Tsutomu Hiroshige

Activity rhythms in the circadian domain appear in suprachiasmatic nuclei lesioned rats given methamphetamine

Female rats were lesioned in the suprachiasmatic nuclei (SCN) electrolytically and treated with methamphetamine. The SCN lesions abolished the circadian locomotor rhythm completely. When methamphetamine was administered in the drinking water, robust rhythmicities in locomotor activity appeared in the SCN lesioned rats, which did not entrain to the 24 hr light cycle. The period of the activity rhythm was dose-dependent; the lower the concentration of methamphetamine was, the shorter the period of the rhythm became. When rats were treated with 0.005% methamphetamine, the mean period was 26.4 hours. In addition, activity time (alpha) became shorter, rest time (rho) longer and alpha/rho ratio lower, when methamphetamine concentration was decreased. After methamphetamine withdrawal, the rhythmicity disappeared and locomotor activity became aperiodic again. When methamphetamine was administered continuously by means of an osmotic minipump, similar rhythmicities appeared in locomotor activity of the SCN lesioned rats. It is concluded that methamphetamine manifests an activity rhythm whose period is in the circadian range. The rhythmicity is independent of the SCN and is not entrained by the light-dark cycle.

Disorganization of the rat activity rhythm by chronic treatment with methamphetamine

Remarkable changes in the circadian activity rhythm of rats were observed when they were chronically treated with methamphetamine dissolved in drinking water. The circadian rhythm was phase-delayed with respect to the light-dark (LD) cycle, and showed signs of relative coordination. In some rats, the circadian organization was disturbed and two activity components appeared, with one component free-running and the other entrained by the LD cycle. After methamphetamine withdrawal, these changes disappeared rapidly but there were transient periods of 2-3 days before establishment of a stable entrainment to the LD cycle. The changes in the circadian rhythm persisted even in constant darkness (DD). The period around 24 hr in DD was significantly shorter during methamphetamine treatment than after the drug withdrawal. These results indicate that neither alteration of the sensitivity to light nor lengthening of the intrinsic period is involved in the methamphetamine induced disorganization of the circadian rhythm. Possible mechanisms are discussed in terms of a multi-oscillatory system.

Effects of parachlorophenylalanine and 5, 6-dihydroxytryptamine on the free-running rhythms of locomotor activity and plasma corticosterone in the rat exposed to continuous light.

Parachlorophenylalanine (PCPA) and 5,6-dihydroxytryptamine (5,6-DHT), depletors of brain serotonin, were administered to the rat and circadian rhythms of locomotor activity and plasma corticosterone were determined simultaneously in individual rats in light-dark cycles (LD) and in 200 lux continuous light (LL). Free-running periods and acrophases on the 12th day in LL (LL12) were calculated by a least squares spectrum method. In PCPA-treated rats which showed 70% depletion of brain serotonin, circadian rhythms of locomotor activity in LL and of plasma corticosterone and ACTH in LD disappeared for several days after the drug injection. Circadian rhythms of locomotor activity reappeared after the LL7 day and free-ran with a phase shift. Free-running periods of these rats did not differ significantly from that of control rats. However, the acrophase of PCPA-treated group on the LL11 day was 5 h advanced as compared to that of control. Circadian rhythm of plasma corticosterone in the PCPA-treated rats was detected on the LL12 day but their peak times were distributed around 24:00 h instead 08:00 h observed rats. The 5,6-DHT-treated rats which showed only 40% depletion of brain serotonin exhibited normal free-running rhythms in both locomotor activity and plasma corticosterone in LL and no difference in the acrophases of these functions on the LL12 day as compared to controls. These results suggest that PCPA affects the circadian clock (or clocks) itself in such a way that it blocks the clock to free-run or at least it effectively shortens the free-running periods of locomotor activity and plasma corticosterone in the rat.

Rhythms in behaviors, body temperature and plasma corticosterone in SCN lesioned rats given methamphetamine

In aperiodic rats with lesions in the suprachiasmatic nuclei (SCN), rhythms with a circadian period in spontaneous locomotion, wheel-running, feeding, drinking, body temperature and plasma corticosterone were restored by chronic administration of methamphetamine. These rhythms were not entrained by a light-dark cycle. Wheel-running, feeding and drinking rhythms in individual rats were in phase in terms of ultradian bout as well as circadian fluctuation. Rhythms of the intraperitoneal temperature appeared accompanying the spontaneous locomotor rhythm. The phase relation between the two rhythms was similar to that of SCN dependent rhythms. Plasma corticosterone also fluctuated in a circadian fashion. The corticosterone peak preceded the activity onset of locomotor rhythm by a few hours, which was similar to the phase relation observed in the SCN intact animals. It is concluded that the oscillatory mechanism underlying the spontaneous locomotor rhythm in SCN lesioned and methamphetamine treated rats drives also other physiological rhythms. The phase-relations among them were similar to those of rhythms driven by the circadian pacemaker in the SCN.

