Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats.

A study was carried out on the effects on sleep of rolipram, an antidepressant that increases the availability of cAMP by inhibiting a phosphodiesterase isoenzyme. Rats were treated with rolipram (0.1 or 1 mg/kg) twice a day (at light and dark onset) for 11 days, after a chronic period of injection of physiological saline for habituation purposes. The sleep-wake activity was recorded for 12 h following the injection at light onset on the baseline day (physiological saline), on rolipram days 1, 5, and 11, and also on day 12, when physiological saline was injected again (withdrawal day). The high (1 mg/kg) dose of rolipram enhanced wakefulness (W) in postinjection h 1 on day 1 of rolipram treatment. After administration of 0.1 mg/kg rolipram, only a tendency to an increase in W was noted. The promotion of W might be attributed, at least in part, to an increased release of noradrenaline due to a cAMP-mediated stimulation of tyrosine hydroxylase.

Promotion of sleep by heat in young rats.

The aim of the experiments was to study the effects of a moderate heat load on sleep in young (26-day-old) rats and to determine whether the sleep-promoting effect of heat results from stimulation of the homeostatic sleep process. The changes in sleep-wake activity, electroencephalogram slow wave activity (SWA) during non-rapid eye movement sleep (NREMS) and cortical temperature (Tcrt) were determined during and after long (24-h) and short (2.5-h) heat loads (elevation of ambient temperature from 26 degrees C to 32 degrees C), and after total sleep deprivation (SD) combined with a short-term heat load. The heat exposures elicited increases in Tcrt and rectal temperature (2 and 1.7 degrees C respectively). The long-term heat load induced persistent, albeit slight enhancements in NREMS. Rapid eye movement sleep (REMS) increased with a 12-h delay during the 24-h heat load. Heat elicited an immediate large increase in SWA. After this initial increase, SWA declined and tended to fall below the baseline level during the last 12 h of the 24-h heat load. SWA and REMS were significantly suppressed after termination of 24-h heat loading. The increased SWA during the short-term heat load was not followed by subsequent alterations in sleep when the ambient temperature had returned to normal. However, after the combination of SD with the short-term heat load the durations of NREMS and SWA were significantly enhanced compared with those found after SD at 26 degrees C. The results are interpreted as suggesting that heat increases NREMS in the young rat by the same mechanism as is involved in the enhancement of NREMS after SD: a stimulation of sleep drive.

Effects of acute and chronic treatment with trazodone, an antidepressant, on the sleep-wake activity in rats.

Rats were treated with trazodone (2.5 or 10 mg kg-1) twice a day (at light and dark onset) for 11 days, after chronic injection of physiological saline. The sleep-wake activity was recorded for 24 h on the baseline day (saline), on trazodone days 1, 5 and 11, and also on day 12, when physiological saline was injected again (withdrawal day). Trazodone administration increased non-REM sleep. The enhancement of non-REM sleep was dose-related and more pronounced during the dark cycle. The promotion of non-REM sleep was enhanced during the chronic treatment. There were no consistent changes in REM sleep. Spectral analysis of the EEG revealed an increase in slow-wave activity after administration of the high dose (10 mg kg-1) of the drug. It is concluded that trazodone, a clinically effective antidepressant, has a non-REM sleep-promoting effect. It is speculated that the promotion of sleep by trazodone may be mediated by serotonergic mechanisms.

Room light impairs sleep in the albino rat.

Since the rat is a nocturnal animal sleep experiments in this species are commonly performed during the light period of the 24-h light-dark (LD) cycle. To examine whether light itself affects sleep, chronically implanted albino rats were continuously recorded for a day under a 12-h light-12-h dark cycle (light intensity approx. 300 lx) and on the subsequent day in constant darkness (DD). In the absence of light, EEG slow-wave activity (0.75-4.0 Hz) in non-REM sleep and sleep continuity were significantly enhanced, while total sleep time and cortical temperature were not affected. The results show that in the albino rat room light impairs sleep by reducing its intensity and continuity.

Antiserum to prolactin decreases rapid eye movement sleep (REM sleep) in the male rat.

