The effects of some psychotropic drugs on conditioned avoidance and aggressive behaviors

Summary Chlorpromazine, chlordiazepoxide, meprobamate, and pentobarbital were evaluated for their ability to alter 3 behaviors: 1. unconditioned escape, 2. conditioned avoidance, and 3. isolation-induced aggression, in the same species of mouse. A comparison of the dose of each drug necessary to alter these behaviors revealed quantitative differences between the drugs by which chlorpromazine and chlordiazepoxide may be differentiated from each other as well as from pentobarbital and meprobamate.Supported by a research grant from the National Institute of Mental Health (MH-07397-02), U.S. Public Health Service.Portion of a thesis presented by Henry F. Cole in partial fulfillment of the requirements for the Master of Science Degree at The Ohio State University.Predoctoral Fellow 1964–65, National Institutes of Health, U.S. Public Health Service.     

Temporary and partial antagonism by l-DOPA of reserpine-induced suppression of a conditioned avoidance response

Summary Mice and rats were trained to avoid shock in a modified shuttle box. Following training the animals were treated with reserpine. The suppression of the conditioned avoidance response induced by reserpine was partially and temporarily reversed by an injection of l-3,4-dihydroxyphenylalanine, and the suppression of locomotor activity was completely antagonized for approximately the same duration.This investigation supported in part by Postdoctoral Fellowship (MPD-10, 562-C3) from the United States Public Health Service, National Institute of Mental Health.The authors wish to thank Miss Anne-Charlotte Lilljeqvist for her expert technical assistance.     

Counterconditioning and extinction of fear fail to transfer from amobarbital to nondrug state

Summary Three dosages of amobarbital sodium all aided albino rats to resume a previously punished lever-pressing response. This finding was obtained in a test of counterconditioning and extinction of fear-motivated avoidance, with 108 animals divided into groups which were given placebo or one of three dosages of amobarbital (10, 20, or 30 mg/kg). In a subsequent test for transfer of counterconditioning and extinction to the nondrug state, with placebo given to all the animals, the superior performance under the drug failed to transfer to the nondrug state. On the contrary, there was the suggestion of an inverse relationship between performance in the test for transfer to the nondrug state and drug dosage during the prior test for effect of amobarbital. This experiment demonstrates that the stimulus-change decrement produced by a shift from the drugged to the nondrug state may prevent the therapeutic retraining under the drug from transferring to the nondrug state.Research grants from the National Institute of Mental Health, U.S. Public Health Service supported this research (MY 2949) and the preparation of the article (MH 07824). Some of the replications were tested by Phyllis Miller and by Roberta Pritzker. A brief report of part of the findings was included in Miller 1961 and 1964.     

Some observations on the interaction of chlorpromazine and free operant avoidance bursts

Summary Rate of avoidance responding underSidman schedules is normally decreased as a function of increasing doses of chlorpromazine. This change is accompanied by a correlated increase in the shock rate as a function of dose. In a subject displaying a strong pattern of post-shock bursts, the usual effect of chlorpromazine dosage on the shock rate was obtained, but the response rate wasincreased correlatively by doses of less than 1.0 mg./kg., i.m. This resulted from the differential effects of the drug upon avoidance responses and post-shock bursts. Experimental manipulation of the baseline avoidance behavior in this subject through the addition of a schedule providing for punishment of responses occurring in bursts immediately following shocks was successful in eliminating bursts of more than one or two responses. A second chlorpromazine series obtained under this added punishment contingency then yielded a typical dose-effect relation for both response and shock rates under chlorpromazine. The possibility that other apparently “idiosyncratic” dose-response functions in behavioral pharmacology may be due to similar special cases of drug-behavior interaction is discussed. This investigation was supported by Grants MY-2244 and MY-5863 from the National Institutes of Mental Health, U.S. Public Health Service. The writers gratefully acknowledge the continued encouragement and support ofMilton H.Anderson, M. D., Medical Superintendent, Evansville State Hospital and principal investigator, Grant MY-2244. Chlorpromazine was kindly supplied by Smith, Kline and French Laboratories, Inc., Philadelphia, Pa.     

Chronic reduction of cholinesterase and the extinction of an operant response

Summary The extinction of an operant response was studied in rats in which cholinesterase activity was chronically inhibited to 30% of normal values. Resistance to extinction was related to the duration that cholinesterase had been reduced. The total number of extinction responses was less than for controls after 0 and 9 days and more after 18 and 36 days of reduced cholinesterase.This investigation was supported by U. S. Public Health Service Grant NB 04427 from the National Institute of Neurological Diseases and Blindness.     

