TAAR1 AGONISTS AS POTENTIAL ANTI-ADDICTION CANDIDATES: PRECLINICAL EVIDENCE

Abstract Background TAAR1 represents an exciting new drug target for the development of medications to treat neuropsychiatric disorders, with most exciting discoveries coming from the positive clinical trials of TAAR1 agonist for the treatment of schizophrenia 1. Aim & Objectives The objective of this presentation is to provide emerging preclinical findings that TAAR1 functions as a modulating “brake” of central dopaminergic system excitability and as such TAAR1 agonists can counter addiction-related effects of a number of commonly abused drugs with cocaine as an example. Methods Commonly used behavioral paradigms designed to measure different aspects of drugs of abuse were employed to examine the reinforcing, motivational and relapse effects of cocaine in rats. Genetic, pharmacological and molecular approaches were used to delineate the underlying mechanisms of TAAR1 agonist-induced anti- addiction effects. Results TAAR1 partial agonist RO-5263397 reduced cocaine intake and cocaine reinforcing efficacy as well as cue, drug and stress-induced reinstatement of cocaine-seeking behavior 2. TAAR1 agonist RO5166017 recapitulated the similar efficacy as RO-5263397. RO5166017 attenuated drug-induced reinstatement of cocaine-seeking and prevented drug priming-induced CaMKIIα activity in the NAc shell. Activation of TAAR1 dampened the CaMKIIα/GluR1 signaling pathway in the NAc shell and reduced AMPAR-EPSCs on the NAc slice. Microinjection of the selective TAAR1 antagonist EPPTB into the NAc shell enhanced drug-induced reinstatement as well as potentiated CaMKIIα activity in the NAc shell. Furthermore, viral-mediated expression of CaMKIIα in the NAc shell prevented the behavioral effects of TAAR1 activation 3. Discussion & Conclusion TAAR1 agonists reduced different aspects of cocaine addiction, and the effects may be mediated via CaMKIIα/GluR1 signaling pathway in the NAc shell. These results provide strong preclinical evidence that TAAR1 agonists have potential as anti- addiction medications against cocaine use disorder. References 1. Achtyes ED, Hopkins SC, Dedic N, Dworak H, Zeni C, Koblan K (2023) Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia. Eur Arch Psychiatry Clin Neurosci, 273(7): 1543-56. 2. Thorn DA, Jing L, Qiu Y, Gancarz-Kausch AM, Galuska CM, Dietz DM, Zhang Y, Li JX. (2014) Effects of the trace amine-associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats. Neuropsychopharmacology, 39(10):2309-16. 3. Liu J, Wu R, Seaman R Jr, Manz KM, Johnson B, Vu J, Huang Y, Zhang Y, Robison AJ, Neve R, Grueter BA, Dietz D, Li JX. (2022) TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc. Mol Psychiatry, 27(4):2136-2145.