Previous reports suggest that blood-born prolactin (PRL) may selectively promote rapid eye movement sleep (REMS). To study the possible involvement of endogenous PRL in sleep regulation, rats were systemically injected with either antiserum to PRL or normal rabbit serum, and the sleep-wake activity was determined during the subsequent 12-h light cycle. The administration of normal rabbit serum in physiological saline did not alter sleep-wake activity compared to control recordings, whereas the PRL antiserum caused a modest and selective suppression in REMS. Immunoreactive PRL was eliminated from the serial plasma samples obtained between 6 to 11 h after the injection of the antiserum. Brain temperature was not affected by the antiserum. The results indicate that physiological pituitary PRL secretion has a slight REMS-promoting activity in the male rat. It is speculated that an increased release of pituitary PRL or the PRL-like substance previously demonstrated in the brain may significantly stimulate REMS.

Growth hormone-releasing hormone antibodies suppress sleep and prevent enhancement of sleep after sleep deprivation.

Previous reports suggest that the hypothalamic growth hormone-releasing hormone (GHRH) promotes sleep, especially non-rapid-eye-movement sleep (NREMS). To evaluate the role of endogenous GHRH in sleep regulation, the effects of antibodies to rat GHRH (GHRH-ab) were studied on normal sleep, brain temperature (Tbr), and GH secretion in experiment I and on enhanced sleep after sleep deprivation in experiment II. In experiment I, affinity-purified GHRH-ab (50 and 200 micrograms) raised in goats and a control goat immunoglobulin G (IgG) preparation were injected intracerebroventricularly (icv) in rats 1 h before the onset of the light cycle, and sleep-wake activity and Tbr were recorded for the next 12 or 23 h. Both doses of GHRH-ab suppressed NREMS and REMS throughout the light cycle. Sleep durations at night were normal. Electroencephalographic (EEG) slow-wave activity, characterized by EEG slow-wave amplitudes, was reduced after GHRH-ab during both the light and the dark cycles. Plasma GH concentrations measured 6-12 h after injection of GHRH-ab (200 micrograms) were diminished. Both the control IgG and GHRH-ab elicited fever. In experiment II, the sleep-wake activity and Tbr of rats were recorded for 24 h in three experimental conditions: base-line with icv injection of IgG, 3-h sleep deprivation with icv IgG injection, and 3-h sleep deprivation with icv GHRH-ab (200 micrograms). After sleep deprivation (+IgG), a prompt increase in EEG slow-wave activity (power density analysis) and late increases in NREMS and REMS durations were found.(ABSTRACT TRUNCATED AT 250 WORDS)

[The hypnogenic effects of delta sleep-inducing peptide (DSIP) analogs: a comparative study in rabbits and rats]. / Gipnogennye éffekty analogov del'ta-sonindutsiruiushchego peptida (DSIP): sravnitel'noe izuchenie u krolikov i krys.

Hypnogenic effects of 3 DSIP analogs with a higher stability against aminopeptidase activity have been studied in rabbits and rats using intraventricular administration (injections and infusions). An analog (D-Ala-2) DSIP augmented slow wave and paradoxical sleep within the 5th, 8th and 11th hours of the recording period. An analog (D-Val-2) DSIP made the same within the 8th and 10th hours, and hexapeptide (D-Ala-2) DSIP (1-6) increased sleep during the 1st, 3rd, and 5th hours. Both nonapeptides augmented sleep in rabbits as well as in rats, though hexapeptide produced this effect in rabbits only, that might be related to some difference in distribution and colocalization of endogenous DSIP-like peptide in the pituitary of two rodent species. It may be suggested that hypnogenic activity of DSIP analogs is determined by the structure of administrated molecule, being mediated by such hormones as GRF and CLIP.

Short light-dark cycles influence sleep stages and EEG power spectra in the rat.

To investigate the influence of light on sleep and the electroencephalogram (EEG), chronically implanted rats were continuously recorded during a baseline day under 12-h light-12-h dark (LD 12:12) conditions, and an experimental day with short LD (LD 1:1) cycles. The percentage of non-REM sleep (NREMS) was higher and the percentage of REM sleep (REMS) lower in the 1-h light [corrected] intervals than in the 1-h dark intervals. The maximum of NREMS induction by 1-h light occurred in the habitual 12-h dark period (activity period), while the largest enhancement of REMS by 1-h darkness occurred in the second half of the habitual 12-h light period (rest period). The EEG of waking, NREMS and REMS was subjected to spectral analysis to determine the power density of the frequency components in the range of 0.25-25.0 Hz. The overall 24-h time course of the EEG-spectra in NREMS was similar under baseline and experimental conditions. Nevertheless, the spectra were modified by the short LD-cycle. In NREMS, the values in the middle and high frequencies (greater than 6 Hz in the rest period; greater than 11 Hz in the activity period) were lower in the 1-h light intervals than in the 1-h dark intervals. In contrast, activity in some frequency bands during waking and REMS was higher in the light than in the dark intervals. It is concluded that the short LD-cycle modulates the vigilance states and induces state-specific changes in the EEG, whereas circadian aspects of sleep are little affected.

