Abstract:
Quinuclidine derivatives (s)-T1, (s)-T2, and (s)-T6 are the ligands of α3β4 nicotinic acetylcholine receptor (nAChR). α3β4 nAChRs are highly expressed in medial habenula (MHb). The MHb connects to the brain rewarding pathway and mediates nicotine induce rewarding effect. Various α3β4 nicotinic acetylcholine antagonists have been investigated for their anti-addictive effect in animal models of nicotine addiction. The present study was aimed to evaluate the anti-addictive effects and mechanisms of quinuclidine derivatives, (s)-T1, (s)-T2, and (s)-T6 in nicotine-induced conditioned place preference (CPP) in mice. In the first experiment, mice received either nicotine (0.5 mg/kg, s.c.), (s)-T1 (1, 3, or 10 mg/kg, s.c.), (s)-T2 (1, 3, or 10 mg/kg, s.c.), or (s)-T6 (1, 3 or 10 mg/kg, s.c.) and performed locomotor activity and CPP. Nicotine and (s)-T6 (10 mg/kg) reduced locomotion time (P < 0.05). In CPP model, nicotine significantly increased CPP score compared to control (P < 0.05), while (s)-T1, (s)-T2, and (s)-T6 significantly decreased CPP scores compared nicotine-treated mice (P < 0.05). In the second experiment, mice received either varenicline (1 mg/kg, s.c.), (s)-T1 (1, 3, or 10 mg/kg, s.c.), (s)-T2 (1, 3, or 10 mg/kg, s.c.), or (s)-T6 (1 or 3 mg/kg, s.c.) 30 min prior to nicotine administration. CPP and locomotor activity were performed. Varenicline, (s)-T1 (1, 3, and 10 mg/kg), (s)-T2 (1 and 3 mg/kg) and (s)-T6 (1 and 3 mg/kg) significantly decreased CPP scores compared to nicotine treatment alone (P < 0.05, P < 0.001, P < 0.05, P < 0.05, P < 0.01, P < 0.05, P < 0.05, P < 0.05, respectively). All doses of (s)-T1, (s)-T2, and (s)-T6 plus nicotine treatment had no effect on locomotion time. In the third experiment, mice received the same treatment as in the second experiment, nucleus accumbens (NAc), striatum, hippocampus and prefrontal cortex (PFC) were collected 40 min after nicotine administration. Dopamine and DOPAC levels were determined using LC/MS/MS. (s)-T1 (1, 3 and 10 mg/kg), (s)-T2 (3 and 10 mg/kg) and (s)-T6 (1 and 3 mg/kg) block nicotine-induced dopamine elevation in the striatum. In addition, (s)-T1 (3 mg/kg) and (s)-T6 (1 and 3 mg/kg inhibited nicotine-induced dopamine elevation in PFC. In conclusion, (s)-T1, (s)-T2, and (s)-T6 can prevented nicotine-induced CPP. The mechanism of action involved the prevention of nicotine induced dopamine elevation in the brain areas involving cue-associate learning of rewarding effect of nicotine.
