Werner P. Koella

The effect of para-chlorophenylalanine on the sleep of cats

1. 1. In this series of experiments we have shown that depletion of serotonin (5-HT) by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA) in cats is attended by a marked loss of sleep. 2. 2. Cats chronically supplied with electrodes to record the EEG, neck EMG and eye movements were contained and observed around the clock in screened, sound-attenuated rooms for up to 19 days. Their “vigilance profile” consisting of a three-level graph (PS = paradoxical sleep; SS = slow sleep; W = waking) was determined and total W-times, SS-times, and PS-times calculated for every 4 and 24 h periods. 3. 3. PCPA was administered in various doses i.p. A single dose of 200 mg/kg was sufficient to reduce sleep to close to zero level. The minimal sleep level occurred about 3 days after injection. Sleep was back, or close, to control level after about 16 days. With smaller doses, lesser sleep reductions were obtained. 4. 4. PS over total sleep ratio remained constant except for a relative increase of PS in those cases where total sleep approached zero level. 5. 5. 5-Hydroxytryptophan (5-HTP; 30 mg/kg i.p.) given 48 h after PCPA restored slow sleep temporarily to levels above control within 10 min after injection. PS started to occur about 5–6 h after 5-HTP. 6. 6. Biochemical analysis for 5-HT of the brains of cats treated with various doses of PCPA confirmed the observations in rats, mice and rabbits; various brain-stem and cortical areas were found to be markedly depleted of (total) 5-HT. 7. 7. It is suggested that discrepancies in the time course of sleep deprivation and total 5-HT content are due to such additional factors as negative feedback. Also, free 5-HT may show time courses of depletion and restoration different from those of total 5-HT.

Extra-blood-brain-barrier brain structures.

Publisher Summary This chapter discusses three extra blood–brain-barrier brain structures that are the area postrema (a.p.), the subcommissural organ (s.c.o.), and the subfornical organ (s.f.o). It presents anatomical, histo- and bio-chemical, pharmacological, and physiological data on the a.p., the s.c.o., and the s.f.o. The area postrema has many morphological similarities to the intercolumnar tubercle and both regions differ from the rest of the ventricular wall. In these two regions, pericapillary glial processes are not closely apposed to the capillary basement membrane. Connective tissue containing collagen fibrils and fibroblasts is seen around the basement membrane. Outside this connective tissue layer is a second basement membrane with glial cells processes applied to it. The subfornical organ or intercolumnar tubercle described by Putnam has many features suggesting that its cytological arrangement is similar to that of the area postrema, but it has received far less attention. Putnam also suggested that it contains nerve cells in the human and monkey. Akert emphasize the relation of the subfornical organ to the septal region. Three main components of the subfornical organ are recognized: the body, a dorsal stalk, and a ventral stalk. The subcommissural organ lacks sinusoid-like blood vessels, and it has a markedly thickened columnar ependymal epithelium.

New subminiature amplifier-transmitters for telemetering biopotentials

Abstract New circuits are described which allow the construction of small, light-weight, and inexpensive amplifier-transmitter units for telemetry of biopotentials.

The cerebellar acoustic response and its interaction with optic responses.

Abstract Cats are anesthetized with chloralose and the evoked potentials are recorded from the exposed cortex of folia VI and VII of the cerebellum by means of conventional techniques. The electrical responses to auditory stimuli are studied in their basic waveform and in their dependence upon some stimulus parameters such as intensity, rate, and upon the recording site. The acoustic responses are found to be very similar to the optically evoked cerebellar response. A biphasic, positive-negative wave constitutes the “main complex” which may be complicated by superimposed spiky components. The refractory period of the elements involved in the production of the acoustic response is extremely long. With moderate stimuli, rates as slow as 0.5 to 0.2 p/sec are necessary to obtain maximal responses. The positive and negative peaks “migrate” over the lobuli VI and VII indicating asynchronous arrival of the volleys in the cerebellar cortex. Acoustic and optic responses are analyzed in their patterns of interaction. Enhancement occurs if the two afferent volleys arrive simultaneously in the cerebellar cortex. Of two heteromodal volleys arriving in the cerebellum asynchronously ( i.e. , at delays of from 20 up to several hundred msec) the second volley to appear is greatly reduced in amplitude. The early components of the responses simulate mutual enhancement as their respective voltages add algebraically. The late components, on the other hand, show marked enhancement, revealing amplitudes which by far exceed the sum of the potentials observed in the controls. These findings are discussed and a number of suggestions are offered with respect to the neuronal organization of projection areas in the cerebellar cortex.

