Circadian wheel-running activity during withdrawal from chronic intermittent ethanol exposure in mice

Abstract

Alcohol withdrawal is associated with affective-behavioral disturbances in both human alcoholics and in animal models. In general, these phenomena are potentiated by increased alcohol exposure duration and by prior withdrawal episodes. Previous studies have also reported locomotor hypoactivity during ethanol withdrawal in rats and mice, but only in novel test environments and not in the home cage. In the present study, we examined the effects of withdrawal from chronic intermittent ethanol (CIE) vapor exposure on the level and circadian periodicity of wheel-running activity in C57BL/6J mice. CIE treatment resulted in reductions in wheel-running activity compared with plain-air controls that persisted for about 1 week after withdrawal. Analysis of circadian waveforms indicated that reduced activity occurred throughout the night phase, but that daily-activity patterns were otherwise unaltered. CIE failed to alter free-running circadian period or phase in animals maintained under constant darkness. These results show that ethanol withdrawal can result in locomotor hypoactivity even in the habitual, home-cage environment, and suggest that withdrawal-related reductions in wheel-running activity may reflect the specific motivational significance of this behavior.

Fig. 1

Schematic illustration of repeated-measures cross-over design. Three separate groups of mice were treated with both CIE and plain air exposure and then placed either LD or DD to measure circadian wheel-running activity (Groups 1 and 2 were tested in LD; Group 3 was tested in DD). The duration of each experimental epoch is represented by the timeline at the bottom. Small shaded rectangle represents 5-day period of baseline activity for comparison to post-treatment activity.

Fig. 2

Standard raster-style circadian actogram of an animal exposed to CIE-treatment. Lines were fitted to activity onsets on each day and back-extrapolated to determine the onset on day 1 following treatment (represented by star symbol). Shaded region denotes lights off. The x-symbol represents the beginning and end of treatment protocol.

Fig. 3

Mean (±SEM) percent activity relative to baseline for days following CIE and plain air treatment conditions, across all groups. A significant reduction in wheel-running activity was found for days 1–6 in CIE-exposed mice (* p < 0.05); see text for details.

Fig. 4

Mean (± SEM) circadian waveforms for CIE and plain air treatment conditions under LD conditions (Groups 1 and 2). Following CIE but not air treatment, reductions in wheel-running activity were exhibited in the active phase (right panel).

Fig. 5

Mean (+ SEM) free-running period and initial phase of activity onset in DD following CIE and plain air treatments (Group 3). No significant differences were found between ethanol- and air-exposed animals for either free-running period (left) or for initial phase of the free-running rhythm (right).