Chronic Alcohol and Withdrawal on Dopamine and GABA in the basolateral amygdala

慢性酒精和戒断对基底外侧杏仁核多巴胺和 GABA 的影响

• 批准号: 7666871
• 负责人: Marvin Rafael Diaz
• 金额: $ 0.2万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666871
• 关键词: Abstinence; Acute; Affect; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Brain region; Breathing; Cell Nucleus; Chronic; Development; Disease; Disinhibition; Dopamine; Dopamine D1 Receptor; Electrophysiology (science); Equilibrium; Ethanol; External Capsule; Feedback; Hour; Human; Intercalated Cell; Interneurons; Measures; Mediating; Neurotransmitters; Output; Play; Population; Process; Protocols documentation; Rattus; Receptor Activation; Relapse; Relative (related person); Risk; Rodent; Role; Stress; System; Techniques; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; Work; alcohol exposure; alcohol response; alcoholism therapy; attenuation; base; drug of abuse; extracellular; gamma-Aminobutyric Acid; high risk; nerve supply; neurotransmission; problem drinker; receptor; transmission process

DESCRIPTION (provided by applicant): Alcoholism is a devastating disease that affects people world-wide, and better treatments for alcoholism are needed. Alcoholism is co-morbid with anxiety disorders, in that people with anxiety disorders are at a high risk of becoming alcoholics. Similarly, alcoholics often develop anxiety disorders during periods of abstinence and withdrawal (WD), therefore increasing the relapse rate. Interestingly, the amygdala, the brain region responsible for initiating and processing anxiety-like behaviors, has been shown to be affected by alcohol. Alcohol and WD increase activity levels in specific nuclei of the amygdala, particularly that of the basolateral amygdala (BLA) - the primary input of the anxiety circuit. Moreover, alterations in neurotransmitter function have also been found in the BLA in response to alcohol and moreso during alcohol WD. Specifically, the GABAergic system, which acts to control over-excitability of the the BLA, may play an important role in the development of WD-induced anxiety. In the BLA, the GABAergic system is comprised of multiple GABAergic inhibitory interneuron populations. Together they regulate the output from the BLA based on the specific input into the BLA. The two better characterized populations are the cortically controlled feedforward-inhibitory interneurons located in the external capsule (paracapular intercalated cell masses - pICM) and the local feedback-inhibitory interneurons. The relative activity level of these two populations has been shown to differentially affect BLA function depending on the dopaminergic (DAergic) innervation from the ventral tegmental area. Specifically, anxiety-like behaviors can be altered by changing GABAergic function through manipulations of specific DA receptors in the BLA. pICM interneuron activity can be suppressed by DA D1 and D3 (recent finding from our lab) receptor activation, while local interneuron activity can be faciliated by DA D1 receptor activation. Interestingly, alcohol and stress increase DA release in the amygdala, and possibly alter the balance between pICM and local interneuron activity. Therefore, using an ethanol inhalation protocol, a well established animal model of alcoholism, we first propose to characterize the pICM and local GABAergic input as they change during chronic intermittent ethanol (CIE) and WD in order to understand how the whole system functions. Secondly, we will characterize how the modulation of pICM and local interneurons by DA is altered during CIE and WD. Understanding the processes involved in the development of alcohol withdrawal-induced anxiety will allow for better treatments for alcoholism and other drugs of abuse. Better treatments will help to decrease the risk of relapse.

描述（由申请人提供）：酒精中毒是一种毁灭性的疾病，会影响全世界的人，需要更好地治疗酒精中毒。酒精中毒是与焦虑症共处的，因为患有焦虑症的人有酗酒者的高风险。同样，酗酒者通常在禁欲和戒断期间（WD）出现焦虑症，因此增加了复发率。有趣的是，杏仁核是负责发起和处理类似焦虑行为的大脑区域，已显示出受酒精的影响。酒精和WD提高了杏仁核的特定核的活性水平，特别是基底外侧杏仁核（BLA）的活性水平 - 焦虑回路的主要输入。此外，在酒精WD期间，在BLA中还发现了神经递质功能的改变。具体而言，控制BLA的过度兴趣的GABA能系统可能在WD诱导的焦虑的发展中起重要作用。在BLA中，GABA能系统由多个GABA能抑制性间神经元种群组成。他们一起调节BLA的输出 基于对BLA的特定输入。两个更好的人群是皮质的 位于外部胶囊（副膜间插入细胞肿块-PICM）和局部反馈抑制性中间神经元中的受控喂食抑制性抑制性抑制性中间神经元。这两个种群的相对活性水平已被证明会差异地影响BLA功能，具体取决于腹侧偏段区域的多巴胺能（DAER）神经。具体而言，可以通过对BLA中特定的DA受体的操纵来改变GABA能功能来改变焦虑样行为。 DA D1和D3（来自我们实验室的最新发现）受体激活可以抑制PICM间神经元的活性，而DA D1受体激活可以促进局部神经元活性。有趣的是，酒精和压力会增加杏仁核中的DA释放，并可能改变PICM和局部神经元活动之间的平衡。因此，使用乙醇吸入方案，一种良好的酒精中毒模型，我们首先建议表征PICM和局部Gabaergic输入，因为它们在慢性间歇性乙醇（CIE）和WD期间会发生变化，以了解整个系统的功能。其次，我们将表征CIE和WD期间DA对PICM和局部神经元的调制。了解戒酒引起的焦虑的发展过程将使酒精中毒和其他虐待药物更好地治疗。更好的治疗方法将有助于降低复发的风险。