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Seasonal variations in photoperiod are associated with alterations in human mood and behavior. Similarly, manipulation of the environmental lighting regimen can exert pronounced effects on affective behavior in experimental animals. These observations may be due, in part, to light-induced alterations in circadian rhythms, but it seems likely that other, non-circadian factors also contribute. Several studies have shown that voluntary alcohol (ethanol) consumption can be affected by lighting conditions in rodents, suggesting that photoperiodic variation may account for seasonal and geographic patterns of human alcohol consumption. Nevertheless, the existing animal data are somewhat inconsistent, and little work in this area has been performed in mice. In the present study, we monitored circadian activity rhythms and voluntary ethanol consumption under standard 12:12 light-dark (LD) cycles, and in constant light (LL) and constant darkness (DD). Experiment 1 employed male C3H/He inbred mice, while Experiment 2 employed males and females from a genetically heterogeneous line (WSC). Relative to LD conditions, ethanol intake and ethanol preference were reduced under both LL and DD in both experiments. Because similar effects were seen in both LL and DD, neither circadian disruption nor a classical photoperiodic mechanism are likely to account fully for these findings. Instead, we suggest that the absence of circadian entrainment may function as a mild stressor, resulting in reduced ethanol consumption., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Seasonal and geographic variations in light exposure influence human mood and behavior, including alcohol consumption. Similarly, manipulation of the environmental lighting regimen modulates voluntary ethanol intake in experimental animals. Nevertheless, previous studies in rats and hamsters have been somewhat inconsistent, and little is known concerning such effects in mice. In the present study, we maintained male C57Bl/6 mice in running-wheel cages under either short- or long-photoperiod light-dark cycles (LD 6:18 vs. LD 18:6); subsequently, the same animals were maintained under short or long "skeleton photoperiods", consisting of two daily 15-min light pulses signaling dusk and dawn (SP 6:18 vs. SP 18:6). Running wheels were locked mechanically for half the animals under each photoperiod. Analysis of running wheel patterns showed that mice displayed stable circadian adaptation to both standard LD cycles and skeleton photoperiods. Mice consumed more ethanol and less water, and thus showed higher ethanol preference, under LD 6:18 and SP 6:18 relative to the corresponding long-photoperiod regimens. While running-wheel access increased water intake, ethanol intake was unaffected by this manipulation. These effects are consistent with previous studies showing that short photoperiods or constant darkness increases ethanol intake in rodents. Further, the similarity of the effects of complete and skeleton photoperiods suggests that these effects are mediated by photoperiod-induced alterations in the circadian entrainment pattern, rather than by light exposure per se., (Copyright © 2015. Published by Elsevier Inc.)

