Abstract:Background and Purpose：Nicotine addiction and abuse remains a global health issue. To date，the fundamental neurobiological mechanism of nicotine addiction remains incompletely understood. Trace amine-associated receptor 1 （TAAR1） is thought to directly modulate dopaminergic system and are thought to be a neural substrate underlying addictivelike behaviors. We aimed to investigate the role of TAAR1 in nicotine addictive-like behaviors. Experimental Approach：TAAR1 expression after nicotine treatment was evaluated by western blotting. c-Fos immunofluorescence and in vivo fast-scan cyclic voltammetry were used to examine the activation of brain regions and dopamine release，respectively. We then thoroughly and systematically examined the role of TAAR1 in mediating nicotine-induced sensitization，nicotine discrimination，nicotine self-administration，nicotine demand curve，and the reinstatement of nicotine-seeking. Local pharmacological manipulation was conducted to determine the role of TAAR1 in the nucleus accumbens （NAcs） in the reinstatement of nicotine-seeking. Minipump was implanted into TAAR 1 knockout mice and their wildtype counterparts to establish physical dependence. One week after the minipump implantation， the pump was retrieved and mecamylamine was used to precipitate physical withdrawal signs including observable signs and anxiety-like behaviors （elevated plus maze）. Key Results：We found that the expression of TAAR1 protein was selectively downregulated in the NAc， with no change in either dorsal striatum or prefrontal cortex. TAAR1 activation was sufficient to block nicotine-induced c-Fos expression in the NAc，while also reducing nicotine-induced dopamine release in the NAc. Systemic administration of TAAR1 agonists attenuated the expression and development of nicotine-induced sensitization，nicotine self-administration， the reinstatement of nicotine-seeking，and increased the elasticity of nicotine demand curve，while intra-NAc infusions of a TAAR1 agonist was sufficient to attenuate nicotine reinstatement. Moreover，TAAR1-knockout rats showed augmented cue-induced and druginduced reinstatement of nicotine-seeking. Mice that were physically dependent on chronic nicotine exposure demonstrated significant withdrawal signs after mecamylamine treatment，and TAAR 1 knockout mice demonstrated more severe withdrawal signs. TAAR 1 agonist reduced the withdrawal signs in the wildtype mice. Conclusions and Implications：These results indicated that modulation of TAAR1 activity regulates nicotine addictive-like behaviors and TAAR1 represents a novel target towards the treatment of nicotine addiction.