Circadian Rhythm of Corticotropin-Releasing Activity in the Hypothalamus of Normal and Adrenalectomized Rats

Circadian periodicity of the hypothalamic content of corticotropin-releasing factor (CRF) was determined in normal and adrenalectomized male rats, using the intrapituitary micro-injection method. It was found that the CRF activity in the rat hypothalamus showed a definite circadian variation, having the peak value at 6 p.m. and the minimum at 8 a.m. under the lighting schedule used here (light between 6 a.m. and 7 p.m. followed by 11 h of darkness). A close temporal relationship with a definite phase shift was observed between the CRF activity and plasma corticosterone level. The finding thus supports the concept that the circadian rhythm of the pituitary-adrenal axis is a direct reflection of the rhythmicity of CRF activity in the median eminence. Furthermore, the persistent periodicity observed in the CRF activity in the absence of circulating corticosterone suggests that the dominating mechanism for the control of the circadian rhythm of CRF activity is of neural origin, being independent of the negative feedback mechanism.

The ventromedial hypothalamic nucleus is not essential for the prefeeding corticosterone peak in rats under restricted daily feeding

The role of the ventromedial hypothalamic nucleus (VMH) in the generation of the prefeeding corticosterone peak was examined in rats under restricted daily feeding, under which daily meal supply was restricted to a fixed time in the early light period. Rats were lesioned in the VMH bilaterally and subjected to restricted daily feeding during two different post-operative phases and with two different durations of food presentation. A restricted feeding with free access to meal for 4 hr was imposed on the VMH-lesioned rats from 2 to 4 weeks after the lesion, when the daily food intake increased significantly (dynamic phase). The restricted feeding induced the prefeeding hormone peak in sham operated rats, but failed to develop it in the VMH-lesioned rats. On the other hand, the hormone peak appeared in the VMH-lesioned rats subjected to the feeding schedule from 8 to 10 weeks after the lesion, when the daily food intake was not different from the control (static phase). Moreover, the VMH-lesioned rats showed the hormone peak even in the dynamic phase when the access to meal was shortened to 1 hr. These results indicate that the VMH is not essential for the generation of the prefeeding corticosterone peak under restricted daily feeding, and suggest that a special metabolic state observed during the dynamic phase of VMH lesion prevents the development of the feeding-associated oscillation or its expression upon plasma corticosterone level.

Changes in Plasma Corticosterone and Hypothalamic CRF Levels Following Intraventricular Injection or Drug-induced Changes of Brain Biogenic Amines in the Rat

In order to study the role of brain biogenicamines in the regulation of ACTH secretion under basal and stress conditions, we examined changes in plasma corticosterone and hypothalamic CRF levels in ma

Sex Difference in Circadian Periodicity of CRF Activity in the Rat Hypothalamus

Sex difference in the circadian periodicity of thehypothalamic content of corticotropin-releasing factor (CRF) was examined in the rat. The CRF content in the female hypothalamus was higher in the mor

Methamphetamine induced locomotor rhythm entrains to restricted daily feeding in SCN lesioned rats

Rats were lesioned in the SCN and treated with methamphetamine dissolved in drinking water. A robust rhythm appeared in spontaneous locomotor activity which was not affected by blinding. Periodic food restriction (RF) of a 24 hr period was imposed on SCN lesioned rats with free-access to food for 4 or 6 hr per day, while water was given ad lib. The locomotor rhythm induced by methamphetamine treatment was phase-set by RF immediately in most cases but with transients in some. The phase-angle difference (psi) between food presentation and the activity onset became more negative by increasing the dose of methamphetamine. Because there was a positive correlation between methamphetamine dose and the period of locomotor rhythm, the change in psi was most likely due to lengthening of the period. After the termination of the RF schedule, the locomotor rhythm started to free-run from the prior phase set by RF. These results indicate that the methamphetamine dependent locomotor rhythm entrains to RF.

Methamphetamine effects on rat circadian clock depend on actograph

Methamphetamine effects on the rest-activity rhythm were examined in 12 blinded rats using two different actographs, an Animex and a running-wheel. D-Methamphetamine was administered chronically by dissolving it in drinking water. During methamphetamine treatment, the rest-activity rhythm measured by an Animex showed a clear sign of relative coordination in addition to the general enhancement of activity level. Analyses of pre- and posttreatment activity rhythms revealed that neither the phase nor the period was affected by methamphetamine treatment. On the other hand, the circadian period was lengthened by methamphetamine treatment when locomotor activity was measured by a running-wheel. These results confirmed our previous findings that the chronic treatment of methamphetamine modified the expression of the circadian rhythms but did not affect the underlying oscillation when measured by an Animex, and further indicated that methamphetamine could affect the underlying oscillation when rats had free access to a running-wheel. It is concluded that the effects of methamphetamine on the circadian clock depend on actograph.