Research
Serotengenic Mechanisms

Investigator: Subash Pandey, Ph.D.

Alterations in serotonergic function have been implicated in alcohol dependence. This is based on studies of serotonin (5HT), its metabolite 5-hydroxy indole acetic acid (5HIAAA), and 5HT receptor subtypes in the brain of alcohol-dependent and withdrawn rats. Anxiogenic behaviors are present at an early stage of ethanol withdrawal. Anxiety is considered an important factor in the continued use of alcohol by alcoholics to avoid the subsequent occurrence of physical signs of withdrawal. Behavioral studies indicate that 5HT2A/2C receptors are involved in producing the anxiogenic behaviors occurring during ethanol withdrawal. The proposed studies will examine the role of the serotonergic mechanisms, more specifically, the molecular mechanisms for the regulation of 5HT2A/2C receptors and their signaling systems in the rat brain during ethanol withdrawal after chronic ethanol intake.

The major objective of the proposed studies are: A) To examine whether the time course for the 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 phosphoinositide hydrolysis; 3) changes in the steps beyond the 5HT2A/2C receptors, i.e., gene expression (mRNA levels) and immunolabeling of the PLC-b isozyme; and 4) changes in the 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be performed in the frontal cortex, the hippocampus, and the amygdala of chow- and liquid diet-fed control and ethanol-withdrawn (0, 12, 24, 72 hr after 15 days of ethanol treatment) rats; and B) to examine if chronic treatment with a 5HT2A/2C antagonist (mianserin) during chronic ethanol consumption causes normalization of the changes in the 5HT2A/2C receptor signaling system (above-mentioned biochemical measures) in the frontal cortex, the hippocampus, and the amygdala during ethanol withdrawal and blocks anxiety as measured by the elevated-plus maze test.

Our proposal is based on the hypothesis that decreased 5HT2A/2C receptor-linked PI signal activity is involved in producing anxiety during ethanol withdrawal after chronic ethanol consumption. 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.