Brain and heart catecholamine levels after l-Dopa administration in reserpine treated mice: Correlations with a conditioned avoidance response

Summary Mice were tested with reserpine before receiving an injection of l-DOPA. At various times after the l-DOPA injection they were sacrificed and the brains and hearts were analyzed for their catecholamine content. Effects on the conditioned avoidance response were further analyzed using reserpine and l-DOPA, and the correlations between the two were discussed.United States Public Health Service Postdoctoral Fellow (MPD-10, 562-C 3), National Institute of Mental Health.This research was supported by the United States Air Force under Grant No. AF-EOAR 63-14 and monitored by the European Office, Office of Aerospace Research (to A. Carlsson).     

Some effects of scopolamine on a passive avoidance response in rats

Summary Results are reported for the effects of scopolamine and methscopolamine on a passive avoidance response in rats. Scopolamine in adequate doses severely disrupted both the acquisition and the retention of this response. Since methscopolamine was without effect, it was concluded that the site of action is in the central nervous system.It was found that the retention deficit cannot be attributed to dissociation and, surprisingly, that rats trained and injected with scopolamine on two consecutive days perform as well as normal controls on the second day. The possibility that this latter effect was due to tolerance found no experimental support.These results seem to suggest that scopolamine can produce response disinhibition. A neuronal hypothesis and a possible site of action for scopolamine were proposed to explain the behavioral data.This work was supported by Research Grant MH 08486-01 from the National Institute of Mental Health, United States Public Health Service. The author gratefully acknowledges the assistance of Allan Krebs who ran some of the animals in Experiments I and II and of Howard Moltz who made many helpful suggestions regarding a draft of this paper.     

The effect of amobarbital sodium on conditioned fear as measured by the potentiated startle response in rats

Summary The startle response in rats to a sudden sound was increased when the startle was elicited in the presence of a flashing light (CS) which had previously been paired with electric shock. The magnitude of this potentiated startle was used as a measure of the conditioned fear elicited by the CS.The effects of different doses of amobarbital sodium on the potentiated startle, the startle in the presence of a flashing light which had not been paired with shock, and the startle to electric shock were tested. It was found that the drug reduced the magnitude of the potentiated startle response and reduced even more the startle to electric shock, but apparently had little, if any, effect on the startle to loud sound in the presence of a neutral CS. The effects lasted for at least 90 min after i.p. injections of the drug.The action of amobarbital was interpreted in terms of a selective reduction in the strength of the fear drive, but other interpretations were not ruled out.The fact that this drug produced differential effects on startle responses elicited in different ways, suggests that such responses may be useful measures of differential psychopharmacological effects.Work on this study was supported by Grant MY 2949 from the National Institute of Mental Health, United States Public Health Service.The author wishes to thank Dr. N. E. Miller who was consulted on every phase of the research and Dr. J. D. Davis who designed the transducer and suggested the system for recording startle responses.     

The site of uptake of iodine by hair

Summary The uptake of radioactive iodide by the vibrissal hairs of the mouse has been studied using a dry autoradiographic technique.Iodide first appears in the hairshaft just deep to the orifice of the sebaceous gland 0.2 to 0.5 mm below the skin surface. l-cystine-S³⁵ on the other hand is taken up in the deeper parts of the hair root in the region of the site of the dermal papilla. Even with heavy uptakes of both substances little overlap occurs.With 9 Figures in the TextDedicated to Prof. Otto Krayer on his 65th birthday.This investigation was supported by U.S.P.H.S. training grant CRT-5008, from the National Cancer Institute, United States Public Health Service.     

Variation in effects of chlorpromazine in three strains of mice

Summary Mice of strains C3HeB/J, C57BL/6J and RF/J were trained in nondiscriminated avoidance (Sidman type). Experimental subject could terminate or defer shock by crossing between cage components. Controls received shock but could not control it. Chlorpromazine in doses up to 4 g/g body weight had no effect on the activity of controls. Avoidance activity, defined as the excess activity of experimentals, was reduced by the drug, particularly in C57BL. C3H avoided best at all drug levels. The poorest strain at low dosage was RF, at higher dosage, C57BL. The results suggest need for care in the choice of phenotypes in experimental pharmacogenetics.This investigation was supported in part by Public Health Service Grant MH-01775 from the National Institutes of Health.The author gratefully acknowledges the technical assistance of Jane Harris.     

Independence of drug-induced damage in sarcoma 37 and carotid blood pressure in mice

Summary Thirty-seven drugs of various pharmacologic types were examined in CAF₁ mice for: a) capacity to induce hemorrhagic-necrosis in Sarcoma 37; and b) the changes induced in systemic blood pressure as continuously recorded with a technic devised for the direct measurement of carotid blood pressure in mice.Of the ten tumor-damaging drugs, five caused a rise of carotid blood pressure, while three others caused a fall. More than 60% of the drugs which did not damage the tumors produced a lowering of systemic blood pressure.Induction of tumor-damage with these drugs was found to be independent of the changes they produced in carotid blood pressure.This paper is dedicated to Professor Rolf Meier, Basle, on the occasion of his 60th birthday anniversary.National Institutes of Health, Public Health Service, U.S. Department of Health, Education and Welfare.Preliminary reports (Pradhan, Achinstein and Shear ^{11, 12}) were given at the Fall 1954 and Spring 1955 meetings of the American Society for Pharmacology and Experimental Therapeutics.     

