Anxiety and Alcoholism: Novel Benzodiazpine Treatments

项目摘要 酗酒和焦虑经常共同发生在人类身上;然而，很难找到一个单一的 治疗对这两种情况都有效。大量证据表明， 酒精戒断的方面[例如，增加焦虑和快感缺乏]称为消极情感状态 在维持过量饮酒方面起着重要作用，也可能与 复发证据还表明，GABA能机制在调节过量酒精中的重要作用 饮酒和与禁欲相关的负面情感状态。目前的初步目标 一项建议是在临床前水平鉴定新型的<$1 GABAA亚型偏好配体， 用于进一步评估治疗过量饮酒和阴性对照的临床疗效的原型 与禁欲有关的情感状态为了实现这一目标，目标1A将采用我们的既定 BDZ结合位点的药效团/受体模型，以合成新型的<$1亚型优选配体， 对地西泮敏感[DS]亚型的效力降低[例如，1-3]。一旦三个代理[例如，CCt，3-PBC， WYS 8]的合成，目的1B将检验其长期口服给药30 连续3d可有效地减轻高酒精饮酒[HAD]大鼠的过度饮酒。 目标1C将检验一个假设，即类似的治疗将减弱与之相关的消极情感状态。 禁欲我们假设，长期BDZ治疗将减轻酗酒和酗酒依赖， 以及与禁欲相关的负面情感状态。第二个目标将是确定选择 GABAA受体亚单位可能在调节过量饮酒和酒精依赖中发挥作用。 与禁欲有关的负面情感状态目标2A将检验抑制1 腹侧苍白球[VP]内的受体亚单位将导致选择性的时间依赖性减少狂欢 酒精反应，而Aim 2B将评估其在外侧/基底外侧内的抑制的假设 杏仁核[BLA]将导致消极情感状态的时间依赖性减少。为了降低1 亚基，一种新的siRNA序列将通过双侧微输注，使用 单纯疱疹病毒-1 [HSV-1]扩增子载体。这些研究应确定新的药物治疗， 在临床前水平进一步评估治疗酒精中毒和焦虑共病的临床疗效。在 此外，他们应该阐明在共病的调节中突出的神经元机制。 条件，这可能是重要的，最终导致成功的治疗共病条件。

Project Abstract Alcoholism and anxiety frequently co-occur in humans; however, it has been difficult to find a single treatment which is effective against both conditions. Substantial evidence suggests that the motivational aspects of alcohol withdrawal [e.g., increased anxiety and anhedonia] referred to as negative affective states play an important role in the maintenance of excessive alcohol drinking, and may also be associated with relapse. Evidence also suggests a salient role for GABAergic mechanisms in regulating excessive alcohol drinking and the negative affective states associated with abstinence. The initial objective of the present proposal is to identify novel ¿1 GABAA subtype-preferring ligands at the preclinical level that may serve as prototypes for further evaluation of clinical efficacy in treating both excessive alcohol drinking and the negative affective states associated with abstinence. To accomplish this, Aim 1A will employ our established pharmacophore/receptor model of BDZ binding sites to synthesize novel ¿1 subtype-preferring ligands with reduced efficacies at diazepam sensitive [DS] subtypes [e.g., ¿1-3]. Once the three agents [e.g., ¿CCt, 3-PBC, WYS8] have been synthesized, Aim 1B will test the hypothesis that their chronic oral administration for 30 consecutive days can effectively attenuate excessive binge alcohol drinking in high alcohol drinking [HAD] rats. Aim 1C will test the hypothesis that a similar treatment will attenuate the negative affective states associated with abstinence. We hypothesize that chronic BDZ treatments will attenuate both binge dependence drinking and the negative affective states associated with abstinence. The second objective will be to identify select GABAA receptor subunits which may play a role in the regulation of excessive alcohol drinking and the negative affective states associated with abstinence. Aim 2A will test the hypothesis that inhibition of the ¿1 receptor subunits within the ventral pallidum [VP] will lead to selective time-dependent reductions in binge alcohol responding, while Aim 2B will evaluate the hypothesis that their inhibition within the lateral/basolateral amygdala [BLA] will lead to time-dependent reductions in negative affective states. To downregulate the ¿1 subunit, a novel siRNA sequence will be delivered into the VP and BLA by bilateral microinfusion using a herpes simplex virus-1 [HSV-1] amplicon vector. These studies should identify novel pharmacotherapies for further evaluation of clinical efficacy in treating comorbid alcoholism and anxiety at the preclinical level. In addition, they should shed light on the salient neuronal mechanisms in the regulation of the comorbid condition, which could be important in ultimately leading to a successful treatment for the comorbid condition.