortico-limbic circuits. Overall, we report increased aggression in these knockout mice in the resident-intruder test, accompanied by reduced self-grooming behavior in the novelty-induced grooming test, and by higher cortical serotonin (5-HT) tissue levels. Further studies are necessary to explore whether TAAR1-based therapies can become potential novel treatments for a wide range of neuropsychiatric disorders associated with aggression.

Trace amine-associated receptors (TAAR1-TAAR9) are a family of G-protein-coupled monoaminergic receptors which might have great pharmacological potential. It has now been well established that TAAR1 plays an important role in the central nervous system. Interestingly, deletion of TAAR9 in rats leads to alterations in the periphery. Previously, we found that knockout of TAAR9 in rats (TAAR9-KO rats) decreased low-density lipoprotein cholesterol levels in the blood. TAAR9 was also identified in intestinal tissues, and it is known that it responds to polyamines. To elucidate the role of TAAR9 in the intestinal epithelium, we analyzed TAAR9-co-expressed gene clusters in public data for cecum samples. As identified by gene ontology enrichment analysis, in the intestine, TAAR9 is co-expressed with genes involved in intestinal mucosa homeostasis and function, including cell organization, differentiation, and death. Additionally, TAAR9 was co-expressed with genes implicated in dopamine signaling, which may suggest a role for this receptor in the regulation of peripheral dopaminergic transmission. To further investigate how TAAR9 might be involved in colonic mucosal homeostasis, we analyzed the fecal microbiome composition in TAAR9-KO rats and their wild-type littermates. We identified a significant difference in the number of observed taxa between the microbiome of TAAR9-KO and wild-type rats. In TAAR9-KO rats, the gut microbial community became more variable compared with the wild-type rats. Furthermore, it was found that the family Saccharimonadaceae, which is one of the top 10 most abundant families in TAAR9-KO rat feces, is almost completely absent in wild-type animal fecal samples. Taken together, these data indicate a role of TAAR9 in intestinal function.