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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.

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Alcohol consumption (both acute and chronic) and alcohol withdrawal have a variety of chronobiological effects in humans and other animals. These effects are widespread, altering the circadian rhythms of numerous physiological, endocrine, and behavioral functions. Thus, some of alcohol's negative health consequences may be related to a disruption of normal physiological timing. Most studies of alcohol's chronobiological effects have been conducted under natural conditions in which environmental stimuli, such as regular cycles of light and darkness, act to coordinate circadian rhythms with the environment and with each other. However, such studies cannot distinguish between effects occurring directly on the circadian pacemaker and those occurring "downstream" from the pacemaker on the physiological control systems. Studies using animals have enabled researchers to begin to examine the effects of alcohol on circadian rhythms under so-called free-running conditions in experimental isolation from potential environmental synchronizers. These studies have provided preliminary evidence that alcohol's chronobiological effects are indeed the result of direct influences on the circadian pacemaker itself. Furthermore, the effects of alcohol on animal circadian rhythms appear similar to the effects seen during administration of antidepressant drugs. Taken together with evidence that the chronobiological effects of alcohol withdrawal in human alcoholics are reminiscent of those described in depressed patients, these observations suggest that alcohol may produce antidepressantlike effects on the circadian pacemaker. One theory suggests that the effects of alcohol on the circadian pacemaker are mediated in part by alterations in serotonin, an important chemical involved in cellular communication within the circadian system. However, other neurochemical systems also are likely to be involved.

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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.

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Dark pulses presented on a background of constant light (LL) result in phase advances during midsubjective day and early subjective night, and phase delays during late subjective night, as shown in the dark-pulse phase response curve. In hamsters, the phase-shifting effects of dark pulses are thought to be mediated by increased activity, as previous studies have shown that restraining animals during dark pulses blocks the phase shifts observed in midsubjective day and late subjective night. This study focuses on dark-pulse-induced phase shifting during early subjective night, examining the influence of both LL intensity and restraint on the magnitude of these phase shifts. Syrian hamsters were maintained in LL of four different illumination levels (1, 10, 100, or 600 lux) and periodically presented with 6-h pulses (dark pulse alone, restraint alone, or dark pulse plus restraint) beginning at circadian time 11. Phase advances were observed in response to dark pulses alone, and the magnitude of these shifts was dependent on background illumination, with significantly larger advances seen under higher intensities. No relationship was found between the amount of activity displayed during dark pulses and phase shift magnitude. Six-hour periods of restraint resulted in phase delays, the magnitude of which was also dependent on background illumination. Restraining hamsters during dark pulses reduced the magnitude of phase advances, but the extent of this reduction could be predicted from the additive effects of the dark-pulse-alone and restraint-alone conditions. These results indicate that the phase-shifting effects of dark pulses during early subjective night are not mediated by behavioral activation and may instead reflect a mirror image of the phase-delaying effects of light pulses at this phase.

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Neonatal exposure to antidepressant monoamine re-uptake inhibitors produces a wide variety of effects on the behavior and physiology of adult rats which are consistent with features of clinical depression. Since depressed patients show characteristic alterations in circadian rhythmicity, our laboratory has examined free-running circadian drinking rhythms in this putative animal depression model. Previously, neonatal desipramine treatment was shown to lengthen free-running period, and increase circadian amplitude, spectral magnitude, and voluntary alcohol intake (10% ethanol v/v) of male rats. The purpose of the present study was to examine the effects of neonatal clomipramine treatment (25 or 30 mg/kg s.c., postnatal days 8-21) on circadian drinking rhythms and alcohol intake of both male and female rats. In addition, effects of alcohol exposure on circadian rhythmicity were also examined. Contrary to expectations, free-running period of clomipramine-treated rats did not differ from saline-treated controls in either constant darkness (DD) or constant light (LL), but spectral magnitude was increased in clomipramine-treated males and females, and circadian amplitude was increased in clomipramine-treated females. Neonatal clomipramine also increased voluntary alcohol intake, and both clomipramine- and saline-treated groups displayed significant period-shortening during alcohol exposure. Taken together, these results suggest that alterations in the amplitude and coherence of circadian rhythmicity may be more consistent than alterations in free-running period in animal depression models, as has been suggested previously for depressed patients.