A HUMAN PLASMA FACTOR INDUCING BEHAVIORAL AND ELECTROPHYSIOLOGICAL CHANGES IN ANIMALS: II. CHANGES INDUCED IN ANIMALS *

The historical background and methods of preparation of biologically active plasma and serum protein extracts, including the procedure currently used to prepare the extracts used in our laboratory, have been presented in the previous paper. We wish now to discuss the biological effect produced by these substances in animals. Blood samples were supplied by acutely ill psychotics within three days after hospitalization and before diagnosis has been established or drug therapy begun, or from chronic schizophrenics not on drug therapy. Usually two psychotics and one nonpsychotic subject were bled a t the same time into ion exchange blood packs (Fenwal). After separation of the cells a t the Protein Foundation Laboratories, Jamaica Plain, Mass., simultaneous processing of the three plasmas was performed by the aforementioned techniques. Using the Winter and Flataker rat climbing test‘ estimates of biological activity were made on samples equivalent to 5 ml. of original plasma injected intraperitoneally into 5 rats each unless otherwise stated. Values for the degree of impairment of climbing ability are listed as climbing-time delay CTD in units termed minute-seconds. Statistical significance of the results was evaluated by an analysis of variance. In our initial experiments we examined the effect produced in trained rats by injections of serum and plasma from nonpsychotic subjects and schizophrenic patients (TABLE 1) . Each sample was injected into 3 to 5 rats depending on the amount available. The first experiment with serum showed no elevation in CTD produced by 1-ml. samples from 19 schizophrenic patients over effects produced by equivalent samples from nonpsychotic subjects. The mean change of the CTD value produced by the psychotics’ serum from the nonpsychotics’ serum was -5.0 mine-sec., an effect that is not significant. Repetition of this experiment a t a later date compared effects on rat CTD produced by sera from 13 schizophrenics with an equal number of nonpsychotics’ samples. No consistent differences between the 2 groups were observed. Plasma samples, however, produced effects which clearly differentiated between the two groups. Whole plasma samples were compared under conditions similar to those employed using serum samples. In this series, usually 2 schizophrenics’ and 1 nonpsychotic’s plasma were tested simultaneously. Injections of plasma from schizophrenics increased the climbing time delay scores of the rats more than 100 per cent over the delay produced by the plasma from the non-psychotic persons. This difference is highly significant (p = <0.001). * The work described in this study was supported in part by Grant MY-2967 of the National Institutes of Health, Public Health Service, Bethesda, Md., by the Ford Foundation, New York, N.Y., and by the Scottish Rite Fund for Dementia Praecox Research, through the National Association for Mental Health, New York, N.Y.

Organizational Aspects of Some Subcortical Motor Areas

Publisher Summary This chapter describes the motor effects induced from a number of extracortical cerebral areas in which the organizational pattern deviates from that of the simple point-to-point representations. The results of central nervous stimulation are described according to anatomical subdivisions. The chapter also demonstrates that for a majority of motor effects, functional correlations and interrelations can be traced throughout almost the entire extent of the suprasegmental neuraxis. The cerebellum plays an important role in the motor behavior. Electrical stimulation of some areas of the brain stem yields motor responses, which are characterized by a complex and often a spatially oriented organization rather than by simple movements, which are produced, by the action of a single muscle or muscle group. The chapter describes the motor phenomena elicited from a number of isolated extracortical areas. The similarity between the (basal) cerebellar and the diencephalic motor effects show that these two areas are components of a larger unit that organizes much of the ereismatic activity.

STEREOTYPED BEHAVIOR AND CYCLIC CHANGES IN RESPONSE PRODUCED BY LSD IN GOATS.

Abstract The ambulation of adult female goats was studied in a modified open field test before and after injections of lysergic acid diethylamide (LSD) in doses of 7·5 or 15 μg/kg body weight. Under the influence of LSD, the animals increased their ambulatory activity and developed stereotyped walking patterns, e.g. squares, circles, figure 8s, or ovals. Each pattern was found to be specific for each animal and did not change with subsequent injections. The stereotyped walking patterns further support the view of a stabilizing and, indeed, a rigidifying action of LSD on behavior. With successive injections of LSD at intervals of 24, 48, 72 or 96 hours, the reaction to the drug fluctuated rhythmically. The cyclical pattern consisted of periods during which the drug sensitivity gradually declined and then abruptly rose to the original level. The pattern of tolerance and loss of tolerance which accompanies repeated doses of LSD suggests mobilization and periodic breakdown of an endogenous anti-LSD mechanism.

Discussion of insomnia and decrease of cerebral 5-hydroxytryptamine after destruction of the raphe system in the cat.

Publisher Summary Experimental studies show that particular structures of the brain are necessary for normal sleep and consequently, that these structures are at least part of a sleep-controlling apparatus. 5-HT is involved in the organization and, possibly, the control of sleep, particularly of slow sleep. Methysergide, a 5-HT-blocking agent, which is frequently employed as a preventive agent for migraine, produces insomnia in a number of subjects. Cats pretreated with 0.6 mg/kg of reserpine exhibit a reduction in slow sleep for about 2 days and loss of the tonic components of paradoxical sleep for up to 4 days. Treatment with p -chlorophenylalanine drastically reduces slow as well as paradoxical sleep in cats. It takes as long as 7–8 days before the animals are recovered from the effect of this compound, which markedly depletes brain 5-HT and to a much lesser extent, catecholamines, by inhibition of the hydroxylase. Small amounts of 5-HT (threshold doses about 0.2 μg/kg) injected into the carotid artery of cats leads to initial transient depression, followed by protracted enhancement of the recruiting response for as long as 20 minutes. 5-HT also produces initial desynchronization of the spontaneous electrocorticogram followed by prolonged hypersynchrony with high voltage slow waves and appearance of, or increase in, sleep spindles.

Studies of Plasma Protein Factors that may be Involved in Psychoses

During the last five years work has been reported from four independent groups indicating the existence of a protein factor in human plasma that may be involved in psychotic behavior. In contrast to many investigations, these studies refreshingly tend to confirm each other.

Effect of Head X-Irradiation on the Uptake of Radiophosphorus by Rat Brains.

Conclusions Whole head irradiation in rats with 20 Krad increases P32 uptake by the brain. These findings confirm the results of Stajic et aL(8), and strongly suggest that ionizing radiation enhances the permeability of the BBB to phosphate. By introducing the time parameter in our study, we also were able to approximate the time of onset of the permeability change. It begins after a delay of at least 24 hours after exposure to irradiation. This delay time explains the negative findings of Florsheim et al(S), who could not have detected the delayed effect because of the temporal arrangement of their experiments. It now must be determined if ionizing radiation of the whole brain or its parts increases the permeability to other molecules, particularly to biogenic amines, and whether whole head irradiation affects the permeability of the brain in toto or whether there are loci of predilection in their reaction to X-ray treatment.