Clinical and epidemiological observations have revealed that alcohol abuse and alcoholism are associated with widespread disruptions in sleep and other circadian biological rhythms. As with other psychiatric disorders, animal models have been very useful in efforts to better understand the cause and effect relationships underlying the largely correlative human data. This review summarizes the experimental findings indicating bidirectional interactions between alcohol (ethanol) consumption and the circadian timing system, emphasizing behavioral studies conducted in the author's laboratory. Together with convergent evidence from multiple laboratories, the work summarized here establishes that ethanol intake (or administration) alters fundamental properties of the underlying circadian pacemaker. In turn, circadian disruption induced by either environmental or genetic manipulations can alter voluntary ethanol intake. These reciprocal interactions may create a vicious cycle that contributes to the downward spiral of alcohol and drug addiction. In the future, such studies may lead to the development of chronobiologically based interventions to prevent relapse and effectively mitigate some of the societal burden associated with such disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronic alcohol (ethanol) intake alters fundamental properties of the circadian clock. While previous studies have reported significant alterations in free-running circadian period during chronic ethanol access, these effects are typically subtle and appear to require high levels of intake. In the present study we examined the effects of long-term voluntary ethanol intake on ethanol consumption and free-running circadian period in male and female, selectively bred ethanol-preferring P and HAD2 rats. In light of previous reports that intermittent access can result in escalated ethanol intake, an initial 2-week water-only baseline was followed by either continuous or intermittent ethanol access (i.e., alternating 15-day epochs of ethanol access and ethanol deprivation) in separate groups of rats. Thus, animals were exposed to either 135 days of continuous ethanol access or to five 15-day access periods alternating with four 15-day periods of ethanol deprivation. Animals were maintained individually in running-wheel cages under continuous darkness throughout the experiment to allow monitoring of free-running activity and drinking rhythms, and 10% (v/v) ethanol and plain water were available continuously via separate drinking tubes during ethanol access. While there were no initial sex differences in ethanol drinking, ethanol preference increased progressively in male P and HAD2 rats under both continuous and intermittent-access conditions, and eventually exceeded that seen in females. Free-running period shortened during the initial ethanol-access epoch in all groups, but the persistence of this effect showed complex dependence on sex, breeding line, and ethanol-access schedule. Finally, while females of both breeding lines displayed higher levels of locomotor activity than males, there was little evidence for modulation of activity level by ethanol access. These results are consistent with previous findings that chronic ethanol intake alters free-running circadian period, and show further that the development of chronobiological tolerance to ethanol may vary by sex and genotype., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Previous studies in mice and rats have shown that selective breeding for high and low ethanol preference results in divergence of circadian phenotype in the selected lines. These results indicate that some alleles influencing ethanol preference also contribute to circadian rhythm regulation. Selective breeding has also been used to produce lines of mice differing in a number of other ethanol-related traits, while studies of phenotypic and genetic correlation indicate that diverse ethanol-related traits are influenced by both shared and unshared genetics. In the present study, we examined several features of circadian activity rhythms in a mouse line selected for binge-like drinking and in mouse lines selected for high and low severity of ethanol withdrawal convulsions. Specifically, Experiment 1 compared High Drinking in the Dark (HDID-1) mice to their genetically heterogeneous progenitor line (HS/Npt), and Experiment 2 compared Withdrawal Seizure-Prone (WSP-2) and Withdrawal Seizure-Resistant (WSR-2) mice. Both line pairs displayed differences in their daily activity patterns under light-dark conditions. In addition, HDID-1 mice showed shorter free-running periods in constant light and less coherent activity rhythms across lighting conditions relative to HS/Npt controls, while WSP-2 mice showed longer free-running periods in constant darkness relative to WSR-2 mice. These results strengthen the evidence for genetic linkages between responsiveness to ethanol and circadian regulation, and extend this evidence to include ethanol-related phenotypes other than preference drinking. However, the present results also indicate that the nature of genetic correlations between and within phenotypic domains is highly complex., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Human alcoholics display dramatic disruptions of circadian rhythms that may contribute to the maintenance of excessive drinking, thus creating a vicious cycle. While clinical studies cannot establish direct causal mechanisms, recent animal experiments have revealed bidirectional interactions between circadian rhythms and ethanol intake, suggesting that the chronobiological disruptions seen in human alcoholics are mediated in part by alterations in circadian pacemaker function. The present study was designed to further explore these interactions using C57BL/6J (B6) and DBA/2J (D2) inbred mice, two widely employed strains differing in both circadian and alcohol-related phenotypes. Mice were maintained in running-wheel cages with or without free-choice access to ethanol and exposed to a variety of lighting regimens, including standard light-dark cycles, constant darkness, constant light, and a "shift-lag" schedule consisting of repeated light-dark phase shifts. Relative to the standard light-dark cycle, B6 mice showed reduced ethanol intake in both constant darkness and constant light, while D2 mice showed reduced ethanol intake only in constant darkness. In contrast, shift-lag lighting failed to affect ethanol intake in either strain. Access to ethanol altered daily activity patterns in both B6 and D2 mice, and increased activity levels in D2 mice, but had no effects on other circadian parameters. Thus, the overall pattern of results was broadly similar in both strains, and consistent with previous observations that chronic ethanol intake alters circadian activity patterns while environmental perturbation of circadian rhythms modulates voluntary ethanol intake. These results suggest that circadian-based interventions may prove useful in the management of alcohol use disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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., (2010 Elsevier Inc. All rights reserved.)

