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.

Keywords: TAAR1; long-access; negative reinforcement; nicotine withdrawal; stress.

FIGURE 1

Nicotine self-administration in rats under different access conditions. (A) Experimental timeline. Two groups (saline/nicotine) of rats underwent self-administration training for 2 weeks (acquisition phase, 1 h/day). Then, nicotine group was divided into two subgroups, that is, short-access group (Nic-ShA, 1 h/day) and long-access group (Nic-LA, 21 h/day). (B) Nicotine groups showed increased infusions compared with saline group during the acquisition phase. There was no difference between Nic-ShA group and Nic-LA group during this period. During the maintain phase, Nic-LA group showed increased total infusions compared with Nic-ShA group. Data are expressed as mean ± standard error of the mean (SEM); *p < 0.05, compared with saline; ^#p < 0.05, compared with Nic-ShA group. Saline: n = 18, Nic-ShA: n = 16, Nic-LA: n = 18

FIGURE 2

Effects of RO5263397 on the abstinence-induced anxiety-like behaviour and mechanical hypersensitivity. (A) Nic-LA group showed a decreased time spent on the open arms, while Nic-ShA group showed no differences. RO5263397 significantly increased the time spent on the open arms in LA rats without affecting Nic-ShA group. (B) No differences were observed among all groups 1 h after the last session for the Von Frey assay. (C) Three days after the last training, Nic-LA group showed a decrease in paw withdrawal threshold compared with saline group, while Nic-ShA group showed no differences. RO5263397 reversed the mechanical hypersensitivity in LA rats. Data are expressed as mean ± standard error of the mean (SEM); *p < 0.05, compared with saline-vehicle; ^#p < 0.05, compared with Nic-LA-vehicle group. n = 8–9 for all groups

FIGURE 3

Effect of RO5263397 on the mecamylamine-precipitated withdrawal symptoms. Three days after the EPM test, mecamylamine-precipitated withdrawal signs were tested. Nic-LA rats had more withdrawal signs compared with saline group. Nic-ShA rats did not differ from saline group in the total withdrawal signs. Systemic administration of RO5263397 significantly reduced the precipitated withdrawal symptoms in the Nic-LA group without affecting the Nic-ShA rats. Data are expressed as mean ± standard error of the mean(SEM); *p < 0.05, compared with saline-vehicle; ^#p < 0.05, compared with Nic-LA-vehicle group. n = 8–9 for all groups

FIGURE 4

Effect of RO5263397 on the motivational properties of nicotine withdrawal. (A) Nic-LA rats showed higher motivation for nicotine after the abstinence compared with Nic-ShA rats, reflected by elevated infusions under a progressive-ratio schedule. Administration of RO5263397 significantly reduced the infusions in the Nic-LA group. B. Nic-LA rats showed increased active lever presses at the progressive-ratio test compared with Nic-ShA rats, while RO5263397 attenuated the increased active lever responses in the Nic-LA group. RO5263397 also decreased the active lever responses in the Nic-ShA group. Data are expressed as mean ± standard error of the mean (SEM); *p < 0.05, compared with Nic-ShA-vehicle; ^#p < 0.05, compared with Nic-LA-vehicle group. n = 8–9 for all groups