N-acetyltransferase Rise Research Articles

Photic entrainment of the mammalian rhythm in melatonin production.

This review summarizes studies on the photic entrainment of the circadian rhythm in the rat pineal melatonin production, namely of the rhythm in N-acetyltransferase (NAT) activity, and compares the NAT rhythm resetting with preliminary results on the resetting of an intrinsic rhythmicity in the suprachiasmatic nucleus (SCN) of the hypothalamus, namely with the entrainment of the rhythm in the light-induced c-fos gene expression. Phase delaying of the NAT rhythm after various light stimuli proceeds within 1 day with almost no transients, whereas during phase advancing of the rhythm only the morning NAT decline is phase advanced within 1 day and the evening rise phase shifts through transients. A light stimulus encompassing the middle of the night may phase delay the evening NAT rise, phase advance the morning decline, compress the rhythm waveform, and eventually lower its amplitude. Similarly, a long photoperiod compresses the NAT rhythm waveform. The magnitude of phase shifts of the NAT rhythm, as well as their direction, depends on a previous photoperiod. Phase shifts of the evening rise in c-fos gene photoinduction in the SCN and of the morning decline are similar to those of the pineal NAT rhythm after all light stimuli studied so far. The data indicate that the resetting of the rhythm in melatonin production in the rat pineal gland reflects changes in the SCN functional state and suggest that the underlying SCN pacemaking system is complex.

Melatonin entrainment of the circadian N-acetyltransferase rhythm in the newborn rat pineal gland.

In 15-day-old control and vehicle-treated rats, the evening rise of the pineal N-acetyltransferase occurred at the same time as in their mothers, whereas in 5-day-old pups, the rise occurred by 2-3 hr earlier. Four-day administration of melatonin in the late day phase advanced the N-acetyltransferase rise in 15-day-old rats as compared with the rise in the vehicle-treated animals; a slight melatonin induced phase advance in 5- and 27-day-old rats was not significant. The data indicate that the newborn rat's circadian pacemaker controlling the rhythmic N-acetyltransferase rise may be entrained by exogenous melatonin. It appears, however, that the maternal melatonin transferred via milk cannot entrain the pup's pacemaker by phase advancing it, since the N-acetyltransferase rise in the pups begins earlier or at the same time as maternal melatonin production driven by the N-acetyltransferase rhythm.

Entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity by melatonin is photoperiod dependent.

Entraining effect of melatonin on the circadian rhythm in rat pineal N-acetyltransferase (NAT) activity was studied under various photoperiods. Melatonin administration prior to dark onset for 5 successive days phase-advanced the evening NAT rise under the light:dark (LD) cycle of either LD 10:14 or LD 8:16, but not under LD 12:12. It is assumed that under the latter regime, the end of a light period exhibited a phase-delaying effect on the NAT rise. The light exposure appeared to be a stronger Zeitgeber than melatonin itself. Data show that melatonin applied in the late light period advances the evening NAT rise under a short photoperiod only; under a longer photoperiod, the phase-advancing effect of melatonin may conflict with a phase-delaying effect of the end of a light period, and the effect of light exposure overrides that of melatonin.

Entrainment of the rat circadian clock controlling the pineal N-acetyltransferase rhythm depends on photoperiod

Entrainment of the circadian clock as a function of time when a light stimulus is presented has been studied in detail while little attention has been paid to a role photoperiod may play in the resetting. To find out whether and how photoperiod affects the entrainment, resetting of the rat circadian pacemaker by delays in the evening light offset and by advances in the morning light onset, respectively, was studied in rats maintained either under a short photoperiod, with 8 h of light and 16 h of darkness per day (LD8:16) or under a long, LD18:6 photoperiod. To assess phase shifts of the clock, the suprachiasmatic nucleus controlled rhythm in the pineal N-acetyltransferase (NAT), namely the time of the evening NAT rise and the time of the morning decline, were followed. One day after a delay in lights off, on LD8:16 the NAT rhythm with a normal amplitude was retained following longer delays of the light offset and the maximum phase delay of the NAT rise was 3 times larger than on LD18:6. One day after an advance in lights on, the NAT decline was phase advanced under both photoperiods; on LD8:16 the maximum shift was 3 times as large as on LD18:6. On LD8:16, the NAT rise was not shifted after shorter advances in lights on and became phase delayed only when the light onset was brought forward to before midnight while on LD18:6 the NAT rise was phase delayed after any, even a mere 1 h, advance in lights on. The data show that magnitude and direction of phase shifts of the NAT rhythm depend not only on the time of light presentation but on photoperiod as well. Difference in resetting of the rhythm under various photoperiods may reflect photoperiod-dependent changes of an underlying pacemaker.

