Sex Differences in Addiction

项目摘要/摘要。 无法维持戒酒是上瘾的标志，但有效的维持疗法 仍然难以捉摸。研究表明，女性可能在药物滥用治疗方面面临独特的问题 与男性相比，女性对滥用药物的心理和生理反应有所不同。女性倾向于 表现出更大的药物依赖，从偶尔吸毒到依赖进展得更快，有更大的 戒烟困难，禁欲时间比男性短。这些影响也同样被观察到。 在雌性动物模型中。因此，有必要了解电路动力学和分子 导致强烈的行为性别差异的特征阻碍了禁欲的成功。我们已经开发出一种 改编自标准药物的新行为模型--寻求-坚持范式(SPP 禁欲范例。采用寻求-持续范式考察了干预的影响 在最初戒毒期间的长期寻毒行为。事实上，在最初的戒毒过程中寻找可卡因 与寻求戒毒密切相关。这些结果反映了临床研究表明，渴望 在最初的禁欲期间，可以预测复发率。将该范例与电生理学相结合， 化学遗传学和功能基因组学方法，我们的目标是通过以下方式最终为治疗提供新的靶点 研究性别特异性信号在驱动可卡因寻求持久性中的作用。我们之前已经 研究发现，背侧海马CA1是去甲肾上腺素(NE)调节的重要下游靶点。 在ED1上寻找可卡因。值得注意的是，蓝斑(LC)(NE)-CA1信号在这种行为中似乎是雌性的。 特异性的，我们假设这一途径的招募参与了更多的可卡因寻求在 女性。在K99阶段的第一年，我将首先确定这种性别差异是否涉及相位或主音轨迹 使用单位记录在行为大鼠的ED1上进行蓝斑放电。在K99阶段的第二年，我将使用RNA- 测序和生物信息学分析确定CA1中可卡因寻求量增加的分子特征 行为。下一步，在我的独立阶段(R00)，我将把先前的化学遗传技术培训与 觉醒行为电生理学的新训练，以确定LC输入抑制或激活对 使用PRSx8启动子的背侧海马区CA1对ED1可卡因寻找和可卡因寻找-持久性的影响 由设计师药物(DREADs)独家激活的驱动设计师受体，允许在 LC-NE神经元。随后，我将利用我的生物信息学培训来确定一组成绩单 通过检查与寻求可卡因负相关的转录本与寻求可卡因的复原力相关联 行为。因此，这些实验将表征LC(NE)-CA1通路在驱动可卡因- 寻找行为和识别CA1中与寻求可卡因的性别差异相关的新基因靶点。这个 这项研究的最终目标是确定激活的神经活动(目标1)的行为意义 转录本(目标2)和招募回路(目标3)驱动可卡因寻求SPP的性别差异。

Project Summary/Abstract. The inability to maintain abstinence is a trademark of addiction yet effective maintenance therapies remain elusive. Women may face unique issues with substance abuse treatment, as research indicates that psychological and biological responses to drugs of abuse differ in women compared to men. Women tend to show greater drug dependence, progress more quickly from casual drug use to dependence, have greater difficulty quitting, and have shorter periods of abstinence than men. These effects have been similarly observed in female animal models. Thus, there is a crucial need for understanding circuit dynamics and molecular signatures that drive robust behavioral sex differences impeding abstinence success. We have developed a novel behavioral model termed the seeking-persistence paradigm (SPP) that was adapted from standard drug abstinence paradigms. The seeking-persistence paradigm is used to investigate the influence of intervention during initial abstinence on long-term drug-seeking behaviors. Indeed, cocaine-seeking during initial abstinence strongly correlates with seeking after drug-abstinence. These results reflect clinical studies indicating that craving during initial abstinence predicts relapse rates. Using this paradigm in combination with electrophysiological, chemogenetic, and functional genomic methods, we aim to ultimately provide novel targets for therapeutics by investigating the role of sex-specific signaling in driving cocaine seeking persistence. We have previously identified that the dorsal hippocampus CA1 is a crucial downstream target for noradrenergic (NE) modulation of cocaine-seeking on ED1. Notably, the locus coeruleus (LC) (NE)-CA1 signal in this behavior appears female- specific, and we hypothesize that recruitment of this pathway engages increased cocaine-seeking observed in females. In year 1 of the K99 phase, I will first determine if this sex difference involves phasic or tonic locus coeruleus firing on ED1 using unit recordings in behaving rats. In year 2 of the K99 phase, I will use RNA- sequencing and bioinformatics analyses to identify a molecular signature in CA1 of increased cocaine-seeking behavior. Next, in my independent phase (R00) I will combine prior training in chemogenetic techniques with new training in awake behaving electrophysiology to identify the effects of inhibition or activation of LC inputs to dorsal hippocampus CA1 on ED1 cocaine seeking and cocaine seeking-persistence, using PRSx8 promoter driven designer receptors exclusively activated by designer drugs (DREADDs) that permit specific expression in LC-NE neurons. Subsequently, I will use my bioinformatics training to identify clusters of transcripts that associate with cocaine-seeking resilience by examining transcripts that negatively correlate to cocaine-seeking behavior. These experiments will therefore characterize the role of the LC(NE)-CA1 pathway in driving cocaine- seeking behavior and identify novel gene targets in CA1 associated with sex differences in cocaine-seeking. The ultimate goal of this research is to identify the behavioral significance of neural activity (Aim 1), activated transcripts (Aim 2), and recruited circuits (Aim 3) driving sex differences in cocaine-seeking SPP.