Estrogens and Olfactomedins May Induce a Feedback Loop that Increases Nicotine Consumption in Females via the Brain Reward Circuitry

• Published in: Physiology (Bethesda, Md.) Vol. 39; no. S1
• Main Authors: Pauss, Sally, Kipp, Zachary, Gipson-Reichardt, Cassandra, Hinds, Terry
• Format: Journal Article
• Language: English
• Published: 01.05.2024
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2024.39.S1.986

Abstract only Estrogen is associated with enhanced nicotine use in women, with enhanced vulnerability to nicotine use disorders being associated with higher levels of circulating estrogen. In ovariectomized (OVX) female rats, estradiol (E2) treatments increased estrogen receptor β (ERβ) and not ERα in a key brain reward region, the nucleus accumbens core (NAcore). Therefore, we hypothesized that ERβ might be important in the reward circuitry for regulating nicotine use in females. To determine ERβ-specific functions that might regulate nicotine use, we analyzed large sequencing datasets of estrogen-induced genes and narrowed the list to those expressed in the brain and that have a hormone function. We found one class of genes known as the olfactomedins (OLFMs), which meet these criteria. Therefore, we wanted to determine whether ERα or ERβ regulates the expression of the OLFM isoforms. We used human uterine cells (Ishikawa) that express both ER isoforms and the OLFMs and found that two-hour E2 treatments induced the expression of OLFM1 and OLFM3. However, nicotine only suppressed the E2-induction of OLFM1 and not the others. We next performed chromatin immunoprecipitation (ChIP) assays with these cells and treatments using antibodies for ERα, ERβ, or GFP control. We found that the OLFM1 promoter was only enriched by ERβ, and no binding of ERα was observed. We next treated OVX female rats with E2, nicotine, E2+nicotine, or vehicle and found that Olfm1 and Olfm2 significantly increased in the NAcore, and all three OLFM isoforms were significantly higher in the ventral tegmental area (VTA), another key region within the mesolimbic reward pathway. Nicotine suppressed the E2-induced OLFM expression in the NAcore and VTA. These new findings suggest that ERβ-induction of the olfactomedins might serve as a feedback loop for driving nicotine addiction processes, which is suppressed when nicotine is on board. These results indicate a potential new target for therapeutic cessation of nicotine use in women. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.