John R. Bergen

Suppression of LSD-25 Effects in Rats by Steroids.∗

Summary A series of 15 steroid hormones and metabolites were tested for their effectiveness to suppress LSD-25 induced behavior changes in rats. All produced significant suppression (p<0.05) except estradiol. Ability to suppress LSD-25 action does not appear to be related to specific molecular groups or to hormonal potency.

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.

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.

The isolation of cortisol and Δ4-pregnene-11β, 17α, 20β, 21-tetrol-3-one from urine of cortisone acetate-treated rats

Abstract 1. 1. A total of 1260 mg. of cortisone acetate was administered interperitoneally to nine rats. 2. 2. From the urine of the cortisone-treated rats, 29.4 mg. of BT-reducing substances was isolated, and 1.6 mg. was isolated from a comparable control group. 3. 3. Two metabolites, cortisol and Δ 4 -pregnene-11β, 17α, 20β, 21-tetrol-3-one, were identified.

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.

Inhibitory effects of steroids on LSD-25 action in man☆

Abstract Studies investigating the efficacy of two steroids in altering the effects of LSD-25 on psychological behavior in humans are presented. Results obtained by the experimental assessment of behavioral change in basic sensori-motor, perceptual and conceptual processes indicate some evidence of an inhibitory effect of the steroids on the degree of behavioral change ordinarily induced by LSD-25 in certain behaviors; however, results obtained from subjective reports fail to indicate inhibition of the LSD-25 effect. These results are shown as similar to results obtained in a previous study of the influence of progesterone in altering LSD-25 effects in man, and in contrast to results of recently reported studies in which the attenuation or potentiation of the LSD-25 experience by pretreatment with a monoamine oxidase inhibitor or amine releaser, respectively, was manifested both subjectively and as objectively measured in the same experimental situations as utilized in the steroid studies. The possible role of acute as compared to chronic administration is discussed in relation to this disparity in results.

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.

Action of steroids on lysergic acid diethylamide (LSD) metabolism.

Summary A method is described which permits the biotransformation of LSD by a rat liver homogenate fraction. The rate of biotransformation is reduced significantly by steroids at concentrations as low as 10-7 M. The view is expressed that steroids block the action and metabolism of LSD by interfering with the LSD-receptor relationship in the cell.

Organic Approaches to Schizophrenia

Great strides have been made in many areas of science in recent decades but progress in the behavioral sciences has been slow by comparison. The mechanisms involved in the normal operations of the brain are not yet understood and, as a consequence, few facts to explain the function of the abnormal mind have been established. The relative neglect of research in neuropsychiatry cannot be due to the unimportance of the problem because the problem is very great. Perhaps the apparent disinclination to investigate mental disease is related to the special problems inherent in psychiatric research. Advances in medical research have generally resulted from experimentation on animals. While animal studies have shed valuable light on some behavioral problems, this approach has limited applications to man because humans possess the ability to develop unique problems within the systems governing behavior, e.g. neuroses and psychoses. Aberrations in behavior can be induced experimentally but it is highly questionable if they correspond to the states seen in the mentally ill.