Melatonin Entrains the Circadian Rhythm in the Rat Pineal N-Acetyltransferase Activity

It has been recently suggested that in mammals the pineal hormone melatonin may be involved not only in transduction of a photoperiodic information, but in a subtle modulation of a phase of the circadian system as well. This suggestion has been based mainly on data about entrainment of the locomotor activity rhythm by melatonin. The present study was undertaken to check whether melatonin may phase-shift also other circadian rhythms, namely the rhythm in pineal N-acetyltransferase activity which is supposed to drive the rhythmic melatonin production in the rat. 50-day-old male Wistar rats were maintained on a regimen of 10 h of light and 14 h of darkness per day. Vehicle or melatonin (1mg/kg rat weight) was injected subcutaneously just before the dark onset. After a single melatonin injection or after administration of melatonin for 5 successive days or after a 4-day treatment with melatonin and a 1-day withdrawal, the evening N-acetyltransferase rise was phase-advanced relative to the rise in rats treated with vehicle only; the phase shift was larger after a repeated than after a single melatonin injection. Under all above-mentioned paradigms of melatonin administration, the morning N-acetyltransferase decline was less phase-advanced than the evening rise. Persistence of the phase advance of the N-acetyltransferase rise after withdrawal of melatonin treatment and a larger phase shift after a repeated than after a single melatonin administration suggest that melatonin may entrain directly a circadian pacemaker controlling the N-acetyltransferase rhythm and affect thus its own rhythmic production.

Mechanism of the re-entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity to an eight-hour advance of the light-dark cycle: phase-jump is involved

During the re-entrainment of the rat pineal N-acetyltransferase (NAT) rhythm to an 8-h advance of a light-dark (LD) cycle accomplished by shortening of one dark period, the advanced light period phase-delayed the evening NAT rise and phase-advanced the morning decline. The phase-relationship between the rise and the decline became so compressed that after the second and the third light period the NAT rhythm was not expressed even in constant darkness and reappeared only within another cycle at the time of the original night. Only after the fourthdvanced light period, the NAT rhythm phase-jumped into the advanced night.

Different Mechanisms of Phase Delays and Phase Advances of the Circadian Rhythm in Rat Pineal N-Acetyltransferase Activity

The circadian rhythm in rat pineal N-acetyltransferase (NAT) activity, which drives the rhythm in melatonin production, is controlled by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus. As the NAT rhythm has two well-defined phase markers--namely, the time of the evening activity rise and of the morning decline--it is suitable for studies of the entrainment of the pacemaker by environmental light. Phase delays of the NAT rhythm proceed more rapidly than phase advances. One day after a brief light pulse applied before midnight, or after a delay in evening lights-off, or a delay of a light-dark (LD) cycle, phase delays of the evening NAT rise result in almost corresponding delays of the morning NAT decline. Consequently, the NAT rhythm is phase-shifted, but its pattern does not change. One day after a brief light pulse applied past midnight, or after bringing forward morning lights-on, or after an advance of an LD cycle, the morning NAT decline is phase-advanced, but the evening rise is not phase-advanced at all or may even by phase-delayed. Consequently, the phase relationship between the evening NAT activity onset and the morning offset may be compressed considerably, and it may take several transient cycles before phase advances of the morning NAT decline are followed by corresponding advances of the evening NAT rise. Due to the phase-delaying effect of evening light on the NAT rise and to the phase-advancing effect of morning light on the NAT decline, the phase relationship between the NAT rise and the decline is compressed on long days and decompressed on short days. Different phase shifts of the evening NAT rise and of the morning decline, even in opposite directions, are consistent with the hypothesis of a complex, two-component (evening-morning, or E-M) pacemaker controlling the NAT rhythm. As the E-M phase relationship determines duration of the high night melatonin production, and the duration of the nocturnal melatonin pulse may convey information on daylength, the data are consistent with the internal coincidence model for photoperiodic time measurement.