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Inbred strains have been used to study genetic and physiological relationships among different aspects of circadian timekeeping, as well as relationships between circadian rhythmicity and other strain-specific traits. The present study characterized several features of circadian timekeeping in genetically hyperactive (WKHA) and genetically hypertensive (WKHT) inbred strains, derived from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. WKHAs and WKHTs differed in free-running period, steady-state entrainment to light-dark cycles, and photic phase shifting, and relationships among these measures were consistent with previous studies of species, strain, and individual differences. Because both WKHTs and SHRs show short circadian periods relative to their respective comparison strains, this trait may cosegregate genetically with hypertension. In contrast, because WKHAs and SHRs show similar photic entrainment and phase shifting, these circadian functions may cosegregate with open-field hyperactivity. Finally, because neither WKHAs nor WKHTs show the SHR's excessive levels of home-cage running wheel activity, this trait is not related to either hypertension or open-field activity. Further work would be required to elucidate specific genetic and/or physiological linkages among these variables.

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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.

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Neonatal treatment with monoamine reuptake inhibitors results in a constellation of neurobehavioral alterations in adult rats that may model human depression. Since alterations in circadian rhythmicity have been reported in both depressed patients and in animal depression models, the present study examined the effects of neonatal desipramine treatment (5.0 mg/kg SC from postnatal day 7 through 22) on free-running circadian drinking rhythms. Rhythmicity was examined in constant darkness (DD), constant light (LL), and during adult desipramine treatment (0.25 mg/ml via the drinking water). Compared with saline-treated controls, neonatal desipramine lengthened free-running period in DD, blunted the period-altering effect of LL, and potentiated the period-altering effect of adult desipramine treatment. Neonatal desipramine treatment also increased circadian amplitude and spectral magnitude, but did not modify the effects of light or adult desipramine on these parameters. These results provide further evidence that behavioral depression is associated with alterations in circadian rhythmicity, and are consistent with the hypothesis that such relationships are mediated by brain monoaminergic systems.

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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.

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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.

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There are several anatomically and functionally distinct retinofugal pathways, one of which is the retinohypothalamic tract (RHT). In this study, horseradish peroxidase conjugated to cholera toxin (CT-HRP), a sensitive neural tracer, was employed to describe the RHT in the female albino rat. Following uniocular injection of CT-HRP, both medial and lateral components of the RHT were evident. The medial component swept caudally into and through the suprachiasmatic nucleus (SCN) and dorsally to the subparaventricular zone. Terminal label was seen in the medial preoptic region, peri-SCN area, retrochiasmatic area, periventricular nucleus, anterior and central parts of the anterior hypothalamic area, and the subparaventricular zone. In contrast to the more focused and symmetrical medial component, the lateral component was diffuse with light terminal label in the lateral preoptic region, olfactory tubercle, lateral hypothalamus, supraoptic nucleus, and medial and posteroventral medial amygdaloid nuclei. The striking exception to this diffuse pattern of the lateral component was an extremely dense columnar terminal field over the dorsal border of the supraoptic nucleus. Whereas the intensity of label in terminal fields of the medial component was often similar on the sides ipsilateral and contralateral to the injection, the lateral component was consistently asymmetrical with greater labeling on the side contralateral to the injection. In addition, a light projection arrived at several thalamic nuclei by returning toward the thalamus from the tectal or pretectal areas via stria medullaris, and thus was not a part of the RHT. Implications for circadian as well as noncircadian photobiologic effects are discussed.

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To explore the multioscillator nature of the neurohumoral circuitry controlling the expression of circadian rhythmicity, rats' wheel running circadian activity rhythms were compared following sagittal knife cuts in the region of the suprachiasmatic nucleus (SSCN), following pinealectomy (PX) and following the combination of SSCN and PX. 25% of animals with knife cuts that passed through one SCN had disturbed running activity under constant illumination; rhythmic disturbances were seen neither in animals with sham knife cuts nor in rats with knife cuts on the midline or lateral to the SCN. Animals with both SSCN and PX were twice as likely to show severe rhythmic disruptions under free-running conditions as rats with SSCN and sham PX. Rats with PX and sham SSCN did not display disrupted activity rhythms. When animals with PX alone or SSCN alone were first observed under free-running conditions and then subjected to a second surgical procedure so that all animals underwent both PX and SSCN, all PX and most SSCN animals demonstrated coherent activity rhythms after the first operation, but 35% showed disruptions in circadian activity patterns only following the second surgery. The activity rhythms of rats with knife cuts placed either on the midline or lateral to the SCN did not deteriorate when combined with PX. Rats with coherent rhythms following knife cuts damaging one SCN had rhythm disruptions after the addition of PX. The effects of pinealectomy may indicate that the pineal gland plays a role in maintaining the coupling relationships in the multioscillator system controlling circadian activity rhythms. The results of this study also suggest that neither the direct commissural connection of the SCNs nor the humoral output of the pineal gland is indispensable for the expression of coherent circadian activity rhythms in the rat.

