The anxiolytic properties of ethanol consumption and anxiogenic aspects of withdrawal from chronic exposure are well established in both humans as well as experimental animal models. Because these anxiety-related effects help potentiate alcohol abuse, it is important to gain a detailed understanding of the cellular and molecular mechanisms that underlie the ethanol-anxiety interaction. While numerous brain regions are known to interact during fear/anxiety, the amygdala, an """"""""emotional"""""""" center in the limbic forebrain, is a central component of the neural anxiety circuitry. A delicate balance between excitatory and inhibitory neurotransmitter systems controls this system, with increases in amygdala excitation leading to enhanced fear/anxiety. Preliminary studies of using acutely isolated neurons from the lateral/basolateral amygdala indicate that chronic ethanol can alter NMDA-type ionotropic glutamate and inhibitory GABAA receptor function while sparing other neurotransmitter systems. Importantly, both receptor systems are sensitive to clinically relevant ethanol concentrations, indicating their functional adaptation during chronic exposure may be among the cellular substrates relating abuse with anxiety. Our central hypothesis, that chronic ethanol exposure and subsequent withdrawal differentially affect major amygdala neurotransmitter systems, will be tested by further examination of glutamate-gated ionotropic receptor and GABAA receptor expression and function within the rat lateral/basolateral amygdala. Specifically, we will utilize whole-cell patch clamp electrophysiology and single-cell reverse transcription/polymerase chain reaction (RT-PCR) with acutely isolated neurons. These studies will be done along with real-time RT-PCR to characterize cellular and molecular adaptations in the lateral/basolateral amygdala to chronic ethanol exposure and withdrawal. We will also assess the physiological ramifications of adaptations to chronic ethanol exposure by measuring post- and pre-synaptic function using whole-cell recordings within lateral/basolateral amygdala in in vitro slice preparations. Finally, we will test the association between receptor/synaptic function, anxiety, and withdrawal by integrating cellular, molecular, synaptic and behavioral measures during a withdrawal time course. Together, these studies will provide important insight into the mechanisms associated with chronic ethanol-induced adaptations related to fear/anxiety and eventually lead to a better understanding of the ethanol-anxiety interaction.
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