Mark J. Perlow

Calcitonin reduces feeding in man, monkey and rat

It is proposed that calcitonin is a hormonal mediator of the satiety reflex. To test this hypothesis, effects of calcitonin on feeding and drinking were measured in rats and in rhesus monkeys. In monkeys, calcitonin produced severe (90%) and prolonged (3-5 days) reduction in feeding, and smaller decreases in drinking. In rats calcitonin decreased feeding in a dose-related manner over 24 hours, but increased drinking and urine output. A modest loss in body weight (2%) was also observed in psychiatric patients given calcitonin. It is suggested that calcitonin reduces feeding either through its effects on calcium metabolism, or by a direct action on the central nervous system.

Photic regulation of the melatonin rhythm: monkey and man are not the same

Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Program, National Institute Mental Health, Saint Elizabeths Hospital, Washington D.C. 20032 and (S.M.R., L.T. and D.C.K.) Section of Neuroendocrinology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md. 20014 (U.S.A.)

The circadian variation of catecholamine metabolism in the subhuman primate.

Cerebrospinal fluid (CSF) was removed continuously in 2- or 3-h aliquots from the lateral and fourth cerebral ventricles of chronic chair restrained rhesus monkeys. Under conditions of 12 h light (06.00-18.00 h) and 12 h darkness (18.00-06.00 h) the concentrations of norepinephrine (NE) were found to describe a circadian pattern, with maximal concentrations occurring during the light hours and minimal concentrations occurring during the dark hours. The patterns were generally coincident with the circadian patterns of brain temperature and body activity. When assayed for 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA), samples of CSF collected over 3-4 days demonstrated no reproducible pattern of change. Fluctuation in the concentration of MHPG did not correspond in direction or magnitude to changes in the concentration of VMA. These random fluctuations may in part be accounted for by the influx of the metabolites from peripheral sources to the brain and CSF, and by the relatively slow movement of these metabolites as they diffuse from brain parenchyma to the CSF.

The circadian variation in dopamine metabolism in the subhuman primate

DOPAMINE (DAI containing neuronal systems in the CNS of man now appear to contribute to the regulation of extrapyramidal motor function (POIRER rr ul.. 1975: KLAWANS er ul.. 1976) as well as of affective state (SNYDER er ul.. 1974: GOODWIN er ul.. 1975). There is also some evidence to suggest that central catecholaminergic pathways participate in the control of such rhythmic phenomena as body temperature (HELLON. 1975). sleep-walking cycles (JOUVET. 1972). and the release of certain anterior pituitary hormones (COPPOLA. 1971; VAN LOON. 1973). These latter observations prompted this attempt to measure circadian fluctuations in cerebral DA metabolism in the primate. Male rhesus monkeys (MUCQCQ I?1&rru). weighing 5 4 . 5 kg were adapted to a primate restraining chair in a well brntilated sound-attenuated chamber in which lights were kept on from 0600 to 1800h and turned o f f from 1800 to 0600 h. Under ketamine hydrochloride (Parke Davis. Detroit. MI) and sodium pentobarbital (Abbott. N. Chicago. IL) anesthesia. cannula were implanted stereotaxically into the right lateral or 4th cerebral ventricles. The cannulae were secured to the skull with stainless steel screws and dental cement. Polyethylene tubing connected to the ventricular cannulae. passed through a small hole in the roof of the chamber to the pumping and collection apparatus. Ventricular fluid was withdrawn continuously 10.4 ml: h) from the cannula and collected in 2 h aliquots. Cerebrospinal fluid remained at room temperature in the collecting tubing for approx 1 h until i t could be refrigerated (4 C). Fractions from each 14-h period were collected in the morning and frozen (-20 C) until assaysed by the gas chromatographic-mass spectroscopy for homovanillic acid (3-methoxy-4-hydroxy-phenyl-acetic acid. HVA) ~GORDOX er ul.. 1974). the principal metabolite of DA in primates (GORDON er ul.. 1975. 1976). Data for this study was obtained from analysis of lateral ventricular fluid samples for 3 contiguous 24-h periods on 4 animals. and rrom fourth ventricular fluid samples for 3 contiguous 24-h periods on one animal. Although HVA concentrations are lower in the fourth. than in the lateral ventricle (GORDON vr ul.. 1075). the pattern of HVA concentration in both \entricks was essentially the same: results obtained from all animals were thus analyzed together. and plotted to compensate for dead space in the collection system. When analyzed as to variation about a daily mean, a graph of HVA concentration describes a circadian pattern as illustrated in Fig. I . A two factor analysis of variance with repeated measures was performed. Individual monkels comprised the non-repeated factor and time of day

