Effects of inhibiting the orexin system on nicotine reward memory and fear memory

The orexin system is associated with various brain functions, including reward processing and the stress response. Previous studies have suggested that orexin receptors (OXRs) antagonists could be beneficial in treating several mental disorders, such as drug addiction and post-traumatic stress disorder. However, the specific role of the orexin system in both appetitive (reward-related) and aversive (fear-related) memories remains unclear. In this study, we used nicotine-induced conditioned place preference (CPP) and fear conditioning models to evaluate the effects of suvorexant, a dual OXRs antagonist, and chemogenetic inhibition of orexin neurons in the lateral hypothalamus (LHA) on the retrieval, reconsolidation, and/or extinction of both nicotine reward memory and fear memory. Our findings indicated that suvorexant impaired the expression of nicotine CPP in a dose-dependent manner. These behavioral results aligned with neurochemical evidence from cFos staining, which showed activation of the LHA and orexin neurons in the LHA following the expression of nicotine CPP. Furthermore, using orexin-cre rats, we found that chemogenetic inhibition of orexin neurons in the LHA also reduced the expression of nicotine CPP. However, neither of these interventions affected the reconsolidation of nicotine reward memory. Moreover, neither suvorexant nor the chemogenetic inhibition of LHA orexin neurons affected the retrieval, reconsolidation, or extinction of fear memory, or anxiety-like behaviors, as evaluated by elevated plus maze and open field tests. In summary, our data suggest that the orexin system plays a crucial role in retrieving nicotine reward memory, and suggest that suvorexant may be a promising pharmacotherapy for treating nicotine addiction.