Effects of chlorpromazine,secobarbital and sleep deprivation on attention in monkeys

Summary In order to develop a method for studying sustained attention in the monkey, animals were trained to perform a rapid, serially-presented visual discrimination task. Two versions of the task were developed, one dependent upon shock avoidance, the other on water reward. The effects of varying doses of chlorpromazine (0.075 to 0.6 mg/kg) and of secobarbital (5 to 25 mg/kg) were studied; the shock avoidance task was also used to measure the effects of continuous work-sleep deprivation for periods up to 48 hours.The results suggest that the task is a useful and reliable measure of attentive behavior and that there are similarities between the monkey attention task and the procedures designed to study attention in man; chlorpromazine produces more impairment in performance than secobarbital; impairment is manifest chiefly in increased errors of omission; chlorpromazine and sleep deprivation seem to share certain common effects which distinguish them from secobarbital. No marked differences in drug effects were found between the water and shock versions of the task. The relation between these findings and those obtained in human subjects was discussed.Supported by grants from the Foundations Fund for Research in Psychiatry (61–241) the National Science Foundation (G-21382) and the National Institute of Mental Health (MH-10324). Thanks are due to Mrs. Diane D. Arenella and Mrs. Ellen B. Stechler for their efficient and devoted technical assistance.Career Development Awardee, Level II of the National Institute of Mental Health K3-MH-14,915.     

Strain differences in the effects of chlorpromazine and chlordiazepoxide upon active and passive avoidance in mice

Summary Four inbred strains of mice were compared on an active and a passive avoidance task in a two-compartment cage. Active mice were trained to cross frequently between compartments to avoid shock; passive mice were shocked for crossing. Yoked controls in both procedures received shocks at the same time as experimentals. Strains learning the active task well did poorly in the passive task; strains poor in active learning were superior on the passive task. The results support the view that strain differences in avoidance learning are more related to variations in strength of a kinetic drive than to strength of fear. Chlordiazepoxide affected crossings similarly in actively and passively trained Ss; chlorpromazine reduced crossings in actively trained and increased crossings in passively trained Ss. This result is consistent with dual motivational systems differentially susceptible to alteration by administration of drugs. Chlordiazepoxide acts primarily upon kinetic drive; chlorpromazine upon fear.This investigation was supported in part by United States Public Health Service Research Grants MH-01775 and MH-11327 from the National Institute of Mental Health.The author acknowledges the technical assistance of Frank Clark and Jane Harris.The principles of laboratory animal care as promulgated by the American Psychological Association were observed in this study.     

The phosphaturic response of thyroparathyroidectomized dogs to the administration of parathyroid hormone by unilateral renal arterial infusion

Summary Acutely thyroparathyroidectomized dogs were administered partially purified parathyroid hormone by way of the left renal artery. When the hormone was given by this route at a relatively high dose, either by injection of 30 or more units or as a continuous infusion at the rate of 30 units/hour, the renal response, an increase in the % of filtered phosphate excreted, was rapid and essentially identical by both kidneys. On the other hand, when the parathyroid hormone preparation was infused into the renal artery at a relatively slow rate (1–12.5 units/hour), the response either was confined to the infused kidney or it was greater by the infused kidney than by the noninfused kidney. Control infusions of physiological salt solution or of a nonparathyroid tissue extract resulted in no differential effect on the infused kidney. These results, added to those of similar experiments in intact dogs by Pullman, Lavender, Aho, and Rasmussen, support the conclusion that parathyroid hormone acts directly on the mammalian renal tubule.With 4 Figures in the TextDedicated to Professor Otto Krayer on his 65th birthday.This investigation was supported in part by a research grant (A-1787) from the National Institute for Arthritis and Metabolic Diseases, U.S. Public Health Service.     

The effect of experimentally-induced stress on pentylenetetrazol seizure threshold in mice

Summary The effect of 20 min of intermittent foot shock on spontaneous activity and overt behavior was studied in mice. In addition, the effect of a pain-induced conditioned emotional response, and of total body immobilization and postural disequilibrium on the pentylenetetrazol seizure threshold was determined. Foot shock decreased spontaneous motor activity, and induced responses characterized by immobility, crouching, and increased defecation. The pain-induced conditioned emotional response, total body immobilization, and postural disequilibrium all lowered seizure threshold. Data are presented which indicate that there is a direct relation between the reduction in seizure threshold and the intensity of the disturbed emotional state. In addition, it is suggested that the observed increase in brain excitability caused by apprehension and anxiety may result from the effect of endogenouslyreleased catecholamines on the central nervous system. Reference is made to the relation between these findings and the effect of emotional disturbances on seizure frequency in human epileptics.This investigation was supported by a research grant (NB-00381) from the National Institute of Neurological Diseases and Blindness, National Institutes of Health, U.S. Public Health Service.University of Utah Research Fellow, 1959–1960.     

