Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, 789 S. Limestone Street, 473 Lee T. Todd Jr. Building, Lexington, KY, 40536-0596, USA.
Biol Sex Differ. 2024 Oct 31;15(1):88. doi: 10.1186/s13293-024-00656-6.
Chronic cigarette smokers report withdrawal symptomology, including affective dysfunction and cognitive deficits. While there are studies demonstrating sex specific withdrawal symptomology in nicotine-dependent individuals, literature examining the underlying biological mediators of this is scant and not in complete agreement. Therefore, in this study, we evaluated the sex specific effects of nicotine and withdrawal on contextual fear memory, a hippocampally dependent aspect of cognition that is disrupted in nicotine withdrawal.
Male and female B6/129F1 mice (8-13 weeks old) were used in all experiments. For the acute nicotine experiment, mice received intraperitoneal saline or nicotine (0.5 mg/kg) prior to contextual fear conditioning and test. For the chronic nicotine experiment, mice received nicotine (18 mg/kg/day) or saline for 11 days, then underwent contextual fear conditioning and test. Following the test, mice underwent minipump removal to elicit withdrawal or sham surgery, followed by the fear extinction assay. Bulk cortical tissue was used to determine nicotinic acetylcholine receptor levels via single point [H]Epibatidine binding assay. Gene expression levels in the dorsal and ventral hippocampus were quantified via RT-PCR.
We found that female mice had a stronger expression of contextual fear memory than their male counterparts. Further, following acute nicotine treatment, male, but not female, subjects demonstrated augmented contextual fear memory expression. In contrast, no significant effects of chronic nicotine treatment on fear conditioning were observed in either sex. When examining extinction of fear learning, we observed that female mice withdrawn from nicotine displayed impaired extinction learning, but no effect was observed in males. Nicotine withdrawal caused similar suppression of fosb, cfos, and bdnf, our proxy for neuronal activation and plasticity changes, in the dorsal and ventral hippocampus of both sexes. Additionally, we found that ventral hippocampus erbb4 expression, a gene implicated in smoking cessation outcomes, was elevated in both sexes following nicotine withdrawal.
Despite the similar impacts of nicotine withdrawal on gene expression levels, fosb, cfos, bdnf and erbb4 levels in the ventral hippocampus were predictive of delays in female extinction learning alone. This suggests sex specific dysfunction in hippocampal circuitry may contribute to female specific nicotine withdrawal induced deficits in extinction learning.
慢性吸烟人群会出现戒断症状，包括情感功能障碍和认知缺陷。虽然有研究表明尼古丁依赖个体存在性别特异性戒断症状，但目前关于潜在生物学介导因素的研究很少，且尚未达成完全一致的意见。因此，在这项研究中，我们评估了尼古丁和戒断对情境恐惧记忆的性别特异性影响，这是一种与认知有关的海马依赖性方面，在尼古丁戒断中会受到干扰。
所有实验均使用 8-13 周龄的 B6/129F1 雄性和雌性小鼠。在急性尼古丁实验中，小鼠在进行情境恐惧条件反射和测试前接受腹腔内生理盐水或尼古丁（0.5mg/kg）处理。在慢性尼古丁实验中，小鼠接受尼古丁（18mg/kg/天）或生理盐水处理 11 天，然后进行情境恐惧条件反射和测试。测试后，小鼠接受微型泵移除以引发戒断或假手术，然后进行恐惧消退试验。通过单点[H]Epibatidine 结合测定法测定皮质组织中的烟碱型乙酰胆碱受体水平。通过 RT-PCR 定量测定背侧和腹侧海马体中的基因表达水平。
我们发现雌性小鼠的情境恐惧记忆表达强于雄性小鼠。此外，在急性尼古丁处理后，雄性但不是雌性受试者表现出增强的情境恐惧记忆表达。相反，在两种性别中，慢性尼古丁处理对恐惧条件反射均没有显著影响。当检查恐惧学习的消退时，我们观察到从尼古丁戒断的雌性小鼠表现出受损的消退学习，但在雄性中未观察到这种影响。尼古丁戒断引起了类似的 fosb、cfos 和 bdnf 抑制，我们将其作为神经元激活和可塑性变化的代表，在两种性别中背侧和腹侧海马体中都有。此外，我们发现，在尼古丁戒断后，腹侧海马体中的 erbb4 表达增加，这是一个与戒烟结果相关的基因。
尽管尼古丁戒断对基因表达水平的影响相似，但 fosb、cfos、bdnf 和 erbb4 水平在腹侧海马体中对女性的消退学习延迟有预测作用。这表明海马回路的性别特异性功能障碍可能导致女性特有的尼古丁戒断引起的消退学习缺陷。