Several lines of evidence implicate reciprocal interactions between excessive alcohol (ethanol) intake and dysregulation of circadian biological rhythms. Thus, chronic alcohol intake leads to widespread circadian disruption in both humans and experimental animals, while in turn, chronobiological disruption has been hypothesized to promote or sustain excessive alcohol intake. Nevertheless, the effects of circadian disruption on voluntary ethanol intake have not been investigated extensively, and prior studies have reported both increased and decreased ethanol intake in rats maintained under "shift-lag" lighting regimens mimicking those experienced by shift workers and transmeridian travelers. In the present study, male and female inbred Fischer and Lewis rats were housed in running wheel cages with continuous free-choice access to both water and 10% (vol/vol) ethanol solution and exposed to repeated 6-h phase advances of the daily light-dark (LD) cycle, whereas controls were kept under standard LD 12:12 conditions. Shift-lag lighting reduced overall ethanol and water intake, and reduced ethanol preference in Fischer rats. Although contrary to the hypothesis that circadian disruption would increase voluntary ethanol intake, these results are consistent with our previous report of reduced ethanol intake in selectively bred high-alcohol-drinking (HAD1) rats housed under a similar lighting regimen. We conclude that chronic circadian disruption is a form of chronobiological stressor that, like other stressors, can either increase or decrease ethanol intake, depending on a variety of poorly understood variables., (2010 Elsevier Inc. All rights reserved.)

Chronic alcohol intake is associated with dramatic disruptions in sleep and other circadian biological rhythms in both humans and experimental animals. In human alcoholics, these disruptions persist during extended abstinence and appear to promote relapse to drinking. Whereas chronic ethanol intake alters fundamental properties of the circadian pacemaker in unselected rats, nothing is known concerning circadian pacemaker function in selectively bred ethanol-preferring and nonpreferring rats, which are the most widely accepted animal models of genetic predisposition to alcoholism. The present experiments were designed to characterize free-running circadian activity (wheel-running) rhythms under both constant darkness and constant light in selectively bred ethanol-preferring (P, HAD2) and nonpreferring (NP, LAD2) rats. Differences in circadian organization between ethanol-preferring and nonpreferring animals were seen for both pairs of selected lines (P vs. NP; HAD2 vs. LAD2), but these differences were not identical in the two line pairs. For example, although P rats showed shorter free-running periods than NP rats only in constant light, HAD2 rats showed shorter free-running periods than LAD2 rats only in constant darkness. In addition, ethanol-preferring HAD2 rats showed a high rate of rhythm "splitting" that was not seen in any of the other three lines. Taken together, these results suggest that the circadian pacemakers of P and NP rats differ mainly in light sensitivity, whereas those of HAD2 and LAD2 rats differ in their intrinsic period.

Chronic alcohol intake and alcohol withdrawal are associated with dramatic disruptions of daily (circadian) biological rhythms in both human alcoholics and experimental animals. The extent to which these observations are due to pharmacological effects on the underlying circadian pacemaker is not known, however, since no human studies and very few animal studies have been conducted under free-running conditions. In the present study, free-running circadian activity (wheel-running) rhythms of rats were monitored before, during and after exposure to either 10% or 20% ethanol solution as the only drinking fluid. Across individuals, both lengthening and shortening of free-running period were observed during ethanol intake, and treatment termination led to either a return to baseline or to an exacerbation of the original ethanol effect. These variable effects appeared to be related to both ethanol concentration and to individual differences in baseline period, such that relatively short free-running period during baseline was associated with greater period-lengthening during ethanol exposure. These bidirectional affects of ethanol on free-running period are generally similar to effects seen previously with other psychoactive drugs, including antidepressants. The results of this study indicate that ethanol influences the circadian pacemaker, and that the chronobiological disruptions seen in human alcoholics may be due, in part, to alterations in circadian pacemaker regulation.

