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

描述(申请人提供)：酒精中毒是一种毁灭性的疾病，影响世界各地的人，需要更好的治疗酒精中毒。酗酒与焦虑症是并存的，因为焦虑症患者成为酒鬼的风险很高。同样，酗酒者在戒酒和戒断(WD)期间经常出现焦虑症，因此增加了复发率。有趣的是，杏仁核--负责启动和处理类焦虑行为的大脑区域--已被证明受到酒精的影响。酒精和WD会增加杏仁核特定核团的活动水平，特别是杏仁基底外侧核(BLA)--焦虑回路的主要输入。此外，在白血球中也发现了神经递质功能的变化，以回应酒精和更多的酒精WD。具体地说，GABA能系统控制BLA的过度兴奋性，可能在WD诱导的焦虑的发展过程中发挥重要作用。在BLA中，GABA能系统由多个GABA能抑制中间神经元群组成。它们共同调节BLA的输出 基于对BLA的特定输入。两个特征较好的种群是皮质 受控前馈抑制中间神经元位于外囊(囊旁间质)和局部反馈抑制中间神经元。这两个群体的相对活动水平已被证明依赖于腹侧被盖区的多巴胺能神经支配而对BLA功能产生不同的影响。具体地说，焦虑样行为可以通过改变GABA能功能来改变，方法是操纵BLA中的特定DA受体。多巴胺D_1和D_3受体的激活可抑制PICM中间神经元的活性，而DA D_1受体的激活可使局部中间神经元的活性增强。有趣的是，酒精和应激增加了杏仁核中DA的释放，并可能改变了PICM和局部中间神经元活动之间的平衡。因此，在酒精中毒动物模型的基础上，我们首先提出了在慢性间歇性酒精中毒(CIE)和慢性间歇性酒精中毒(WD)过程中，PICM和局部GABA能输入的变化特征，以了解整个系统的功能。其次，我们将描述在CIE和WD期间，DA对PICM和局部中间神经元的调制是如何改变的。了解酒精戒断引起的焦虑的发展过程将有助于更好地治疗酒精中毒和其他药物滥用。更好的治疗将有助于降低复发的风险。

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.