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

描述（由申请人提供）：酒精中毒是一种毁灭性的疾病，影响世界各地的人们，需要更好的治疗酒精中毒。酒精中毒与焦虑症是共病的，因为焦虑症患者成为酒精中毒者的风险很高。同样，酗酒者在戒断和戒断（WD）期间经常会出现焦虑症，因此增加了复发率。有趣的是，杏仁核，负责启动和处理焦虑样行为的大脑区域，已被证明会受到酒精的影响。酒精和WD会增加杏仁核特定核团的活动水平，特别是基底外侧杏仁核（BLA）-焦虑回路的主要输入。此外，在BLA中也发现了神经递质功能的改变，以响应酒精和酒精WD。具体而言，GABA能系统，其作用是控制BLA的过度兴奋性，可能在WD诱导的焦虑的发展中发挥重要作用。在BLA中，GABA能系统由多个GABA能抑制性中间神经元群组成。它们共同调节BLA的输出 根据BLA的具体输入。两个更好的特征人群是皮质 位于外囊（囊旁闰细胞团- pICM）和局部反馈抑制性中间神经元中的受控前馈抑制性中间神经元。这两个群体的相对活动水平已被证明差异影响BLA功能取决于多巴胺能（DA能）神经支配的腹侧被盖区。具体地说，焦虑样行为可以通过改变GABA能功能来改变，这是通过操纵BLA中的特异性DA受体来实现的。pICM中间神经元活性可被DA D1和D3（我们实验室的最新发现）受体激活所抑制，而局部中间神经元活性可被DA D1受体激活所促进。有趣的是，酒精和压力增加了杏仁核中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，使用乙醇吸入方案，一个完善的酒精中毒的动物模型，我们首先建议表征pICM和局部GABA能输入，因为它们在慢性间歇性乙醇（CIE）和WD期间发生变化，以了解整个系统的功能。其次，我们将描述在CIE和WD期间DA如何改变pICM和局部中间神经元的调制。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.