Circadian Wheel-Running Activity During Withdrawal from Chronic Intermittent Ethanol Exposure in Mice

Alcohol withdrawal is associated with behavioral, affective, and neurophysiological disturbances in both human alcoholics and in animal models of alcohol dependence. These effects include disruptions in sleep and circadian rhythms as well as increased expression of anxiety- and depression-like behaviors. In order to expand the phenotypic characterization of ethanol withdrawal, we have been examining the effects of withdrawal from chronic intermittent exposure to ethanol vapor (CIE) vapor exposure on circadian patterns of running-wheel activity in inbred (C57BL/6J and C3H/HeJ) mice. Following baseline activity measurements, mice were exposed to either one, two or three 4-day CIE treatment cycles in which 16 hours of daily ethanol vapor exposure alternated with 8 hours of exposure to plain air, while control animals were exposed only to plain air in an identical environment. Ethanol exposure began at the onset of the dark phase of the daily 12:12 LD cycle, and each exposure period was initiated by an injection of 1.6 g/kg ethanol and 1.0 mmol pyrazole, i.p., to rapidly stabilize blood ethanol concentrations, while controls received pyrazole in saline only. In both strains, ethanol withdrawal was associated with pronounced reductions in wheel-running, but these effects were more profound and more enduring in the "withdrawal-sensitive" C3H/HeJ strain relative to the "withdrawal-resistant" C57BL/6J strain. Interestingly, C3H/HeJ mice also displayed a significant shortening of free-running period during withdrawal from ethanol. Further, monitoring of home-cage water drinking via contact-sensing lickometers showed no effects of ethanol withdrawal, indicating that the observed reductions in locomotor activity are not due to non-specific factors such as malaise or lethargy. Instead, these effects probably reflect the specific biobehavioral significance of running-wheel activity, generally considered to be an intrinsically rewarding form of motivated exploratory behavior. Subsequent experiments will utilize a wider range of mouse strains in order to characterize the neurogenetic bases of withdrawal-related hypo-locomotion.