Rapid adjustment of the pineal N-acetyltransferase rhythm to change from long to short photoperiod in the Japanese quail (Coturnix coturnix japonica).

The dynamics of adjusting the pineal N-acetyltransferase rhythm from long to short photoperiod was assessed in the Japanese quail (Coturnix coturnix japonica). The transition from LD 16:8 to LD 8:16 was accomplished by symmetrical prolongation of the dark period. In LD 16:8, the period of elevated nocturnal activity lasted approximately 7 hours. During the first prolonged night, the evening N-acetyltransferase rise advanced by almost 3 hours relative to the rise in LD 16:8 and occurred at the same time as during the 3rd, 7th, and 14th day after the transition. The morning N-acetyltransferase decline did not shift during the first long night; during the third night it was delayed relative to the decline in LD 16:8 by more than 2 hours and occurred at the same time as during the 7th and 14th night following the LD 16:8 to LD 8:16 transition. Three, 7, and 14 days after the transition, the period of elevated N-acetyltransferase activity lasted approximately 12 hours. Hence extension of the N-acetyltransferase rhythm profile proceeded first into the evening and then only into the morning hours, and it was accomplished within 2 to 3 days.

Entrainment of the rat pineal rhythm in melatonin production by light.

Environmental light entrains the rat pineal N-acetyltransferase rhythm which controls melatonin production. One day after 1 min light pulses applied before midnight, or after delays in the evening switch off of light, or after a delay of the light-dark cycle, the evening N-acetyltransferase rise and the morning decline are phase delayed almost to the same extent. Consequently, the pattern of the rhythm does not change. One day after 1 min light pulses applied past midnight, or after bringing forward the morning light onset, or after an advance of the light dark-cycle, the morning N-acetyltransferase decline is phase advanced, but the evening rise is either not phase shifted or it may be even phase delayed. Consequently, the pattern of the rhythm may be changed considerably or the rhythm may be abolished. The data are consistent with an hypothesis of a two-component pacemaker controlling the N-acetyltransferase rhythm. Under all photoperiods which we encounter in nature, the pattern of the N-acetyltransferase rhythm is determined by the entraining effect of light on the pacemaker, but not by the suppressant effect of light.

Dynamics of discrete entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity during transient cycles.

To elucidate entrainment of a pacemaker controlling the N-acetyltransferase (NAT) rhythm in the rat pineal gland, we studied the phase response curves (PRCs) of this rhythm. We exposed 50- to 60-day-old male Wistar rats maintained in a light-dark cycle (LD 12:12) to a 1-min light pulse at different times before midnight or at various times throughout the whole night. We then released them into constant darkness and studied the morning NAT decline during the night when rats were pulsed before midnight, as well as the evening NAT rise and the morning decline after 4 days following the pulses. The PRC for the first NAT decline and the PRCs for the NAT rise and decline after 4 days were compared with published transient PRCs (Illnerová and Vanĕcek, 1982b), in order to obtain a complete picture of the dynamics of the NAT rhythm entrainment during the transient cycles. Phase delays in the NAT rise due to a pulse before midnight were complete (i.e., identical to those of day 4) on day 1. Phase delays in the NAT decline were almost complete on day 1, while incomplete phase delays were observed on day 0. Phase advances in the NAT rise and decline due to a pulse past midnight had different dynamics: Advances in the decline were complete on day 1, while advances in the rise were absent on day 1 and much smaller than in the decline on day 4. The results are discussed in terms of a two-component (E-M) pacemaker controlling the NAT rhythm. The NAT rise may reflect the phase of the E-component, while the decline reflects the M-component. Phase delays of the E-component are accomplished within one cycle, and so are phase advances of the M-component. However, although delays of E already result in delays of M one cycle after the pulse, it takes several transient cycles before advances of M begin to induce advances of E.

Entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity by prolonged periods of light.

Entertainment of the circadian rhythm in the pineal N-acetyltranferase activity by prolonged periods of light was studied in rats synchronized with a light:dark regime of 12:12 h by observing phase-shifts in rhythm after delays in switching off the light in the evening or after bringing forward of the morning onset of light. When rats were subjected to delays in switching off the light of up to 10 h and then were released into darkness, phase-delays of the evening N-acetyltransferase rise during the same night corresponded roughly to delays in the light switch off. However, phase-delays of the morning decline were much smaller. After a delay in the evening switch off of 11 h, no N-acetyltransferase rhythm was found in the subsequent darkness. The evening N-acetyltransferase rise was phase-delayed by 6.2 h at most 1 day after delays. Phase-delays of the morning N-acetyltransferase decline were shorter than phase-delays of the N-acetyltransferase rise by only 0.7 h to 0.9 h at most. Hence, 1 day after delays in the evening switch off, the period of the high night N-acetyltransferase activity may be shortened only slightly. The N-acetyltransferase rhythm was abolished only after a 12 h delay in switching off the light. Rats were subjected to a bringing forward of the morning light onset and then were released into darkness 4 h before the usual switch off of light. In the following night, the morning N-acetyltransferase decline, but not the evening rise, was phase advanced considerably. Moreover, when the onset of light was brought forward to before midnight, the N-acetyltransferase rise was even phase-delayed. Hence, 1 day after bringing forward the morning onset of light, the period of the high night N-acetyltransferase activity may be drastically reduced. When rats were subjected to a 4 h light pulse around midnight and then released into darkness, the N-acetyltransferase rhythm in the next night was abolished. The data are discussed in terms of a two-component pacemaker controlling the N-acetyltransferase rhythm. It is suggested that delays in the evening switch off of light may disturb the N-acetyltransferase rhythm the next day only a little, as the morning component may adjust to phase-delays of the evening component almost within one cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Cysteamine effects on somatostatin, catecholamines, pineal NAT and melatonin in rats

The thiol reagent cysteamine was administered to adult male rats with the aim of investigating its effect on different neural and pineal components. As expected, immunoreactive somatostatin decreased in the median eminence (ME) ( p < 0.05) and gastric antrum ( p < 0.05) after cysteamine; however, no significant change was observed in the pineal IRS content after drug treatment. A decrease in norepinephrine was observed in the ME ( p < 0.001), hypothalamus ( p < 0.001) and pineal gland ( p < 0.05), together with a rise in ME ( p < 0.005) and hypothalamic dopamine ( p < 0.005) content; these results are consistent with a dopamine-beta-hydroxylase inhibiting effect of cysteamine. No effect was observed on hypothalamic serotonin and 5-hydroxyindole-acetic acid content. Pineal N-acetyltransferase (NAT) activity was significantly higher ( p < 0.05) after cysteamine than after saline, but no statistically significant effect was observed on pineal melatonin content. The mechanism involved in the NAT rise is presumably not related to the known stimulatory effect of norepinephrine, which fell after cysteamine. It is suggested that cysteamine may act at an intracellular level, inhibiting NAT degradation, an effect demonstrated in vitro and thought to be related to a thiol:disulfide exchange mechanism.

Entrainment of the circadian rhythm in rat pineal N-acetyltransferase activity under extremely long and short photoperiods.