The effect of light on sleep and the EEG of young rats.

Sleep states, the power spectra of the cortical electroencephalogram (EEG) and cortical temperature (Tcrt) were determined in young rats (age 23-24 days). Recordings were made for 1 day under habitual 12 h light: 12 h dark (LD 12:12) conditions and on the subsequent day under continuous darkness (DD). The amount and distribution of the vigilance states differed little between experimental conditions. Sleep occurred predominantly during the actual (LD) or habitual (DD) 12-h light period. The EEG power density in the actual light period was lower than in the habitual light period. These differences were largest in the delta range for the EEG of non-rapid eye movement of sleep (NREMS) and in the theta range for the EEG of REM sleep (REMS) and waking. EEG power density in NREMS was somewhat lower in the LD dark period than in the corresponding DD period. The typical 24-h pattern of EEG power density in NREMS, which reflects processes underlying sleep regulation, was little affected by the experimental conditions. It is concluded that the light during an LD 12:12 schedule suppresses the EEG but has little effect on the vigilance states.

Brain and core temperatures and peripheral vasomotion during sleep and wakefulness at various ambient temperatures in the rat.

Changes in brain, core and tail skin temperatures (Tbr, Tc and Tt) associated with transitions in the arousal states were recorded in rats throughout the 24-h diurnal cycle at 10 degrees C, 21 degrees C and 29 degrees C. Falling asleep was accompanied by decreases in both Tbr and Tc and vasodilation at 10 degrees C and 21 degrees C. At 29 degrees C, tail vessels were permanently dilated, and further dilation was not found on sleep onset. Tbr and Tc, however, continued to decrease during non-rapid-eye-movement sleep (NREMS); these changes are likely to result from reductions in heat production and increased conductive heat loss. The changes in Tbr, Tc and Tt on awakening mirrored those on falling asleep. It is suggested that the suppression of sleep in the cold and the enhancement of NREMS in the heat promote thermoregulation. Rapid-eye-movement sleep (REMS) was associated with sharp rises in Tbr. The rise in Tbr was the largest in the cold and was attenuated at 29 degrees C. Tc decreased and Tt increased in the cold, whereas Tc tended to increase and Tt to decrease in the heat. The paradoxical peripheral vasomotion during REMS supports previous suggestions on severe thermoregulatory impairment during REMS in other species.

Sleep regulation in rats during early development.

Sleep states and power spectra of the electroencephalogram (EEG) were determined in freely moving young rats. Recordings during 24 h were obtained from the same animals at three different ages. Already at the age of 23 days waking predominated in the 12-h dark period. Rapid-eye-movement sleep (REMS) declined between the age of 23 and 40 days. Its 24-h maximum was situated in the dark period at 23 and 29 days of age and in the light period at 40 days. Slow-wave activity (SWA; 0.75-4.0 Hz) of the non-REMS (NREMS) EEG showed marked age-related changes: a declining trend in the 12-h light period was absent at 23 days, moderate at 29 days, and prominent at 40 days. At 23 days, SWA progressively declined within ultradian sleep episodes and at 24 days was massively increased after 2-h sleep deprivation (SD). At the age of 30 days, 6-h SD induced much smaller changes. The distinct 24-h pattern of high-frequency activity (10.25-25.0 Hz) was present at all ages and may represent an EEG correlate of a circadian process. We conclude that homeostatic mechanisms regulating NREMS intensity are already operative a few days after weaning.

Effects of alternating 45-min light-dark cycles on sleep in the rat.

We studied the effect of alternating 45-min light-dark (L-D) cycles on sleep in rats. Introduction of short L-D cycles did not abolish the normal circadian rhythm of sleep-wake activity. The amount of non-REM sleep was however increased in the L and decreased in the D 45-min periods. REM was promoted in the D and inhibited in the L 45-min periods. The influence of L-D or D-L transitions depended on the sleep wake activity immediately before the transition.

Growth hormone-releasing factor enhances sleep in rats and rabbits.

