Tyler Ryan E, Bluitt Maya N, Van Voorhies Kalynn J, Liu Wen, Magee Sarah N, Pitrolo Elisabeth R, Cordero Victoria L, Ornelas Laura C, Krieman Caroline G, Bender Brooke N, Mosera Alejandro M, Besheer Joyce
Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC.
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC.
bioRxiv. 2024 Oct 31:2024.10.30.621141. doi: 10.1101/2024.10.30.621141.
Traumatic stress is associated with high rates of problematic alcohol use, but how the persistent effects of trauma impact sensitivity to alcohol remain unknown. This study examined the persistent effects of traumatic stress exposure on sensitivity to alcohol and underlying neurobiological mechanisms in rats.
Male (N=98) and female (N=98) Long-Evans rats were exposed to the predator odor TMT, and two weeks later, molecular, neuronal, and behavioral sensitivity to alcohol were assessed. Next, rats were trained to discriminate alcohol from water (male N=70; female N=56), and the impact of TMT on interoceptive sensitivity to alcohol and the alcohol-like effects of systemic GABA receptor activation were evaluated. Lastly, functional involvement of GABA and NMDA receptors in the prelimbic cortex (PrL) and the anterior insular cortex (aIC) was investigated.
TMT exposure sex-dependently altered PrL , and elevated aIC and in males. TMT increased PrL c-Fos in males, which was attenuated by alcohol administration. Alcohol-induced locomotor and startle response effects were attenuated in the TMT group in both sexes. TMT exposure potentiated interoceptive sensitivity to alcohol in males but not in females, and this effect was driven by GABA receptors in the PrL. Greater stress reactivity during TMT exposure was associated with higher interoceptive sensitivity to alcohol, and alcohol exposure history was linked to a heightened stress response to TMT in males.
Traumatic stress increased interoceptive sensitivity to alcohol in males, but not females, through PrL GABA receptor adaptations, potentially enhancing the stimulatory, and by extension the rewarding, effects of alcohol.
创伤性应激与酒精使用问题的高发生率相关，但创伤的持续影响如何影响对酒精的敏感性仍不清楚。本研究探讨了创伤性应激暴露对大鼠酒精敏感性及潜在神经生物学机制的持续影响。
将雄性（N = 98）和雌性（N = 98）的长 Evans 大鼠暴露于捕食者气味 TMT 中，两周后评估其对酒精的分子、神经元和行为敏感性。接下来，训练大鼠区分酒精和水（雄性 N = 70；雌性 N = 56），并评估 TMT 对酒精内感受敏感性的影响以及全身 GABA 受体激活的类酒精效应。最后，研究了 GABA 和 NMDA 受体在前边缘皮层（PrL）和前岛叶皮层（aIC）中的功能作用。
TMT 暴露对 PrL 的影响存在性别依赖性，雄性大鼠的 aIC 升高。TMT 增加了雄性大鼠 PrL 中的 c-Fos，酒精给药可使其减弱。TMT 组中，酒精诱导的运动和惊吓反应效应在两性中均减弱。TMT 暴露增强了雄性大鼠对酒精的内感受敏感性，但对雌性大鼠无此作用，且这种作用由 PrL 中的 GABA 受体驱动。TMT 暴露期间更大的应激反应性与对酒精更高的内感受敏感性相关，而酒精暴露史与雄性大鼠对 TMT 的应激反应增强有关。
创伤性应激通过 PrL GABA 受体适应性增加了雄性大鼠对酒精的内感受敏感性，但对雌性大鼠无此作用，这可能增强了酒精的刺激作用，并进而增强了其奖赏作用。
