Role of trace amine-associated receptor 1 in nicotine’s behavioral and neurochemical effects

Abstract

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 addictive-like behaviors. We aimed to investigate the role of TAAR1 in nicotine addictive-like behaviors. 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. 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 drug-induced reinstatement of nicotine-seeking. 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.

Drug addiction: a curable mental disorder?

“…Studies from our lab and others have shown that TAAR1 agonists were effective to attenuate the behavioral and biochemical effects of stimulants such as cocaine and amphetamines [52]. Our recent study also demonstrated that activation of TAAR1 was effective to reduce nicotine-induced dopamine release and neural activation in the NAc [55]. Furthermore, TAAR1 agonists attenuated several kinds of nicotine-related behaviors, e.g., nicotine-induced behavioral sensitization, nicotine discrimination, nicotine self-administration, and reinstatement of nicotine-seeking [55].…”

“…Our recent study also demonstrated that activation of TAAR1 was effective to reduce nicotine-induced dopamine release and neural activation in the NAc [55]. Furthermore, TAAR1 agonists attenuated several kinds of nicotine-related behaviors, e.g., nicotine-induced behavioral sensitization, nicotine discrimination, nicotine self-administration, and reinstatement of nicotine-seeking [55]. Furthermore, we demonstrated that the dosages of TAAR1 agonists that effectively inhibited addiction-related behaviors had no effect on general motor activity [55].…”

“…Furthermore, TAAR1 agonists attenuated several kinds of nicotine-related behaviors, e.g., nicotine-induced behavioral sensitization, nicotine discrimination, nicotine self-administration, and reinstatement of nicotine-seeking [55]. Furthermore, we demonstrated that the dosages of TAAR1 agonists that effectively inhibited addiction-related behaviors had no effect on general motor activity [55]. These results indicated that modulation of TAAR1 could selectively regulate abuse-related behaviors of several drugs of abuse.…”

Trace Amines and Their Receptors

“…Furthermore, direct infusion of a TAAR1 agonist into the nucleus accumbens also prevented drug-seeking behaviors, whereas TAAR1-KO enhanced nicotine-seeking behaviors. Intriguingly, chronic nicotine administration selectively decreased nucleus accumbens TAAR1 expression (Liu et al, 2018). In this way, chronic nicotine administration may be removing a cellular brake on dopaminergic activity in the central reward centers, thereby promoting its rewarding and addicting properties.…”

“…Administration of TAAR1 agonists was able to decrease nicotine-induced hyperactivity (Liu et al, 2018;Sukhanov et al, 2018), sensitization (Liu et al, 2018;Sukhanov et al, 2018), self-administration (Liu et al, 2018), cue-and drugprimed reinstatement (Liu et al, 2018), and discriminative stimulus effects (Liu et al, 2018), while simultaneously increasing the elasticity of the nicotine demand curve (Liu et al, 2018). These beneficial effects of TAAR1 activation were associated with a decrease in the nicotine-induced dopamine release and c-fos expression in the nucleus accumbens, confirming prevention of hyperactivity of the dopamine reward centers (Liu et al, 2018). Furthermore, direct infusion of a TAAR1 agonist into the nucleus accumbens also prevented drug-seeking behaviors, whereas TAAR1-KO enhanced nicotine-seeking behaviors.…”