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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.

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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.

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Experimental and clinical studies indicate that the alpha-adrenergic agonist clonidine can alter mood and activity. However, the behavioral effects of this agent are complex and appear to depend on duration of treatment. Recent work from this laboratory demonstrated that clonidine systematically alters the period, amplitude, and level of free-running circadian activity rhythms in rats. The present study confirms and extends previous observations by employing a longer duration of clonidine treatment. The results show that chronic clonidine administration reversibly shortens the free-running period and reduces the amplitude of the free-running rhythm in constant light. Furthermore, clonidine treatment can increase or decrease the level of activity, depending on baseline activity level, and these effects are not consistently reversed following the termination of treatment. These observations support the hypothesis that noradrenergic systems influence both the circadian periodicity and the level of spontaneous activity, and that clonidine may influence these two parameters by acting at different neural or neuronal loci.

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This study examined the effects of the alpha 2-adrenergic agonist clonidine on free-running circadian activity rhythms in rats, using a dosing regimen similar to one previously shown to induce behavioral depression in the swim test. In constant light, clonidine consistently shortened the free-running circadian period, reduced circadian amplitude, and reduced the overall level of locomotor activity. These effects were reversed after the termination of clonidine treatment. In constant darkness, clonidine reduced circadian amplitude, but both increases and decreases in free-running period and activity level were observed. Clonidine-induced changes in free-running period and activity level were systematically related to individual differences in baseline activity in both constant light and constant darkness. These results demonstrate that clonidine can alter both the rhythmicity and the level of spontaneous activity, and are consistent with the hypothesis that monoaminergic systems may mediate relationships between behavioral state and circadian rhythmicity.

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Rhinomanometric observations of nasal airway patency were obtained for each nasal passage every 10 min throughout an uninterrupted 8-h session. The 49 airflow observations for each nasal passage were subjected to autocorrelation analysis, a statistical technique for quantifying periodicities in a temporal sequence of observations. No significant periodicities were found in any of the 16 subjects when the autocorrelation functions were interpreted by conventional statistical criteria. However, when less stringent criteria were applied, we found suggestive evidence for rhythmicity in one (7 subjects) or both nasal passages (2 subjects). The relationship in patency between the two sides of the nose was characterized with correlation coefficients. These correlations were significantly negative in 7 subjects, indicating bilateral reciprocity of patency. In addition, the correlations were significantly positive in one, and nonsignificant in 8 subjects. Only a minority of subjects (13%) displayed the classical nasal cycle, i.e., rhythmicity in both nasal passages as well as reciprocity of patency between passages.

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Alterations in circadian rhythms have previously been associated with estrous and seasonal changes in reproductive state. In the present study we explored the effects of the reproductive events of pregnancy and parturition on free-running circadian activity rhythms in the rat. Free-running rhythms were monitored before mating, during pregnancy, and following parturition and removal of pups. Systematic and long-lasting alterations of the period of the free-running activity rhythm were seen following parturition. The effects of estrous, seasonal, and gestational reproductive states on circadian rhythms may be mediated by the endocrine events which accompany these states.

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The dorsal and median mesencephalic raphe nuclei provide a robust projection to the hypothalamic suprachiasmatic nucleus, the site of a putative neuronal circadian pacemaker. Although it has been suggested that the raphe may play a role in the circadian timing system, this role has not yet been specified. In the present report, we examined the circadian activity patterns of rats with large mid-brain lesions aimed at the median and dorsal raphe nuclei under conditions of light-dark entrainment, and while free-running in constant light and constant darkness. The results indicate that midbrain raphe lesions may interfere with the expression of free-running circadian activity rhythms.

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