Anxiety and Alcoholism: Novel Benzodiazpine Treatments

酒精中毒和焦虑在人类中经常并存；然而，很难找到单一的治疗方法。 这对这两种情况都有效。确凿的证据表明， 酒精戒断(例如，焦虑和快感缺乏增加)被称为负面情感状态 在维持过量饮酒方面起着重要作用，也可能与复发有关。 证据还表明，GASA能机制在调节过度饮酒中起着重要作用 以及与禁欲相关的消极情感状态。本提案的最初目标是 确定新的A1 GASAA亚型-临床前水平的首选配体，可作为 进一步评价酗酒与负性情绪并存的临床疗效 与禁欲有关的国家。为了实现这一点，目标一号将利用我们现有的 用于合成新型A1亚型偏爱配体的SDL结合位点的药效团/受体模型 安定敏感(DS)亚型(例如，1、2、3、5)的有效性一旦两种药物(例如， 3-PSC)已经合成，目标2将测试他们慢性口服30年的假设 连续饮酒可有效缓解高酒精饮酒中的过度饮酒 (HAD)大鼠使用drinking-in-the-dark-multiple-scheduled-access[DIDMSA]模型。我们假设 长期的SDL治疗将减轻过度饮酒的影响。目标3将检验这一假设 慢性SDL治疗将减轻负面情绪状态(例如，增加的焦虑和快感缺乏) 与禁欲有关。第二个目标将是确定选定的GASAA受体亚基 可能在过度饮酒及相关的负性情绪状态的调节中起作用 带着节制。目标4将检验这样一种假设，即抑制腹侧脑内A1受体亚单位 梅毒螺旋体(VP)将导致酗酒反应的选择性时间依赖性降低。下调监管 A1亚基，一个新的siRNA序列将通过使用疱疹病毒的双侧微量注射进入VP 单纯疱疹病毒1型(HSV-1)扩增载体。这些研究应该确定新的药物疗法，以便进一步 临床前水平治疗酒精中毒与焦虑共病的临床疗效评价此外, 他们应该阐明在调节共病酒精中毒和酒精中毒中的显著神经元机制。 焦虑，这可能是最终导致成功治疗合并症的重要因素。

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 GASAergic 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 a1 GASAA 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 1 will employ our established pharmacophore/receptor model of SDl binding sites to synthesize novel a1 subtype-preferring ligands with reduced efficacies at diazepam sensitive (DS) subtypes (e.g., a1,2,3,5)' Once the two agents (e.g., I3CCt, 3-PSC) have been synthesized, Aim 2 will test the hypothesis that their chronic oral administration for 30 consecutive days can effectively attenuate excessive binge alcohol drinking in the high alcohol drinking (HAD) rats using the drinking-in-the-dark-multiple-scheduled-access [DIDMSA] model. We hypothesize that chronic SDl treatments will attenuate excessive binge drinking. Aim 3 will test the hypothesis that chronic SDl treatment will attenuate negative affective states (e.g., increased anxiety and anhedonia) associated with abstinence. The second objective will be to identify select GASAA receptor subunits which may playa role in the regulation of excessive alcohol drinking and the negative affective states associated with abstinence. Aim 4 will test the hypothesis that inhibition of the a1 receptor subunits within the ventral' pallidum (VP) will lead to selective time-dependent reductions in binge alcohol responding. To down regulate the a1 subunit, a novel siRNA sequence will be delivered into the VP 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 comorbid alcoh.olism and anxiety, which could be important inultimately leading to a successful treatment for the comorbid condition.