Neural Substrates of Cigarette Craving, Withdrawal, and Relief: Male-Female Differences

在美国，吸烟是可预防的死亡和疾病的主要原因，而女性不成比例地 吸烟会对健康造成一些影响，如心脏病和宫颈癌。与男性相比， 女性会经历更强烈的戒断症状，并且更难维持长期戒断 吸烟和戒烟治疗对男性和女性的帮助并不相同。潜在的差异 在大脑功能驱动这些男女差异仍然未知，了解他们可以指导 开发个性化戒烟疗法。 谷氨酸能神经传递是戒烟治疗的一个有前途的靶点，但男性-女性 尚未研究可能影响多巴胺能治疗功效的差异。减少 显著性网络中的谷氨酸水平，特别是背侧前扣带皮层（dACC）中的谷氨酸水平可能有助于 戒烟。吸烟者dACC中的谷氨酸（Glu）含量高于不吸烟者，并表现出阳性反应。 dACC Glu与默认模式网络内对吸烟相关线索的反应性的相关性。鉴于这些 研究结果和性别差异在健康个体的大脑谷氨酸水平，重要的是要测试男性，女性 dACC Glu对戒断过程中的渴望和消极状态的影响以及戒断后的缓解的差异 吸烟，以及这些状态下的神经基质。 我们将联合收割机自我报告措施与磁共振波谱（MRS）和功能磁共振成像（MRI）相结合。 磁共振成像（fMRI），以解决三个具体目标：目标1。确定男性和女性在 dACC中的Glu信号与戒烟期间的香烟渴望和消极状态（消极影响， 心理退缩和焦虑）。目标二。确定男性和女性在谷氨酸相关性方面的差异， dACC与吸烟引起的渴望和消极状态的缓解（即，负强化;和目标3. 确定dACC中Glu与静息状态功能连接相关性的男女差异 （rsFC）在大规模神经网络内部和之间。该项目的目标是吸烟前评估 Glu在神经网络的dACC和rsFC中的作用;然而，吸烟前和吸烟后的评估（自我报告，fMRI， 和MRS）将在60名吸烟者（30名男性和30名女性）过夜（约12小时）戒烟后完成。妇女将 在卵泡期和黄体期，在2个不同的日期完成这些评估，以评估 生殖周期和卵巢激素的影响。 这些发现可以帮助推进个性化，性别特异性戒烟疗法的发展。 相关性（参见说明）： 谷氨酸能神经传递是戒烟治疗的一个有前途的靶点，但男女差异， 其可影响多巴胺能治疗的功效，尚未被研究。我们将联合收割机的自我报告 磁共振波谱和功能性磁共振成像测定性别 大脑谷氨酸盐与戒烟相关的内部状态之间的差异， 诱导缓解这些状态，以及它们背后的神经基质。这些发现可以帮助推进 开发个性化、针对性别的戒烟疗法。

Smoking is the leading cause of preventable death and disease in the U.S., and women disproportionately suffer some health consequences of smoking, such as heart disease and cervical cancer. Compared to men, women experience stronger withdrawal symptoms and have more difficulty maintaining long-term abstinence from smoking, and smoking-cessation treatments are not equally helpful to men and women. The underlying differences in brain function that drive these male-female differences remain unknown, and understanding them can guide development of personalized smoking-cessation therapies. Glutamatergic neurotransmission is a promising target for smoking cessation therapy, but male-female differences that can impact the efficacy of glutamatergic treatments have not been investigated. Reducing glutamate levels within the Salience Network, especially in the dorsal anterior cingulate cortex (dACC) may facilitate smoking cessation. Smokers have higher glutamate (Glu) in the dACC than nonsmokers and exhibit a positive correlation of dACC Glu with reactivity within the default-mode network to smoking-related cues. Given these findings and sex differences in brain glutamate levels in healthy individuals, it is important to test for male-female differences in the influence of dACC Glu on craving and negative states during withdrawal and their relief after smoking, as well as the neural substrates that underlie these states. We will combine self-report measures with magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) to address three specific aims: Aim 1. Determine male-female differences in the association of Glu signal in the dACC with cigarette craving and negative states during abstinence (negative affect, psychological withdrawal, and anxiety). Aim 2. Determine male-female differences in the association of Glu in the dACC with smoking-induced relief of craving and negative states (i.e., negative reinforcement); and Aim 3. Determine male-female differences in the association of Glu in the dACC with resting-state functional connectivity (rsFC) within and between large-scale neural networks. The aims of this project focus on pre-smoking assessments of Glu in the dACC and rsFC of neural networks; however, pre- and post-smoking assessments (self-report, fMRI, and MRS) will be completed in 60 smokers (30 men and 30 women) after overnight (~12h) abstinence. Women will complete these assessments on 2 separate days, during the follicular and luteal phases, to allow evaluation of menstrual-cycle and ovarian hormone effects. The findings can help advance development of personalized, sex-specific smoking cessation therapies. RELEVANCE (See instructions): Glutamatergic neurotransmission is a promising target for smoking cessation therapy, but male-female differences, which can impact the efficacy of glutamatergic treatments, have not been investigated. We will combine self-report measures with magnetic resonance spectroscopy and functional magnetic resonance imaging to determine sex differences in the association of brain glutamate with internal states linked to cigarette withdrawal, with smoking- induced relief of these states, and the neural substrates that underlie them. The findings can help advance development of personalized, sex-specific, smoking-cessation therapies.