Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders. Issue 1 (January 2023)

• Record Type: Journal Article
• Authors: Halff, Els F.; Rutigliano, Grazia; Garcia-Hidalgo, Anna; Howes, Oliver D.
• Is Part Of: Trends in neurosciences. Volume 46:Issue 1(2023)
• Page Start: 60
• Page End: 74
• Publication Date: 2023-01
• Subjects: psychosis -- circuits -- antipsychotic -- pathophysiology -- neurotransmitters -- intracellular signalling; Neurology -- Periodicals; Neurophysiology -- Periodicals; Neurobiology -- Periodicals; 612.8
• DOI: 10.1016/j.tins.2022.10.010
• Languages: English
• ISSNs: 0166-2236

Abstract

Abstract: Schizophrenia remains a major health burden, highlighting the need for new treatment approaches. We consider the potential for targeting the trace amine (TA) system. We first review genetic, preclinical, and clinical evidence for the role of TAs in the aetiopathology of schizophrenia. We then consider how the localisation and function of the trace amine-associated receptor 1 (TAAR1) position it to modulate key brain circuits for the disorder. Studies in rodents using Taar1 knockout (TAAR1-KO) and overexpression models show that TAAR1 agonism inhibits midbrain dopaminergic and serotonergic activity, and enhances prefrontal glutamatergic function. TAAR1 agonists also reduce hyperactivity, attenuate prepulse inhibition (PPI) deficits and social withdrawal, and improve cognitive measures in animal models. Finally, we consider findings from clinical trials of TAAR1 agonists and how this approach may address psychotic and negative symptoms, tolerability issues, and other unmet needs in the treatment of schizophrenia. Highlights: Schizophrenia pathophysiology is thought to result from a combination of aberrant dopaminergic, glutamatergic, and serotonergic signalling; however, current treatments only address the downstream effects of striatal dopamine overproduction. Rodent knockout and overexpression models of trace amine-associated receptor (TAAR1) have uncovered that TAAR1 is a key regulator of monoaminergic and glutamatergic signalling in brain regions relevant to schizophrenia. Recently developed synthetic TAAR1 agonists enable TAAR1-mediated inhibition of dopaminergic signalling in the striatum and upregulate glutamatergic signalling in prefrontal cortex. Preclinical research and outcomes from clinical trials together suggest that TAAR1 agonists can normalise neurochemical changes of relevance to schizophrenia but without displaying side effects common to current antipsychotic treatments.