Origins of catecholamine metabolites in monkey cerebrospinal fluid.

THE CONCENTRATION of HVA present in CSF drawn from the lateral ventricles of experimental animals and man is much higher than that present in fluid drawn from the lumbar subarachnoid space (GULDBERG et al., 1966; GORDON & OLIVER, 1971; CHASE et al., 1973). Since the HVA found in lumbar CSF has been shown to come from the brain rather than from the spinal cord, (CURZON et al., 1971; POST et a[., 1973; YOUNG et a/., 1973), the concentration of lumbar HVA can be considered the result of this metabolite entering the CSF from the periventricular brain structures less the amount removed by a probenecid-sensitive active transport system during passage of the fluid from the cerebral ventricles to the lumbar subarachnoid space. In contrast to HVA (GORDON & OLIVER, 1971; CHASE et al., 1973) MHPG is present in lateral ventricular and lumbar CSF of man in roughly equal concentrations. In rat brain where MHPG exists primarily as the acidic sulfate conjugate it, like other organic acids, will accumulate in response to probenecid administration (MEEK & NEFF, 1972). The majority of MHPG in human CSF is present as the free, neutral compound (GORDON & OLIVER, 1971; GORDON rt al., 1973; WILK et al., 1971; BERTILLSON, 1973) and little if any elevation in total MHPG is seen in lumbar CSF following probenecid treatment in man (GORDON et al., 1973). The recent development of a sensitive gas chromatography-mass fragrnentography technique for the simultaneous determination of HVA, MHPG and VMA (GORM)N et a/., 1974) in the same sample of CSF, has made possible comparison of the levels of these metabolites in the small vol of CSF that can be obtained from the lateral, third and fourth ventricles and lumbar subarachnoid space of monkeys.

Daily Rhythms in Cortisol and Melatonin in Primate Cerebrospinal Fluid

Cerebrospinal fluid was continuously collected from the cisternal-cervical subarachnoid space of chair-restrained rhesus monkeys. The concentrations of melatonin and cortisol were measured in the cerebrospinal fluid. Under diurnal lighting (light:dark, 12:12 h) melatonin concentrations were elevated during darkness and low during illumination. The melatonin rhythm persisted in constant darkness but was suppressed in constant illumination. Under diurnal lighting, cortisol concentrations were elevated in the early portion of the light period. This daily rhythmicicty of cortisol secretion was not altered by constant illumination or constant darkness. The differential response of the two hormones to constant light suggest that the daily fluctuation of melatonin secretion was not responsible for the daily rhythmicity of cortisol secretion in the rhesus monkey.

The effects of environmental lighting on the daily melatonin rhythm in primate cerebrospinal fluid

The effects of alterations in environmental lighting on the daily rhythm in cerebrospinal fluid concentrations of melatonin were studied in the rhesus monkey. It was found that acute exposure to darkness during the day did not markedly increase normally low daytime CSF melatonin levels, that light suppressed the normally high CSF melatonin values at night, and that 12-h phase shifts in the diurnal lighting cycle caused 12-h phase shifts in the rhythm. The daily rhythm persisted for 6.5 days of study in constant darkness and the phase of the rhythm was not affected in constant darkness by a 12-h phase shift in the daily delivery of food and daily care of the animals. These results support the notion that the melatonin rhythm in this primate species is endogenous in nature, and that light can act to both coordinate the rhythm to the 24-h day and to acutely suppress melatonin production.

