Alterations in serotonergic function have been implicated in alcohol dependence. This is based on studies of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), and 5HT receptor subtypes in the brain of alcohol-dependent and withdrawn rats. Anxiogenic behaviors are present at an early stage of alcohol withdrawal. Behavioral studies indicate that 5HT2A/2C receptors are involved in producing the anxiogenic behaviors occurring during ethanol withdrawal. The role of the 5HT2A/2C receptor system, i.e., 5HT 2A/2C receptor density and mRNA levels, 5HT2A/2C receptor-linked phosphoinositide (PI) hydrolysis, and gene expression (MRNA levels) and translation (Immunolabeling) of the phospholipase C (PLC)-B isozyme, in anxiety during ethanol withdrawal, is largely unknown. The proposed studies will examine the role of the serotonergic mechanisms, more specifically the 5HT 2A/2C receptor system, in anxiety related to ethanol withdrawal. The major objectives of the proposed studies are A): To examine whether the time-course for development of anxiety during ethanol withdrawal is associated with the time-course for: 1) changes in 5HT2A and 5HT2C receptors; 2) changes in 5HT2A/2C receptor-linked PI hydrolysis; 3) changes in steps beyond the 5HT2A/2C receptors, i.e., gene expression (mRNA levels) and translation (immunolabeling) of the PLC-B isozyme; 4) changes in gene expression (mRNA levels) of 5HT2A/2C receptors during ethanol withdrawal. These biochemical measures will be performed in the frontal cortex, the hippocampus, and the amygdala of chow and liquid diet-fed control and ethanol-withdrawn (0, 12, 24, and 72 hrs after 15 days of ethanol treatment) rats; and B): To examine if chronic treatment with a 5HT2A/2C receptor system (5HT2A/2C receptor binding and mRNA levels, 5HT2A/2C receptor-linked PI hydrolysis, and mRNA levels and immunolabeling of the PLC-B isozyme) in the frontal cortex, the hipppocampus, and the amygdala during ethanol withdrawal and also blocks anxiety as measured by the elevated plus maze test (open arm activity). Thus, the proposed research will provide a better understanding of the molecular mechanisms for the regulation of the 5HT2A/2C receptor system in alcohol dependence and may facilitate the development of specific serotonergic drugs that can be used in the prevention and treatment of specific ethanol withdrawal symptoms, e.g., anxiety.
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