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.
Highlights
Tobacco smoking is the leading cause of preventable disease in North America and Western Europe, where it accounts for one in five deaths [1,2,3]
These neuroplastic changes may alter the degree to which the orexin system is involved in nicotine-seeking, which would explain why we found an effect on nicotine-seeking after chronic access, but not short-term access
We have demonstrated that the dual orexin receptor antagonist, TCS1102, blocks orexin-Ainduced food self-administration but has only a small, transient effect on cue/nicotine compound reinstatement after chronic access to nicotine
Summary
Tobacco smoking is the leading cause of preventable disease in North America and Western Europe, where it accounts for one in five deaths [1,2,3] Existing therapies such as partial nicotinic receptor agonists are somewhat effective, yet relapse rates remain high [4]. The orexin/ hypocretin system may be a potential therapeutic target because it is activated by acute nicotine administration [5] It has been widely implicated in the appetitive motivational properties for several drugs of abuse, including alcohol, cocaine, and opioids, as well as non-drug reinforcers such as high-fat food [6,7,8].
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