Previously, it was suggested that a hypothalamic mechanism links somatotropin [growth hormone (GH)] secretion to sleep regulation, and this may explain the temporal correlation between GH release and nonrapid eye movement sleep (NREMS) on sleep onset. The purpose of these experiments was to study whether growth hormone-releasing factor (GRF), a hypothalamic peptide responsible for stimulation of GH secretion, also has the capacity to promote sleep in rats and rabbits. Artificial cerebrospinal fluid or GRF (human GRF-[1-40], 0.01, 0.1, and 1 nmol/kg) was intracerebroventricularly injected to rats at dark onset, and the electroencephalogram (EEG), brain temperature (Tbr), and motor activity were recorded for 24 h. Rabbits received the same doses of GRF during the light period, and sleep-wake activity was monitored for 6 h. GRF promoted NREMS and rapid eye movement sleep (REMS) and increased EEG slow-wave activity in both rats and rabbits. NREMS increased in postinjection hour 1 after low doses of GRF, whereas the effect was more prolonged after higher doses. REMS increased in response to the low and middle doses of GRF in postinjection hour 1 in rats and in hour 2 after each dose in rabbits. The diurnal rhythms of sleep-wake activity, motor activity, and Tbr were not affected in rats. Because GRF promotes sleep and also stimulates GH secretion, it is a likely candidate for linking GH secretion and sleep regulation.

Effects of nocturnal intraperitoneal administration of cholecystokinin in rats: simultaneous increase in sleep, increase in EEG slow-wave activity, reduction of motor activity, suppression of eating, and decrease in brain temperature.

Rats received an i.p. injection of cholecystokinin-octapeptide sulfate ester (CCK; 4, 10 or 50 micrograms/kg) or physiological saline at dark onset, and the 24-h sleep-wake cycle (12-h-dark and 12-h-light phases), spontaneous motor activity and brain temperature (Tbr) were recorded. EEG activity was studied through spectral analysis for 2.5 h, and food intake was measured at the end of postinjection hour 1. In response to CCK, non-REM sleep increased at the expense of wakefulness, and the sleep-promoting effect was substantiated by an increase in EEG slow-wave activity. Motor activity, Tbr and food intake decreased. The effects vanished in postinjection hour 2; the diurnal rhythms were not modified. The changes varied as a function of the dose: the effects were significant following 10 micrograms/kg, and even higher in response to 50 micrograms/kg CCK. The results indicate that i.p. CCK definitely promotes non-REM sleep. This effect may belong to the behavioral sequence elicited by the peptide, which is often attributed to satiety. As evidenced by the reduction of Tbr, CCK also exerts strong autonomic actions, which might interfere with the behavioral responses.

Effects of acute and chronic treatment with an atypical antidepressant drug, nomifensine, on the sleep-wake activity in rats.

After the chronic administration of saline, rats were treated with nomifensine (0.1 or 1.0 mg/kg, twice a day, at light and dark onset) for 11 days. The sleep-wake activity was recorded for 24 h on the baseline day (saline), on nomifensine days 1, 5 and 11, and also on day 12, when saline was injected again (withdrawal day). Another group of rats was treated with saline throughout the experiment, without significant effect on the sleep-wake activity. The smaller dose of nomifensine increased non-REM sleep (NREMS) at the expense of wakefulness (W) in the light period. The effect persisted throughout the chronic treatment. A late increase in REM sleep (REMS) was noted on nomifensine days 5 and 11. Nomifensine failed to affect the sleep-wake activity in the dark period. On withdrawal, the baseline percentages of the vigilance states were recovered. As evaluated through spectral analysis of the EEG, the increase in NREMS was accompanied by an increase in slow wave activity. The higher dose of nomifensine elicited an increase in W and a reduction in both sleep states, followed by changes in W and NREMS in the opposite directions. These effects were evident in both the light and the dark periods of the day. Chronic treatment resulted in circadian variations in the effects. Withdrawal of the drug abolished the arousal reaction, but the late increase in NREMS persisted. The dose-dependent biphasic effects of nomifensine on sleep-wake activity can be explained by considering the proposed indirect dopamine and possibly noradrenaline agonist activity of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine autoreceptor antagonists: effects on sleep-wake activity in the rat.

