Neuroinflammatory and glutamatergic mechanisms of nicotine seeking

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PROJECT SUMMARY/ABSTRACT Nicotine use is a substantial burden to public health. Further, craving and relapse to smoking appear to vary as a function of sex and of menstrual cycle phase in women, whereby increases in 17β-estradiol (E2) and progesterone (P4) are associated with addiction vulnerability and resilience, respectively. P4 has been examined clinically as a smoking cessation agent and appears to show promise for women. However, studies incorporating men have shown unclear or limited efficacy in men. Its derivative, allopregnanolone (ALLO), was recently approved by the Food and Drug Administration (FDA) as a treatment for post-partum depression, although it not approved as a smoking cessation agent. In preclinical studies, hormones interact with nicotine neurobiology as a function of sex. We have found that neuroimmune signaling within the nucleus accumbens core, a key brain region associated with drug reward, is driven by nicotine seeking and consumption in a sex-specific fashion, whereby female rats are more susceptible to neuroimmune consequences induced by nicotine use as compared to males. Specifically, we have shown that NAcore microglia are more activated by nicotine in females than in males. Further, we have shown that activation of the nuclear factor-kappa B (NF-κB) pathway occurs following nicotine self-administration (SA), and is necessary to inhibit in order for other pharmacotherapies to reduce nicotine seeking. We have also shown that nicotine demand intensity (as measured via behavioral economics) is sensitive to synthetic and ovarian hormones. Under this diversity supplement, Mr. Kendrick will uncover potentially critical contributions of neuroimmune signaling within the reward pathway to the therapeutic effects of P4 and ALLO as a function of sex in reducing nicotine consumption. We will test necessity of these compounds to inhibit neuroimmune activation within the NAcore in order to exert therapeutic effects in reducing nicotine consumption. In Aim 1, we will test if inhibition of NAcore NF-κB signaling is necessary for P4 and ALLO to decrease nicotine demand intensity. We hypothesize that this will be true in females but not males. In Aim 2, we will establish the conditional relationship of necessity through bidirectional chemogenetic manipulation of microglia while chronically administering P4, ALLO, or vehicle during nicotine SA. We hypothesize that P4 and ALLO will reduce nicotine consumption and microglial activation, but that chemogenetic activation of microglia will occlude this effect. We further hypothesize that this will only be evident in females. Together, these studies will be the first to establish necessity of NAcore neuroimmune inhibition (via NF-κB and microglial activation) in the efficacy of two potential steroid-based pharmacotherapies for smoking cessation across both sexes. This will also be the first set of studies to determine if ALLO shows preclinical efficacy in decreasing nicotine demand in both sexes. This line of research has the potential to guide strategies for promoting smoking cessation through discovery of novel neural mechanisms, and may justify examination of other possible therapeutics that have anti- inflammatory properties for smoking cessation which may yield higher efficacy across both sexes.