Pharmacological Implications of Circadian Rhythms

PHARMACOLOGICAL IMPLICATIONS OF CIRCADIAN RHYTHMS Circadian patterns for rectal temperature and biogenic amine levels in the midbrain and caudate nucleus were established in rodents maintained under stable laboratory conditions for at least three weeks on an automatically-timed light program in which the light phase lasted from 0800 to 2000 hours daily. Levels of norepinephrine (NE), histamine (H) and acetylcholine (ACh) in the rat were maximal during the dark phase of the illumination cycle coinciding with maxima for rectal temperature and motor activity and were minimal during the light phase when these nocturnal animals are quiescent. The circadian pattern for serotonin (5-HT) is twelve hours out of phase with the other parameters measured. Bilateral adrenalectomy did not alter these patterns qualitatively, although quantitative changes were observed, ~· ~·, peak rectal temperature was significantly lowered. Pentobarbital sodium reversed the rectal temperature pattern significantly. Minima occurred during the dark phase of the illumination cycle. Significant increases in NE maxima in midbrain and caudate nucleus and in caudate nucleus H were observed after pentobarbital sodium. The 5-HT pattern however was depressed. The onset and duration of sleep induced by pentobarbital sodium exhibited a circadian pattern. Onset time v was significantly longer and duration significantly shorter during the dark phase coinciding with ACh, NE, H, rectal temperature and motor activity maxima. Peak blood H levels were noted at the end of the light phase and the circadian patterns were unaltered by pentobarbital sodium. Blood glucose patterns were bimodal in nature. A primary peak occurred at the end of the dark phase toward the end of the normal feeding period, while a secondary peak occurred at the end of the light phase. These patterns were unaltered by pentobarbital sodium. Norepinephrine levels in rat hypothalamus were sigq.ificantly higher at 0300 hours than at 1500 hours, reflecting similar changes observed in midbrain and . caudate nucleus. Significant reductions and elevations were obtained by pretreatment with reserpine or dl-OOPA and pargyline (an MAO inhibitor), respectively. An examination of the ultrastructure of the hypothalamus and caudate nucleus showed that circadian changes were demonstrable when synaptic vesicles in tissue removed at 0300 and 1500 hours were counted. The number of granular vesicles (presumably containing NE) were significantly higher at 0300 hours in the anterior hypothalamus and caudate nucleus, but not in the posterior hypothalamus. The number of agranular vesicles (presumably containing ACh) was higher at 0300 hours, but only in vi the posterior hypothalamus was this increase statistically significant. Granular vesicle counts from tissues of rats pretreated with reserpine or dl-DOPA and pargyline were similar to those of the control study in that they were higher at 0300 hours than at 1500 hours. A more variable pattern was obtained with the agranular vesicle counts. The most significant finding was the greater number at 1500 hours in the tissues from reserpinized animals. A similar finding was obtained in the anterior hypothalamus after dl-DOPA and pargyline administration. Circadian patterns for the toxicity of cholinergic compounds were demonstrated in mice. LD50's for ACh, pilocarpine and oxotremorine were minimal (greatest toxicity) during the dark phase of the illumination cycle. The circadian pattern for atropine toxicity was essentially a mirror image with maximum toxicity (minimal LD50) during the light phase. A quaternary anticholinesterase, neostigmine, is most toxic during the late dark phase, while a tertiary anticholinesterase, physostigmine, was least toxic at that time and became progressively more toxic during the late light and early dark phase of the illumination cycle. Atropine methyl nitrate decreased toxicity of acetylcholine and physostigmine but the circadian pattern was essentially unchanged. An ultradian toxicity pattern having two peaks, one at midday, the second at midnight, was obtained with· carbachol. vii