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. ? ? ? ?
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