ALCOHOLISM AND ENDOGENOUS OPIOID ACTIVITY

大脑的阿片系统在奖励机制中发挥着重要作用，最近它已成为使用阿片拮抗剂纳曲酮进行治疗的靶点。我们最近的发现提供了强有力的证据，证明酗酒者的后代中枢阿片类药物活动受到抑制，这是一种在酗酒之前就出现的异常。然而，我们对健康个体和酒精依赖人群之间内源性阿片系统的潜在差异知之甚少。事实上，很少有人类数据涉及酒精依赖者的阿片系统是否存在异常，以及这种差异是遗传决定因素的结果，还是大量饮酒的结果，或者两者兼而有之。缺乏对内源性阿片类药物在酒精中毒中的作用的了解，主要是由于在人类受试者身上进行测量的困难。然而，下丘脑-垂体-肾上腺(HPA)轴可以提供有用的内源性阿片活性测量。这是因为HPA轴允许对下丘脑阿片系统进行非侵入性的功能评估。我们建议利用这一神经内分泌策略来测量酒精依赖者在疾病的不同阶段的阿片活性。在具体目标1中，我们将测量酒精依赖患者在早期戒酒中的阿片类药物活性，并与对照组进行比较。我们将通过生成剂量反应曲线，然后计算引起一半最大激素反应(ED50)所需的纳洛酮剂量来确定每个受试者对纳洛酮的敏感性。我们将把这种阿片活性的测量与行为和生理测量相联系，例如酒精渴望、情绪和酒精戒断症状。酗酒者和对照组将由家族史阳性(FHP)和家族史阴性(FHN)的受试者平等地代表。在特定目标II中，我们将与对照组相比，测量酒精依赖者在监督戒酒8周期间的ED50值的变化。在具体目标3中，我们将确定受控戒断期间在CRC上获得的纳洛酮敏感性(ED50)测量是否可以预测出院后复发的时间。这项研究将提供关于内源性阿片系统的活性作为酒精中毒的功能和作为酒精中毒家族史的功能的信息。这一发现将影响我们对易患和维持大量饮酒的神经化学因素的理解。

The brain's opioid system plays an important role in reward mechanisms and recently it has been targeted in treatment efforts using the opiate antagonist, naltrexone.. Our recent findings provide strong evidence for dampened CNS opioid activity in the offspring of alcoholics, an abnormality predating heavy alcohol drinking. However, we know little about the underlying differences in the endogenous opioid system between healthy individuals and the alcohol dependent population. Indeed, little human data exists which address the question of whether there are abnormalities in the opioid system in alcohol dependent individuals and whether such differences are a consequence of genetic determinants, or a consequence of heavy alcohol use or a combination of both. The lack of knowledge of the role of endogenous opioids in alcoholism has been due primarily to difficulties in making measurements in human subjects. However, the hypothalamic-pituitary-adrenal (HPA) axis can provide useful measurements of endogenous opioid activity. This is because the HPA axis allowing a non-invasive, functional assessment of the hypothalamic opioid system. We propose to utilize this neuroendocrine strategy to measure opioid activity in alcohol dependent persons at various stages of their disorder. In Specific Aim 1, we will measure opioid activity in alcohol dependent individuals in early abstinence monitored on thje CRC and compare to controls. We will determine each subjects sensitivity to naloxone by generate a dose response curve and then calculating the dose of the naloxone required to induce a half-maximal hormone response (ED50). We will relate this measurement of opioid activity to behavioral and physiological measures such as alcohol craving, mood and alcohol withdrawal symptoms. Alcoholics and controls will be equally represented by family history positive (FHP) and family history negative (FHN) subjects. In Specific Aim II, we will measure the change in ED50 values during eight weeks of supervised abstinence on the CRC in alcohol dependent subjects compared to the control group. In Specific Aim 3 we will determine if naloxone sensitivity (ED50) measurements obtained during controlled abstinence on the CRC predicts the time to relapse after discharge. This study will provide information on the activity of the endogenous opioid system as a function of alcoholism ad as a function of family history of alcoholism. This findings will impact our understanding of the neurochemical factors that predispose to- and maintain heavy alcohol drinking.