Activation of trace amine‐associated receptor 1 attenuates nicotine withdrawal‐related effects

Abstract

Nicotine addiction is a leading avoidable brain disorder globally. Although nicotine induces a modest reinforcing effect, which is important for the initial drug use, the transition from nicotine use to nicotine addiction involves the mechanisms responsible for the negative consequences of drug abstinence. Recent study suggested that trace amine-associated receptor 1 (TAAR1) is a promising pharmacological target for the modulation of positive reinforcing effects of nicotine. However, whether TAAR1 plays a part in the negative reinforcement of nicotine withdrawal remains to be determined. Here, using a long-access (LA) self-administration model, we investigated whether LA rats show increased nicotine intake and withdrawal symptoms in comparison with saline and ShA rats and then tested the effect of TAAR1 partial agonist RO5263397 on nicotine withdrawal effects. We found that rats from long-access group showed significant abstinence-induced anxiety-like behaviour, mechanic hypersensitivity, increased number of precipitated withdrawal signs and higher motivation for the drug, while rats from short-access did not differ from saline group. TAAR1 partial agonist RO5263397 significantly reduced the physical and motivational withdrawal effects of nicotine in LA rats, as reflected by increased time spent on the open arm in the elevated plus maze (EPM) test, normalized paw withdrawal threshold, decreased withdrawal signs and motivation to self-administer nicotine.This study indicates that activation of TAAR1 attenuates the negative-reinforcing effects of nicotine withdrawal and further suggests TAAR1 as a promising target to treat nicotine addiction.

Activation of trace amine‐associated receptor 1 (TAAR1) transiently reduces alcohol drinking in socially housed mice

“…Similarly to this observation, RO5263397 decreased the motivation for methamphetamine self‐administration under a progressive ratio schedule of reinforcement 18 . The same compound also significantly decreased nicotine's physical and motivational withdrawal effects in the long‐access self‐administration rat model 53 . This indicates the possible involvement of TAAR1 activation in the regulation of motivational behaviour associated with drug addiction.…”

“…18 The same compound also significantly decreased nicotine's physical and motivational withdrawal effects in the long-access self-administration rat model. 53 This indicates the possible involvement of TAAR1 activation in the regulation of motivational behaviour associated with drug addiction.…”

Activation of trace amine-associated receptor 1 (TAAR1) transiently reduces alcohol drinking in socially housed mice

“…19 The same compound also significantly decreased nicotine's physical and motivational withdrawal effects in the long-access self-administration rats model. 45 This indicates the possible involvement of TAAR1 activation in the regulation of motivational behavior associated with drug addiction.…”

“…Similarly, RO5263397 decreased the motivation for methamphetamine self-administration under a progressive ratio schedule of reinforcement (Pei et al 2017). The same compound also significantly decreased nicotine’s physical and motivational withdrawal effects in the long-access self-administration rats model (Wu et al 2022). This indicates the possible involvement of TAAR1 activation in the regulation of motivational behavior associated with drug addiction.…”

Electroacupuncture alleviated depression‐like behaviors in ventromedial prefrontal cortex of chronic unpredictable mild stress‐induced rats: Increasing synaptic transmission and phosphorylating dopamine transporter

“…Here, ameliorated depression was along with raised TAAR1 and PKA expression of rats after EA treatment. TAAR1 is a novel target gathering more and more attention in regulating the dopaminergic nervous system and related disorders 31,62 . As an intracellular G protein‐coupled receptor (GPCR), TAAR1 elevates cAMP levels and downstream signal transduction such as PKA, which is also known as cAMP‐dependent PKA.…”