Cerebrospinal fluid gamma-aminobutyric acid: daily pattern and response to haloperidol.

UKDER normal circumstances, animal behavior fluctuates widely over the 24-h day. These variations are correlated with each other and with physiological and biochemical changes in the CNS as recently demonstrated by the reported circadian fluctuation in dopamine (DA) (PERLOW et al., 1977~). and norepinephrine (NE) metabolism ( P E R LOW et al., 1978) in the rhesus monkey brain. These findings suggest that increased catecholamine turnover is associated with wakefulness, incrcased body temperature, increased body activity, and the release of certain anterior pituitary hormones. Since there appears to be a relationship between gamma-amino butyric acid (GABA) and DA metabolism, (CATTABENI et a[., 1977: COLLINS, 1973; HORNYKlhWlCZ et a[., 1976; KIM & HASSLER, 1975; MAO et al., 1977; MCGEER & MCGEER, 1976: REUBI et al.. 1977; LAIITI & LOSEY, 1974; ANDEN, 1974), it is of interest to determine whcther a circadian variation can be observed for this amino acid transmitter candidate. To examine this, GABA was measured in the CSF of rhesus monkeys over the 24-h day and following acute treatment with haloperidol. In contrast to neural tissue, where GABA metabolism is rapid (ALDERMAK & SHELLERBERGER, 1974; BALCOM et a[., 1975; ELLIOTT & FLOREY, 1956; KNIER[F:N et al., 1977; RICHARDSON & SCUDDER, 1976), CSF GABA appears to be stable a t room temperature (22°C) for at least 24 h (Enna, unpublished data). Since little or no GABA in the brain or in the CSF comes from peripheral sources (TOWER, 1960; ROBERTS & KIJRIYAMA, 1968; VAN GELDEN & ELLIOTT, 1958), it was hoped that, like DA and NE, GABA in the CSF might reflect some aspect of GABA release from neurons close to brain surfaces (BURYAKOVA & SYTINSKY, 1975; DEFEUDIS & MITCHELL, 1970: TVERSEN et a[., 1971; OBATA & TAKEDA, 1969). This later consideration was strengthened by recent studies indicating that in Huntingtons Disease, the reduction in brain GABA and GABA synthetic enzymes, is accompanied by a reduction in GABA conccntration in the CSF (BIRD et al., 1973; ENNA et al., 1 9 7 7 ~ ; GLAESER et al., 1975: MCGEER et al., 1973; PERRY et al., 1973). Adult male rhesus monkeys (Macaca mulatta, 5.5-6.5 kg) were adapted to chronic restraint in primate chairs in a sound-attenuated chamber with the lights on from 0600 to 1800 h, and off from 1800 to 0600 h. I n four animals, cannula were stereotaxically implanted into the right lateral cerebral ventricle as previously described (PERLOW er a/., 1977~). In five additional animals, a polyethylene tube was inserted, pcrcutaneously, bctween lumbar vertebra into the subarachnoid space. The catheter was

Cerebrospinal Fluid Melatonin

The history of melatonin starts in 1917, with the discovery that mammalian pineal gland extracts have the ability to lighten amphibian skin.14 About 40 years later, the skin-lightening constituent of the pineal gland, melatonin, was isolated and chemically identified as N-acetyl-5-methoxytryptamine by Lerner et al. 13

The effect of intravenous growth hormone infusion on cerebrospinal fluid somatostatin levels in the rhesus monkey

CSF was continuously withdrawn over 13 days from the cervical subarachnoid space of two rhesus monkeys during the intravenous infusion of saline or human growth hormone (GH) and samples collected during sequential 2 h periods were assayed for somatostatin (SRIF). SRIF-like immunoreactivity (SRIF-LI) concentrations were decreased during GH infusion as compared to saline infusion (P less than 0.005) and the maximal effect occurred during the hours of darkness (18.00-06.00 h). Since in vivo GH administration stimulates hypothalamic SRIF-LI release, CSF SRIF-LI does not appear to be derived primarily from the hypothalamus but rather from extrahypothalamic brain by a mechanism inhibited by GH.