Neuropharmacology Component - Martin-Fardon

复发易感性是成功治疗酒精使用障碍(AUD)的一个挑战，使复发 预防是治疗和药物开发工作的中心重点。压力是一个主要因素 导致慢性复吸和吸毒成瘾的强迫性。甲状旁腺激素(Hcrt；增食欲素) 系统调节生理过程，包括摄食、能量新陈代谢、唤醒和压力，并且是 是被酒精招募的。下丘脑(HYP)内仅有下丘脑(HYP)内的下丘脑，包括外侧核。 Hyp(Lh)、背内侧HYP(DMH)和穹隆周围区(PFA)，并投射到 调节药物寻找的神经回路，包括内侧前额叶皮质(MPFC)。慢性药物使用 调节由促肾上腺皮质激素释放因子(CRF)介导的应激反应 下丘脑-垂体-肾上腺(HPA)轴和HPA轴之外的下丘脑外脑应激区(例如， 杏仁中央核[CEA]和终纹床核[BNST])。HCRT/CRF交互作用 存在可能参与慢性复发和以药物成瘾为特征的负面情感状态的人。 强啡肽(Dyn)促进抑郁样行为并通过k阿片介导应激的厌恶效应 受体(Kors)信号。尽管Hcrt和Dyn是共同定位和共同释放的，但在腹侧被盖 丘脑室旁核(PVT)和丘脑室旁核(VTA)在中枢神经系统的调节中起相反的作用。 药物导向的行为。Martin-Fardon组件将测试Hcrt/CRF和Hcrt/Dyn在 下缘皮质(IL)--mPFC的一个亚区，对酒精寻求和表现出抑制控制。 有酒精依赖史的大鼠的长期缺陷--依赖后的变化以及 这些系统在应激诱导的雄性和雌性大鼠酒精寻求行为的恢复中起关键作用 禁欲后期(2周)。这将通过以下方式实现：(1)探讨HCRT/CRF和HCRT/DYN IL介导应激诱导的酒依赖大鼠寻酒行为恢复的相互作用 (2)确定IL中IL-Hcrt-r/CRF1/KOR信号是否上调 由于戒酒过程中的酒精依赖；以及(3)确认HYP(Hcrt)®IL回路的重要性 在应激诱导的酒精寻找行为的恢复过程中使用抑制性设计受体 设计药物对Orx-CRE大鼠体内Orx细胞具有选择性激活作用。该项目将提供 病理性(寻酒)行为中IL-Hcrt-r/CRF1/KOR信号转导机制的研究 并可能确定酒精渴求和预防复发的新靶点。

Relapse vulnerability is a challenge for the successful treatment of alcohol use disorder (AUD), making relapse prevention a central focus of treatment and medication development efforts. Stress is a major factor that contributes to the chronic relapsing and compulsive nature of drug addiction. The hypocretin (Hcrt; orexin) system regulates physiological processes including feeding, energy metabolism, arousal, and stress, and is recruited by alcohol. Hypocretin neurons are only located in the hypothalamus (HYP) that includes the lateral HYP (LH), dorsomedial HYP (DMH), and perifornical area (PFA) and project to major components of neurocircuitry that mediates drug seeking including the medial prefrontal cortex (mPFC). Chronic drug use dysregulates stress responses that are mediated by corticotropin-releasing factor (CRF) in both the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain stress areas outside the HPA axis (e.g., central nucleus of the amygdala [CeA] and bed nucleus of the stria terminalis [BNST]). An Hcrt/CRF interaction exists that could participate in chronic relapsing and negative affective states that characterize drug addiction. Dynorphin (Dyn) promotes depressive-like behavior and mediates the aversive effects of stress via k opioid receptors (KORs) signaling. Even though Hcrt and Dyn are co-localized and co-released, in the ventral tegmental area (VTA) and the paraventricular nucleus of the thalamus (PVT), they play opposing roles in the mediation of drug-directed behavior. The Martin-Fardon component will test whether Hcrt/CRF and Hcrt/Dyn interaction in the infralimbic cortex (IL) -- a subregion of the mPFC that exerts inhibitory control over alcohol seeking and shows long-term deficits in rats following a history of alcohol dependence -- changes following dependence and whether these systems are pivotal in stress-induced reinstatement of alcohol-seeking behavior in male and female rats at late (2 weeks) abstinence. This will be achieved by (1) exploring whether the Hcrt/CRF and Hcrt/Dyn interactions in the IL mediate stress-induced reinstatement of alcohol-seeking behavior in alcohol-dependent animals during abstinence; (2) establishing whether the IL Hcrt-r/CRF1/KOR signaling in the IL is upregulated due to alcohol-dependence during abstinence; and (3) confirming the importance of the HYP(Hcrt)®IL circuit during stress-induced reinstatement of alcohol-seeking behavior using an inhibitory Designer Receptor Exclusively Activated by Designer Drugs construct selective for Orx cells in Orx-Cre rats. This project will provide insights into the involvement of the IL Hcrt-r/CRF1/KOR signaling during pathological (alcohol-seeking) behavior and may identify novel targets for alcohol craving and relapse prevention.