Effects of Withdrawal from Chronic Intermittent Ethanol Vapor on the Level and Circadian Periodicity of Running‐Wheel Activity in C57BL/6J and C3H/HeJ Mice

Abstract

Background Alcohol withdrawal is associated with behavioral and chronobiological disturbances that may persist during protracted abstinence. We previously reported that C57BL/6J (B6) mice show marked but temporary reductions in running-wheel activity, and normal free-running circadian rhythms, following a 4-day chronic intermittent ethanol vapor (CIE) exposure (16 hours of ethanol vapor exposure alternating with 8 hours of withdrawal). In the present experiments, we extend these observations in two ways: (1) by examining post-CIE locomotor activity in C3H/HeJ (C3H) mice, an inbred strain characterized by high sensitivity to ethanol withdrawal, and (2) by directly comparing the responses of B6 and C3H mice to a longer-duration CIE protocol. Methods In Experiment 1, C3H mice were exposed to the same 4-day CIE protocol used in our previous study with B6 mice (referred to here as the 1-cycle CIE protocol). In Experiment 2, C3H and B6 mice were exposed to three successive 4-day CIE cycles, each separated by 2 days of withdrawal (the 3-cycle CIE protocol). Running-wheel activity was monitored prior to and following CIE, and post-CIE activity was recorded in constant darkness to allow assessment of free-running circadian period and phase. Results C3H mice displayed pronounced reductions in running-wheel activity that persisted for the duration of the recording period (up to 30 days) following both 1-cycle (Experiment 1) and 3-cycle (Experiment 2) CIE protocols. In contrast, B6 mice showed reductions in locomotor activity that persisted for about one week following the 3-cycle CIE protocol, similar to the results of our previous study using a 1-cycle protocol in this strain. Additionally, C3H mice showed significant shortening of free-running period following the 3-cycle, but not the 1-cycle, CIE protocol, while B6 mice showed normal free-running rhythms. Conclusions These results reveal genetic differences in the persistence of ethanol withdrawal-induced hypo-locomotion. In addition, chronobiological alterations during extended abstinence may depend on both genetic susceptibility and an extended prior withdrawal history. The present data establish a novel experimental model for long-term behavioral and circadian disruptions associated with ethanol withdrawal.

Circadian rhythms and addiction: Mechanistic insights and future directions.

“…Both AVP and VIP are differentially distributed across the ventral (core) and dorsal (shell) SCN, respectively (Antle & Silver, 2005), which contributes to their distinct functional roles in the SCN (Aton, Colwell, Harmar, Waschek, & Herzog, 2005; Yan et al, 2007). Reductions of AVP and VIP signaling in the SCN provide a plausible mechanism by which chronic alcohol drinking or during alcohol withdrawal alters circadian responses to photic stimuli and circadian period (Logan, McCulley, Seggio, & Rosenwasser, 2012; Rosenwasser, Logan, & Fecteau, 2005b; Seggio, Fixaris, Reed, Logan, & Rosenwasser, 2009; Seggio, Logan, & Rosenwasser, 2007). …”

Brain DNA damage and behavioral changes after repeated intermittent acute ethanol withdrawal by young rats

“…*p<0.05 compared to control group (Spanagel and Holter 1999). The reduction in locomotor activity during ethanol withdrawal could be secondary to the general withdrawal-induced malaise or lethargy, as ethanol vapor-exposed mice display hypolocomotion and reductions in food intake and body weight (Logan et al 2012). Hypolocomotion is better detected when the ethanolwithdrawn animals are observed in a novel setting, as was the case in our study, which could be interpreted as sensitivity to emotional stress or anxiety (Williams et al 2012).…”

“…Hypolocomotion was seen in this study after 6 h of ethanol deprivation both by looking at the animals' mobility in peripheral and central quadrants in the OF and in the EPM tests. Hypolocomotion during acute ethanol withdrawal has been detected in some other studies, with different models (Zhang et al 2007;Logan et al 2012). Our animals were receiving an ethanol-containing meal, modeling the intermittent use of ethanol seen in the initial phases of the human alcohol consumption problem, when there are some periods of alcohol deprivation, followed by repetitive recurrences of alcohol use Fig.…”

“…Repeated alcohol withdrawal sessions increase anxiety-like behaviors associated with alcohol withdrawal (Rylkova et al 2009) and potentiate the severity of alcohol withdrawal-induced seizures (Becker and Hale 1993). Withdrawal severity is generally positively correlated with BEC (Logan et al 2012), and to a certain extent, emotionality behaviors induced by alcohol withdrawal are dependent on the concentration of alcohol in the liquid diet and the amount of drug taken by the individuals (Rylkova et al 2009). To verify how several cycles of ethanol withdrawal/re-exposure interfere with ethanol consumption, a model of liquid meal with and without ethanol was applied.…”

“…Rodents show increases in anxiety-and depression-like behaviors for several weeks after induction of ethanol dependence by exposure to ethanol drinking or vapors and may also present changes in motor activity (Logan et al 2012). However, different and apparently inconsistent effects of alcohol withdrawal have been described regarding motor activity, and the motor activity changes appear very dependent on the experimental methodology, as reviewed recently (Logan et al 2012). In general, one expects to see hyperlocomotion during alcohol withdrawal.…”