A variety of photic and nonphotic stimuli can phase-shift the mammalian circadian pacemaker. It has been suggested that the phase-response curves (PRCs) characterizing these diverse stimuli may comprise two major PRC families, one typified by the photic PRC describing the response to brief light pulses, and the other typified by the nonphotic PRC describing the response to stimuli evoking behavioral arousal and/or locomotor activity. Additionally, the mammalian circadian pacemaker can be phase-shifted by dark pulses presented on a constant-light (LL) background. While dark pulse-induced phase shifting was interpreted originally as a mirror-image photic effect, other observations suggest that the dark pulse PRC may instead belong to the family of nonphotic, activity-dependent PRCs. In a recent study, we reexamined the phase-shifting effects of dark pulses in the Syrian hamster, and concluded that the dark pulse PRC reflects both nonphotic and photic mirror-image mechanisms. In the current report, we reanalyze previously published hamster PRC data using polynomial curve-fitting procedures. The results of these analyses reveal that (a) the photic and nonphotic PRCs have identical shape but opposite phasing, and (b) the dark pulse PRC can be modeled by simple summation of nonphotic and photic mirror-image PRCs. This model predicts accurately the shape of the dark pulse PRC, particularly the extension of the phase-advance region into the subjective night.

Chronic treatment of rats with clonidine, an alpha-adrenoceptor agonist, alters the period and amplitude of free-running circadian activity rhythms, as well as the level of home cage locomotor activity. Agents that alter free-running period are presumed to act directly on the circadian pacemaker or on its input pathways. Because shortening of free-running period during clonidine treatment has been observed consistently under constant light but not under constant darkness, and because increasing light intensity itself lengthens free-running period, this agent may influence the circadian pacemaker by modulating light-evoked activity in the photic input pathway. The present study reexamined the possible dependence of clonidine-induced alterations of free-running circadian activity rhythms on lighting conditions. Similar effects were seen in both constant light and constant darkness, indicating that the effects of clonidine on the circadian pacemaker are not due to blockade of light-evoked activity in the photic input pathway. Instead, clonidine may act directly on the circadian pacemaker, or on other unspecified mechanisms influencing free-running period.

This study sought to define the generality of a previous finding that the spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rat strains differ in free-running circadian period when maintained in running-wheel cages under constant light. Circadian drinking rhythms were monitored in SHRs and WKYs housed without access to running wheels under an increasing series of light intensities beginning with constant darkness. Strain differences in circadian period were seen only at relatively high light intensities, indicating that SHRs and WKYs differ in circadian light sensitivity. Since SHRs and WKYs differ in circadian period with or without access to running wheels, this strain difference is not likely to depend on differential locomotor activity levels. SHRs and WKYs also differed in spectral profile and circadian waveform, but only under low light intensities. At higher intensities, dissociation of rhythmicity was seen in both strains.

The spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) inbred rat strains have been subjected to extensive behavioral and neurochemical characterization. The present study examined free-running circadian activity rhythms in these two strains. Because previous studies indicated that free-running rhythms are altered during chronic clonidine administration, and that SHRs and WKYs may respond differentially to clonidine, the effects of this agent on rhythmicity were compared in the two strains. SHRs were hyperactive and showed shorter free-running periods than did WKYs. Clonidine administration altered free-running rhythms similarly in the two strains, but reduced activity levels only in the relatively hyperactive SHRs. These results are consistent with the hypothesis that central noradrenergic systems influence circadian locomotor activity rhythms.

Rats were exposed to repeated sessions of inescapable footshock, and behavioral depression was subsequently assessed by measuring escape performance during exposure to escapable shock in a different testing environment. Free-running circadian activity rhythms were assessed using running wheels for approximately three weeks before and after administration of inescapable shock. Several animals showed lengthening of free-running period and decreases in activity level following shock. Similar effects were also seen in rats that were removed from their running wheels, placed within the shock apparatus, and not given shock, but not in nonhandled control animals. Furthermore, period lengthening in shocked and handled rats was positively correlated with escape performance, suggesting that circadian rhythm alterations occurred in those animals that were best able to cope with shock or handling-related stressors. In contrast, individual differences in circadian period and activity level during baseline conditions were not predictive of either escape performance or circadian rhythm alterations. These results suggest that successful behavioral adaptation to stress may be associated with alterations of circadian rhythmicity.

