SEROTONERGIC CHARACTERIZATION OF ETHANOL WITHDRAWAL

点击翻译按钮获取中文摘要

This proposal seeks to expand experiments on characterizing ethanol withdrawal with respect to its symptoms and their mechanisms. Abuse of ethanol produces dependence characterized by a pattern of withdrawal consisting of subjective symptoms such as anxiety. Although the key role of these symptoms in initiating and maintaining ethanol abuse is well recognized, animal research on the subjective symptoms has been difficult. In the current funding period, it was demonstrated that ethanol withdrawal produces a PTZ-like internal stimulus that can be used to produce parametric data on the subjective symptoms of withdrawal. The HZ-like stimulus occurring during ethanol withdrawal was modulated by drugs acting at the gamma-amino butyric acid-type A (GABAA) receptor- chloride ion channel complex. However, PTZ-IDS was insensitive to modulation of brain serotonin (5HT) systems. The 5HT systems have been implicated in ethanol dependence and found important in our own experiments employing other behavioral measures. In order to better characterize the role of 5HT in the development of ethanol dependence and withdrawal using drug discrimination approach, new experiments are proposed to employ a 5HT agonist, 1(3-chlorophenyl)piperazine, mCPP, as a discriminative stimulus to characterize an animal model of the withdrawal symptoms. It is proposed: 1) to demonstrate that the mCPP IDS in animals is modulated by drugs which are either anxiogenic or anxiolytic in humans, 2) to demonstrate and characterize the spontaneous occurrence of a mCPP-like stimulus during ethanol withdrawal in relation to the intensity of the stimulus as a function of cumulative ethanol dose, 3) to modify the withdrawal stimulus by selected 5HT receptor subtype agonists and antagonists, and 4) to compare and contrast the PTZ and mCPP stimuli during ethanol withdrawal to determine the manner in which the 5HT and GABA systems relate to one another in producing "anxiety"-like behavior. Use of this method will provide important new data and extend the results obtained in our other animal models of anxiety. This research is significant because it provides information directly related to etiology and treatment of ethanol abuse.