The effects of the putative dopamine (DA) autoreceptor antagonists cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, (+)-UH 232, and cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-AJ 76, on sleep-wake activity, EEG, and motor activity in the rat were studied. Both drugs induced a dose-dependent increase in wakefulness (W) and a reduction in non-REM sleep (NREMS). A definite tendency to a suppression of REM sleep (REMS) could also be observed. The results of spectral analysis indicated that EEG slow wave activity, a marker of sleep intensity, was particularly sensitive to the drugs. Slight differences between the two drugs were observed: (+)-AJ 76 seemed to be more efficacious than (+)-UH 232 in stimulating motor activity. (+)-UH 232 tended to suppress slow wave activity more strongly than (+)-AJ 76. It is suggested that the increase in W following administration of (+)-AJ 76 resulted predominantly from locomotor activation, while (+)-UH 232 might also act on dopaminergic mechanisms involved in the regulation of sleep.

Structure-activity relationship in the effects of delta-sleep-inducing peptide (DSIP) on rat sleep.

DSIP and its analogues, [D-Trp1]-DSIP, [D-Tyr1]-DSIP, and [D-Trp1]-DSIP1-6, were injected ICV (7 nmol/kg) into rats at dark onset, and the sleep-wake activity was recorded during the 12-hr dark period and the subsequent 12-hr light period. The effects were evaluated with respect to baseline records obtained after artificial CSF injections. DSIP did not increase sleep, whereas both [D-Trp1]-DSIP and [D-Tyr1]-DSIP promoted sleep in the first part of the night. [D-Trp1]-DSIP1-6 had a prompt arousing effect. It is suggested that the sleep-promoting analogues act by facilitating slight endogenous sleep tendencies at some time after dark onset, while DSIP is degraded quickly and is therefore not effective. The increase of W after [D-Trp1]-DSIP1-6 may indicate that DSIP contains a fragment with an arousing effect. The results corroborate the notion that the active DSIP molecule has a pseudo-cyclic structure.

Capsaicin pretreatment reduces the gastric acid secretion elicited by histamine but does not affect the responses to carbachol and pentagastrin.

Gastric acid secretion was studied following stimulation with a subcutaneous injection of histamine (0.1, 0.5 or 5 mg/kg), carbachol (4, 40 or 160 micrograms/kg) or pentagastrin (25 or 250 micrograms/kg) in conscious rats pretreated with either capsaicin or the vehicle. The secretory response to histamine (0.5 or 5 mg/kg) was greatly reduced in the capsaicin-treated rats, while the slight effect of 0.1 mg/kg histamine and the increase of secretion in response to carbachol and pentagastrin were not affected. The basal secretion was also normal in the capsaicin-treated rats. It is suggested that unlike the effects of carbachol and pentagastrin, the increase of acid secretion elicited by histamine involves a capsaicin-sensitive mechanism. Since capsaicin is a specific neurotoxin for the peptide-containing primary sensory neurons, the present results may indicate that the neurons contribute essentially to the effect of histamine on gastric acid secretion.

Vasoactive intestinal polypeptide promotes sleep without effects on brain temperature in rats at night.

The possible sleep-promoting activity of vasoactive intestinal polypeptide (VIP) was contrasted with the physiological sleep suppression in the diurnal active period through the i.c.v. injection of 100 ng VIP into rats at dark onset. The sleep-wake activity and brain temperature (Tbr) were recorded for 24 h (dark period and light period, 12 h each), and the effects were evaluated with respect to records obtained after artificial cerbrospinal fluid injection. Without altering the normal course of Tbr, VIP induced a prompt and persistent increase of sleep. Wakefulness was significantly suppressed and non-REM sleep increased for 6 h, while REM sleep increased for 3 h. The obvious sleep-promoting action of VIP, unrelated to thermoregulatory effects, supports the notion that the peptide might be involved in sleep regulation.

Effects of intracerebroventricular injection of delta sleep-inducing peptide (DSIP) and an analogue on sleep and brain temperature in rats at night.

The effects of ICV injections of DSIP and omega-amino-caprilyl-DSIP (C-DSIP) on the sleep-wake activity and brain temperature (Tbr were studied in rats. The substances (7 nmol/kg) were injected at dark onset, and the sleep-wake activity and Tbr were recorded for 24 hr (dark and light periods, 12 hr each). Relative to the control recordings obtained after artificial CSF injection, the duration of sleep did not increase after either DSIP or C-DSIP. The only significant reaction was an increase of W 6 to 9 hr after the injection of either peptide. The course of Tbr after DSIP and C-DSIP was also identical to that recorded after the injection of artificial CSF. It seems that DSIP administered in a single ICV injection at dark onset does not promote sleep. The increase in W might be attributed to an indirect effect of DSIP or to a degradation product of the peptide.