Neuropharmacology Component - Martin-Fardon

复发脆弱性是成功治疗酒精使用障碍（AUD）的一个挑战， 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， 导致毒瘾的慢性复发和强迫性。下丘脑泌素（Hcrt;食欲素） 系统调节生理过程，包括进食、能量代谢、唤醒和应激，并且 被酒精招募下丘脑泌素神经元仅位于下丘脑（HYP），包括外侧 HYP（LH）、背内侧HYP（DMH）和穹窿周围区（PFA），并投射到 神经回路介导药物寻求，包括内侧前额叶皮层（mPFC）。长期吸毒 在这两种情况下，由促肾上腺皮质激素释放因子（CRF）介导的应激反应失调， 下丘脑-垂体-肾上腺（HPA）轴和HPA轴外的下丘脑外脑应激区（例如， 杏仁核中央核（CeA）和终纹床核（BNST）。Hcrt/CRF相互作用 存在可能参与慢性复发和消极的情感状态，这是药物成瘾的特征。 强啡肽（Dyn）促进抑郁样行为并通过阿片样物质介导应激的厌恶效应 受体（KORs）信号传导。尽管Hcrt和Dyn是共同定位和共同释放的，但在腹侧被盖区， 在丘脑腹侧区（VTA）和室旁核（PVT）的介导中， 药物导向的行为Martin-Fardon组件将测试Hcrt/CRF和Hcrt/Dyn相互作用是否在 边缘下皮层（IL）--mPFC的一个亚区，对酒精寻求施加抑制控制， 酒精依赖史后大鼠的长期缺陷-依赖后的变化以及是否 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 在后期（2周）禁欲。这将通过（1）探索Hcrt/CRF和Hcrt/Dyn是否 IL中的相互作用介导了酒精依赖者寻求酒精行为的应激诱导恢复 （2）确定IL中的IL Hcrt-r/CRF 1/KOR信号传导是否被上调 由于戒酒期间的酒精依赖;以及（3）确认HYP（Hcrt）®IL回路的重要性 在使用抑制性设计者受体的压力诱导的寻求酒精行为的恢复过程中， 在Orx-Cre大鼠中对Orx细胞具有选择性的设计师药物构建体专门激活。本项目将提供 了解IL Hcrt-r/CRF 1/KOR信号在病理（酒精寻求）行为中的参与 并可能确定酒精渴望和复发预防的新目标。

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.