TY - JOUR T1 - Ovarian hormones regulate nicotine consumption and accumbens glutamatergic plasticity in female rats JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0286-21.2022 SP - ENEURO.0286-21.2022 AU - Erin E. Maher AU - Zachary A. Kipp AU - Jonna M. Leyrer-Jackson AU - Shailesh Khatri AU - Emma Bondy AU - Genesee J. Martinez AU - Joshua S. Beckmann AU - Terry D. Hinds, Jr. AU - Heather A. Bimonte-Nelson AU - Cassandra D. Gipson Y1 - 2022/06/10 UR - http://www.eneuro.org/content/early/2022/06/10/ENEURO.0286-21.2022.abstract N2 - Women report greater cigarette cravings during the menstrual cycle phase with higher circulating levels of 17β-estradiol (E2), which is metabolized to estrone (E1). Both E2 and E1 bind to estrogen receptors (ERs), which have been highly studied in the breast, uterus, and ovary. Recent studies have found that ERs are also located on GABAergic medium spiny neurons (MSNs) within the nucleus accumbens core (NAcore). Glutamatergic plasticity in NAcore MSNs is altered following nicotine use; however, it is unknown whether estrogens impact this neurobiological consequence. To test the effect of estrogen on nicotine use, we ovariectomized (OVX) female rats that then underwent nicotine self-administration acquisition and compared them to ovary-intact (sham) rats. The OVX animals then received either sesame oil (vehicle), E2, or E1+E2 supplementation for 4 or 20 days prior to nicotine sessions. While both ovary-intact and OVX females readily discriminated levers, OVX females consumed less nicotine than sham females. Further, neither E2 nor E1+E2 increased nicotine consumption back to sham levels following OVX, regardless of the duration of the treatment. OVX also rendered NAcore MSNs in a potentiated state following nicotine self-administration, which was reversed by 4 days of systemic E2 treatment. Finally, we found that E2 and E1+E2 increased ERα mRNA in the NAcore, but nicotine suppressed this regardless of hormone treatment. Together, these results show that estrogens regulate nicotine neurobiology, but additional factors may be required to restore nicotine consumption to ovary-intact levels.Significance statementWe report that both ovariectomized (OVX) and ovary-intact female rats acquire nicotine self-administration, with ovary-intact females consuming more nicotine than OVX females. Neither treatment with 17-β-estradiol (E2) or a combination of E2 and its metabolite, estrone (E1), reversed OVX-induced suppression of nicotine consumption. We further report that cessation of ovarian hormones due to OVX increased AMPA/NMDA ratios of accumbens medium spiny neurons (MSNs) in nicotine-experienced females, which is reversed by E2 supplementation. Collectively, these studies demonstrate the important contributions of estrogens to nicotine neurobiology and highlight differences in how ovarian hormones impact nicotine neurobiology and behavior. These studies may provide insight into the critical role of the hypothalamic-pituitary-ovarian axis in regulating nicotine consumption in women. ER -