Acute ethanol withdrawal (""""""""hangover"""""""") is a major concern in settings where any compromise to one's sense of well-being or performance could lead to dangerous (e.g., automobile driving) and even disastrous results (e.g., health care or aviation industries). However, its role in alcohol abuse and alcoholism is still poorly understood. Our animal studies show that acute ethanol withdrawal resembles the alcohol abstinence syndrome produced after the cessation of chronic alcohol exposure. This state represents a generally, high-dose, delayed ethanol effect (EDE), defined by a pattern of physiologic, behavioral, and subjective features, maximal 12-30 hours after a single dose. While infrequently studied, the EDE, or """"""""hangover"""""""" state, like the chronic withdrawal state, may provide the occasion for performance impairment and increases in ethanol consumption to """"""""self-medicate"""""""" the dysphoric symptoms accompanying such withdrawal. The physiological/theoretical basis for both acute and chronic withdrawal effects has been viewed as a biphasic """"""""opponent-process"""""""" response, reflecting an adjustment of homeostatic systems governing the particular biobehavioral processes being measured. However, our recent telemetry data of EEG, temperature, and locomotor activity in rats given single ethanol doses suggest an alternative explanation for EDE, i.e., low to moderate doses phase-shift-and high doses disrupt the circadian rhythms which regulate the variation of these variables throughout the day. In other words, at least a component of the EDE closely resembles the circadian phase-shifts and desynchrony effects (PSE) associated with """"""""jet-lag"""""""" and shift-work cycles. Our proposed studies are intended to further elucidate the physiological, behavioral, and subjective features of EDE, to explore its possible linkage with other conditions which also produce circadian rhythm disruptions (PSE), and to clarify its role in promoting ethanol consumption. Four projects will use a rat model and research designs and methods common in chronobiological research. Project-A will determine whether ethanol-induced changes in activity and temperature actually resemble or interact with rhythm disturbances produced by phase-shifts of the environment light-dark (LD) cycle (PSE). We now have shown that rats can be trained to make specific responses when the EDE-state is present. EDE-specific responses persist for 18-40 hours after a single high dose of ethanol, but are blocked by acute ethanol. Project-B will use this EDE- discrimination model to determine (a) whether PSE states have interoceptive features which are discriminated as being like the trained EDE-state and (b) the common pharmacological mechanisms mediating both states. Project-C will assess whether EDE and/or PSE states are indeed aversive (tests with state-specific place conditioning). Project-D will examine whether the EDE and/or PSE states enhance oral ethanol intake. The last two studies will provide data on whether """"""""hangover"""""""" actually contributes to ethanol intake, perhaps by some """"""""self-medication"""""""" of the aversive properties of the EDE state.
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