Entrainment of a pacemaker driving the circadian rhythm in rat pineal N-acetyltransferase activity was studied under extremely long and short photoperiods. Adult male rats maintained under the light-dark regime (LD) 18:6 or under the regime LD 6:18 were exposed to a 1-min light pulse at different times at night, then they were released into darkness, and the next night phase-shifts of the evening N-acetyltransferase rise and of the morning N-acetyltransferase decline caused by light pulses were determined. The evening rise was phase-delayed by at most 0.5 h under LD 18:6, but by as much as 2.8 h under LD 6:18. The morning decline was phase-advanced by at most 1.9 h under LD 18:6, but by as much as 3.5 h under LD 6:18. Hence, the magnitude of phase-shifts and consequently patterns of phase-response curves, which show possibilities of discrete entrainment, depend on the photoperiods under which animals are maintained. A 1-min light pulse applied within 1 h before the end of the dark period phase-advanced the morning N-acetyltransferase decline under LD 18:6 as well as under LD 6:18, while a pulse applied within 1 h after the beginning of the dark period phase-delayed the evening N-acetyltransferase rise only in rats maintained under LD 18:6, but not in those kept under LD 6:18. It seems that under very long photoperiods, the N-acetyltransferase rhythm may be entrained by evening as well as by the morning light, while under very short photoperiods the rhythm may be synchronized by morning light only.

Circadian rhythm in inducibility of rat pineal N-acetyltransferase after brief light pulses at night: control by a morning oscillator

1. The organization of the pacemaker driving the rhythm of N-acetyltransferase inducibility by darkness at night in the rat pineal gland was studied in male Wistar rats by observing changes of the rhythm caused by brief light pulses. 2. When rats maintained for a second day in constant darkness were exposed to a 1-min light pulse before or at 0000 hours, N-acetyltransferase activity, following the initial drop, began to rise anew to the usual high night level. After a pulse at or past 0030 hours, N-acetyltransferase activity did not increase throughout the rest of the night. The boundary between re-inducibility and non-inducibility of N-acetyltransferase by darkness after a 1-min light pulse was thus around 0015 hours. 3. When rats were exposed to a 1-min light pulse the first night and then released into constant darkness, the boundaries between N-acetyltransferase re-inducibility and non-inducibility by darkness after a pulse presented in the second night were phase-shifted relative to the boundary in unpulsed rats. Pulses given before midnight the first night phase-delayed the boundary the second night; pulses given after midnight, phase-advanced the boundary. The advances were more pronounced than the delays. 4. The phase-response curve (PRC) showing shifts of the boundary the next night after a 1-min light pulse was the same as the PRC reported for shifts of the morning N-acetyltransferase decline, which are thought to represent phase-shifts of the morning oscillator controlling the decline. It differed markedly from the PRC reported for shifts in the evening N-acetyltransferase rise, which is thought to represent phase-shifts of the evening oscillator controlling the rise. 5. As the PRC showing shifts of the boundary between N-acetyltransferase re-inducibility and non-inducibility after light pulses and the PRC showing shifts of the morning N-acetyltransferase decline are the same, they may be both manifestations of phase-shifts of the morning oscillator. The boundary may indicate a certain phase of the morning oscillator, in which the oscillator begins to be sensitive to light and can be phase-advanced to a phase when N-acetyltransferase activity is low. N-acetyltransferase inducibility at night might thus be solely a function of the phase of the morning oscillator at the time of light pulse presentation.

Two-oscillator structure of the pacemaker controlling the circadian rhythm of N-acetyltransferase in the rat pineal gland

1. The organization of the pacemaker driving the circadian rhythm of N-acetyltransferase activity in the rat pineal gland was studied by observing changes of the rhythm caused by 1 min light pulses applied at night. These pulses proved to be effective phase-shifting signals. 2. After 1 min light pulses applied in the first half of the night. N-acetyltransferase activity began to increase anew following a lag period, as if the evening rise in N-acetyltransferase were phase-delayed. After 1 min light pulses applied past midnight, N-acetyltransferase activity declined rapidly and did not increase to the high night value through the rest of night as if the morning decline in N-acetyltransferase were phase-advanced. 3. The phase-response curve (PRC) showing phase-shifts of the evening N-acetyltransferase rise one day after 1 min light pulses had only phase-delays. The PRC showing phase-shifts of the morning N-acetyltransferase decline one day after the pulses had phase-advances as well as phase-delays; however the phase-advances were more pronounced. 4. The data are consistent with a hypothesis of two-oscillator pacemaking system for the N-acetyltransferase rhythm, proposed originally by Pittendrigh and Daan (1976) for the locomotor activity rhythm in nocturnal rodents.