Anxiety and Alcoholism: Novel Benzodiazpine Treatments

项目摘要 酗酒和焦虑经常在人类中同时出现；然而，很难找到一种单一的 对这两种情况都有效的治疗。确凿的证据表明，动机 戒酒的各个方面[例如，焦虑和快感减退]被称为负面情绪状态 在维持过度饮酒方面发挥重要作用，也可能与 旧病复发。证据还表明，GABA能机制在调节过量酒精方面具有显著作用 饮酒和与禁欲相关的消极情感状态。当前的首要目标是 建议在临床前水平上确定新的GABAA亚型偏爱配体，可以作为 进一步评价过度饮酒和阴性对照临床疗效的原型 与禁欲有关的情感状态。为了实现这一目标，目标1A将利用我们已建立的 BDZ结合位点的药效团/受体模型用于合成新的1亚型偏爱配体 对安定敏感的[DS]亚型的疗效降低[例如？1-3]。一旦三种药物[例如CCT，3-PBC， WYS8]都是合成的，Aim 1B将测试他们慢性口服30年的假设 连续饮酒可有效减轻高饮酒[HAD]大鼠过量饮酒。 Aim 1C将验证这样的假设，即类似的治疗将减弱相关的负面情感状态 带着节制。我们假设慢性BDZ治疗将减轻这两种酗酒依赖 以及与禁欲相关的消极情感状态。第二个目标将是确定选定的 GABAA受体亚基在过度饮酒调控中的作用 与禁欲相关的消极情绪状态。目标2A将检验这样的假设：抑制1 腹侧苍白球[VP]内的受体亚基将导致选择性的时间依赖性的狂欢减少 酒精反应，而目标2B将评估他们在外侧/基底外侧抑制的假设 杏仁核[BLA]将导致负性情感状态随时间的减少。要压低？1 亚单位，一个新的siRNA序列将通过双侧微量注射进入VP和BLA，使用 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 从临床前水平进一步评价酒精中毒与焦虑共病的临床疗效。在……里面 此外，他们应该阐明在调节合并症的显著神经机制。 情况，这可能是最终导致成功治疗并存情况的重要因素。

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.