The dual orexin receptor antagonist TCS1102 does not affect reinstatement of nicotine-seeking

Abstract

The orexin/hypocretin system is important for appetitive motivation towards multiple drugs of abuse, including nicotine. Both OX1 and OX2 receptors individually have been shown to influence nicotine self-administration and reinstatement. Due to the increasing clinical use of dual orexin receptor antagonists in the treatment of disorders such as insomnia, we examined whether a dual orexin receptor antagonist may also be effective in reducing nicotine seeking. We tested the effect of intracerebroventricular (i.c.v.) administration of the potent and selective dual orexin receptor antagonist TCS1102 on orexin-A-induced food self-administration, nicotine self-administration and reinstatement of nicotine-seeking in rats. Our results show that 30 μg of TCS1102 i.c.v. abolishes orexin-A-induced increases in food self-administration but does not reduce nicotine self-administration. Neither i.c.v. 10 μg nor 30 μg of TCS1102 reduced compound reinstatement after short-term (15 days) self-administration nicotine, but 30 μg transiently reduced cue/nicotine compound reinstatement after chronic self-administration (29 days). These results indicate that TCS1102 has no substantial effect on motivation for nicotine seeking following chronic self-administration and no effect after shorter periods of intake. Orexin receptor antagonists may therefore have little clinical utility against nicotine addiction.

Fig 1. Experimental procedures.

(A) In Experiments 2 and 3, rats were first trained for nicotine self-administration. They were then tested for self-administration before undergoing extinction and tests for cue-induced, nicotine-primed and cue/nicotine compound reinstatement. (B) In Experiment 4, rats were first trained for nicotine self-administration for 15 days. They then underwent extinction and testing for cue/nicotine compound reinstatement.

Fig 2. TCS1102 abolishes orexin-A-induced food self-administration.

The number of magazine entries following administration of 2.5 μg OX-A and 30 μg of TCS1102 (OX-A/TCS1102) was significantly reduced compared to the 2.5 μg OX-A and 20% Vitamin E-TPGS (OX-A/TPGS) condition (n = 15). * P < 0.05 compared to OX-A/TPGS.

Fig 3. TCS1102 has no effect on nicotine self-administration.

(A) TCS1102 had no effect on 1 h operant intravenous self-administration of nicotine in rats (n = 13) following intracerebroventricular microinjections of 1, 3 or 10 μg TCS1102. (B) Active nosepoke responding over the course of the session was also not altered.

Fig 4. TCS1102 has only a transient effect on cue/nicotine compound reinstatement.

(A) There was no effect on the magnitude of cue-induced reinstatement by centrally administered 10 μg of TCS1102. (B) There was also no effect on the timecourse of cue-induced reinstatement. (C) Similarly there was no effect of centrally administered 10 μg TCS1102 on overall responding or (D) the timecourse of active nosepokes during nicotine-primed reinstatement. (E) Although there was not a statistically significant reduction on overall responding during cue/nicotine compound reinstatement, there was a (F) small, transient reduction in active nosepokes during the first 15 minutes. * p < 0.05 for vehicle vs TCS10. Numbers on the figure indicate the allocation to each condition from a total of 12–13 rats per test. Data are means ± SEM.

Fig 5. TCS1102 has no effect on cue/nicotine compound reinstatement after short-term self-administration.

(A) In a separate cohort of rats (n = 14) trained for 15 days, cue/nicotine primed reinstatement was not affected by central administration of 10 or 30 μg of TCS1102. (B) TCS1102 also had no effect on active nosepokes over the course of the session. Data are means ± SEM.