Two studies explore the relationship between rhythmicity and behavioral depression. Behavioral depression was induced using inescapable footshock, and assessed by measuring subsequent responses to escapable shock, in rats housed under different light-dark conditions. Experiment 1 compared escape performance in free-running and entrained animals following inescapable shock. Free-running and entrained animals did not exhibit differential vulnerability to the effects of inescapable shock. In addition, there were no systematic effects on phase following shock. However, several free-running animals showed increased circadian period following shock, and lengthening of period was significantly correlated with escape performance. Individual differences in baseline period or phase were not predictive of escape performance. In Experiment 2, "aftereffects" of entrainment to long or short light-dark cycles were utilized to create groups of animals with long or short free-running periods. After the administration of inescapable shock, escape performance was tested. There were no significant differences among experimental groups in escape performance. These results suggest that plasticity of circadian period, but not baseline period per se, may be associated with the ability to adapt to environmental challenges.

The purpose of this experiment was to investigate the relationship between daily patterns of wheel running activity and feeding behavior. Wheel running and bar pressing for food were continuously recorded from rats which had concurrent access to both wheels and food. In a second condition, wheel running and (non-reinforced) bar pressing were recorded during food deprivation. In a third condition, bar pressing for food was recorded while wheel running was prevented. During ad lib access to wheels and food, both behaviors occurred primarily during the dark phase of the light-dark cycle. However, the nocturnal distribution of these responses differed: the early dark hours were primarily devoted to running, while feeding occurred in small, frequent meals. Maximal food intake occurred during the late dark hours, when meals were larger and less frequent, and there was little running. During three days of complete food deprivation, both wheel running and meal initiation attempts (as indicated by nonreinforced bar pressing) maintained their normal daily patterns. However, during wheel deprivation, changes occurred in the temporal distribution of meals which equalized early and late dark food intake. These results show that the availability of an alternative activity, like wheel running, can be an important determinant of daily feeding patterns. However, the daily pattern of wheel running is not influenced by food availability. Different behaviors may show differential plasticity in the coordination of an overall daily behavioral program.

Two temporal variables have been implicated in the timing of postpartum heat in Norway rats: time of day and time since parturition. The nature of the interaction between these variables is not clearly understood. We extend previous observations on this problem to freely behaving animals continuously videotaped during parturition and postpartum mating in a seminatural habitat. The timing of postpartum mating is best described by a model in which an interval timer is coupled to a circadian gating mechanism. Interactions between circadian and interval timing mechanisms may be widespread in the neuroendocrine control of behavior.

Rats maintained on limited-access daily feeding schedules develop food-anticipatory activity rhythms which coexist with the photic circadian activity rhythm. These food anticipatory rhythms appear to depend upon a food-entrainable circadian oscillator which is separate and distinct from the light-entrainable circadian oscillator system. This study explored the long-term behavior of the putative food-entrainable oscillator in the presence and in the absence of a feeding schedule, and under light-dark cycles and constant light. The results suggest that a food-entrainable oscillator can show persisting self-sustained oscillations in the absence of a feeding schedule, and that the food- and light-entrainable circadian oscillators may show varying degrees of coupling, depending upon feeding conditions. Such a flexible coupling arrangement may allow the oscillator system to function as a "continuously consulted clock" in the adaptive temporal coordination of behavior with stable and unstable environmental periodicities.

Feeding and drinking rhythms were studied in rats maintained under 24-hr light-dark (LD) cycles with various photoperiods, under two-pulse (2P) and one-pulse (1P) skeleton photoperiods, and under constant dark (DD). Rhythmic waveforms were similar under complete LD cycles and corresponding skeleton photoperiods, indicating that these rhythms mainly reflect the entrainment of underlying circadian pacemakers. Little or no role was found for masking effects of light on circadian feeding and drinking waveforms. Entrainment was found to depend mainly on the timing of the dawn light signal, whether it was a 15-min light pulse or a dark-to-light transition initiating a complete photoperiod. Furthermore, the use of 1P schedules revealed that a dawn signal was sufficient for entrainment. These results closely match those obtained for motor activity measures in other nocturnal rodent species, and generally conform to the predictions of Pittendrigh's nonparametric theory of entrainment. Furthermore, the close correspondence of the two rhythms during entrainment, phase-jumps, and free-running (DD) conditions indicates that they are controlled by common circadian pacemakers.