Anxiety and Alcoholism: Novel Benzodiazpine Treatments

焦虑和酗酒：新型苯二氮平治疗方法

• 批准号: 7938981
• 负责人: Harry L June
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938981
• 关键词: Abstinence; Affective; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anhedonia; Anxiety; Attenuated; Benzodiazepines; Bilateral; Binding Sites; Chronic; Development; Diazepam; Evaluation; GABA Receptor; Genes; Globus Pallidus; Heavy Drinking; Herpesvirus 1; Human; Individual; Lateral; Lead; Ligands; Light; Maintenance; Modeling; Neurons; Oral Administration; Pharmacotherapy; Phase; Play; Procedures; RNA Interference; Rat-1; Rattus; Regulation; Relapse; Role; Schedule; Seizures; Small Interfering RNA; Technology; Testing; Time; Tremor; Withdrawal; alcohol abstinence; binge drinking; chronic alcohol ingestion; clinical efficacy; deprivation; drinking; effective therapy; novel; pharmacophore; pre-clinical; prototype; receptor; stem; vector

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.

酗酒和焦虑经常在人类中同时发生;然而，很难找到一种单一的治疗方法 其对这两种情况都有效。大量证据表明， 酒精戒断（例如，增加的焦虑和快感缺乏）被称为消极的情感状态， 在维持过量饮酒中起重要作用，也可能与复发有关。 证据还表明，GASA能机制在调节过量饮酒中的重要作用 以及与禁欲相关的负面情感状态。本提案的初步目标是 在临床前水平鉴定新的α 1 GASAA亚型偏好配体， 进一步评估治疗过度饮酒和负性情感的临床疗效 与禁欲有关的国家。为了实现这一目标，目标1将采用我们的既定 SD 1结合位点的药效团/受体模型，以合成新的α 1亚型优选配体， 对地西泮敏感（DS）亚型的效力降低（例如，a1，2，3，5）“一旦两个代理（例如，I3CCt， 3-PSC）的合成，目的2将检验其长期口服给药30 连续多日饮酒能有效地减轻高饮酒者的过度饮酒 (HAD)大鼠使用在黑暗中多次预定访问[DIDMSA]模型。我们假设 长期的SD 1治疗会减轻过度的酗酒。目标3将检验以下假设 慢性SD 1治疗将减弱负性情感状态（例如，增加焦虑和快感缺失） 与禁欲有关第二个目标是鉴定选择的GASAA受体亚单位， 可能在调节过量饮酒和相关的负面情感状态中发挥作用 禁欲目的4将验证腹侧海马区a1受体亚单位抑制的假说。 苍白球（VP）将导致选择性的时间依赖性减少酗酒反应。下调 a1亚基，一种新的siRNA序列将通过使用疱疹病毒的双侧微输注递送到VP中。 单纯病毒-1（HSV-1）扩增子载体。这些研究应确定新的药物治疗， 在临床前水平评估治疗酒精中毒和焦虑共病的临床疗效。此外，本发明还提供了一种方法， 他们应该阐明在调节共病酒精中毒中突出的神经元机制， 焦虑，这可能是重要的，最终导致成功的治疗共病条件。