Further studies on assay and testing of fixation-preventing psychotropic drugs

Summary Chlordiazepoxide (Librium) was found to prevent conflict induced behavior fixations during a discrimination problem if administered during the preceding conflict stage. A replication of the experiment with a chemical congener, diazepam, did not show similar effects. Since the difference in results could have been due to differences in dose, comparisons were made between different dosages of these two drugs utilizing an assay technique that measured the effect of the drugs on response latency. Response latency was presumed to be dependent upon the complex of drives existing in the situation. On the basis of the comparative tests, a dosage of diazepam was found that also prevented behavior fixations. It is proposed that these drugs of the benzodiazepine class exert their effects by reducing an animal's involvement with negative incentives.This research was supported by grant M-01061 from the National Institute of Mental Health, U.S. Public Health Service and a grant from Hoffmann-La-Roche, Nutley, New Jersey.     

Some effects of d-amphetamine on the behavior of pigeons under intermittent reinforcement

Summary The effects of d-amphetamine (0.25 to 8.0 mg/kg) were studied on key-pecking behavior under variable interval (high response rate) and DRL reinforcement (low response rate) in pigeons. Doses of 2.0 mg/kg and above progressively decreased VI responding, as was the case for DRL with doses 4.0 mg/kg and above. No consistent increases in response output on either reinforcement schedule were observed with any dose of the drug, even though prior studies have suggested that amphetamine ought to increase DRL behavior. When their behavior was reduced by d-amphetamine, DRL birds often earned many more grain reinforcements than usual, but frequently did not consume them. No effects of d-amphetamine were observed on a color discrimination tested in the VI birds.We acknowledge the advice of Dr. William B. Morse and Dr. Evalyn Segal, and the expert technical assistance of Peter Gorinsky. This research was performed at the Dept. Pharmacology, Royal College of Surgeons of England and was supported in part by a Public Health Service Special Fellowship (No. MH 25608) to the first author from the National Institute of Mental Health and by NIMH Grant-Number MH-06635 to the Royal College of Surgeons.     

Tolerance and cross-tolerance among psychotomimetic drugs

Summary A fixed-ratio schedule of milk reinforcement (FR 30) was used to study tolerance to the effects of d-LSD, l-LSD, BOL, psilocybin, mescaline, and d-amphetamine in the rat. A decrease in the amount of disruption of bar-pressing occurs with repeated daily administration of appropriate doses of all of the psychotomimetic compounds, and cross-tolerance was also demonstrated.This research was supported by Public Health Service Research Grant, MH-03363, from the National Institute of Mental Health.     

Effects of drugs on avoidance behavior

Summary Thirty-five rats were observed on two occasions in a novel environment, and then trained in a Sidman avoidance response. Each was tested in the avoidance situation following injection of a single dose of chlorpromazine, d-amphetamine, atropine, and scopolamine.Effects of the drugs on avoidance behavior were similar to those reported in earlier studies. Changes from baseline values in response rate and shock rate under drug were found to be the best measures of individual rats' susceptibilities to the drugs.Susceptibilities to the response-stimulating effects of amphetamine, atropine and scopolamine were highly interrelated, but susceptibility to chlorpromazine was distinct. Susceptibility to chlorpromazine was greatest in rats with high baseline rates of responding and shock avoidance. Change in shock rates after administration of stimulant drugs was greatest in rats with high baseline rates of shocks (poor avoiders). Increase in response rate under the stimulants was greatest in animals that tended to groom and freeze in the novel environment, rather than boldly exploring.The effects of the stimulants are discussed in terms of a model relating to the balance of excitation versus inhibition in response to aversive stimulation. Differences in baseline avoidance rates and in susceptibilityThis experiment was supported by grant MH-04139 from The National Institute of Mental Health and by The California Department of Mental Hygiene.     

Brain stimulation reward „Thresholds” self-determined in rat

Summary The self-stimulation technique of Olds is modified to permit a continuous determination of the smallest current levels that will produce a rewarding effect by stimulating positive brain sites. The animal receives brief brain shocks that decrease in intensity in small steps by operating one lever, and indicates which current step stimulated insufficiently by resetting the current at a second lever. Preliminary data suggest that the technique will provide a valuable tool for the investigation of the central nervous system actions of drugs.Public Health research fellow of the National Institute of Mental Health.