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.     

Drugs,shock intensity,and the CER

Summary The effects of chronic small doses of reserpine (0.2 mg./kg.) and of chlorpromazine (1.5 mg./kg.) upon the CER were studied using albino rats as subjects. It was found that reserpine reliably reduced the CER at a relatively low shock intensity (0.8 ma.) but, with a more severe shock (1.0 ma.), the results were equivocal. Chlorpromazine inhibited the CER at 1.0 ma. At the dosage and time parameters studied, chlorpromazine induced less depression of VI rate than did reserpine; recovery from reserpine effects was generally more gradual than was recovery from chronic chlorpromazine treatment.This research was supported by Research Grant MY 3363 from the National Institute of Mental Health. The author would like to thank D. X. Freedman, M.D., for providing laboratory facilities and to acknowledge the technical assistance of Miss C. V. Perotti.     

The selective action of chlorpromazine on behavior suppressed by punishment

Summary Rats were trained to press a response lever to obtain pellets of food at irregular intervals averaging four minutes. A white noise signal was added during alternate two minute segments of time, during which a schedule of punishment for all responses was superimposed on the food reinforced behavior. The punishment was sufficiently severe to reduce the rate (frequency) of pressing to about 1 per cent of its nonpunished level. Five individual dose-response curves were then plotted to show the effects of 1/2, 1, 2, and 4 mg./kg. chlorpromazine, s. c., on the punished rate as a percentage of its nonpunished counterpart. Fourfold to ninefold increases were registered for individual animals. This result was interpreted in terms of a selective action of the drug on the punished behavior, combined with a more general sedative or depressive effect on the food reinforced behavior.This investigation was supported by a research grant (MY-3648) from the National Institute of Mental Health, Public Health Service.     

Effects of drugs on nondiscriminated avoidance behavior

Summary Thirteen male, Long-Evans rats were trained to press a lever to postpone a brief electric shock. Each rat was subjected to several different doses of chlorpromazine, d-amphetamine, atropine and benactyzine, and then tested for four hours under a mixed schedule of extinction and nondiscriminated avoidance behavior. In comparison with interspersed control sessions, chlorpromazine produced a consistent depression. Amphetamine increased response rates at moderate doses, and led to severely toxic reactions at higher doses. The three anticholinergic drugs produced qualitatively similar reactions within rats, but very different patterns of response between rats. Most animals showed higher response rates, but a few were depressed.Rats differed markedly in their response to all of the drugs. Both quantitative differences in the dosage necessary to produce a common effect and qualitative differences in the pattern of response to the drug were seen.Supported by research grant No. MY-4139 from the National Institute of Mental Health and by the California Department of Mental Hygiene.     

The differential effects of chlorpromazine and pentobarbital on two forms of conditioned avoidance behavior in peromyscus maniculatus gracilis

Summary A series of experiments was designed to compare the conditioned behavior of a subspecies of deermouse (Peromyscus maniculatus gracilis) in two response situations: 1. avoidance of shock by climbing a pole, and 2. avoidance of shock by remaining on a non-electrified pan located at grid level. This subspecies is semi-arboreal in its natural habitat. As was expected, an experimentally-induced response analogous to those to which the animal is phenotypically predisposed is rapidly acquired and resistant to spontaneous extinction. Thus, the pole response was acquired more rapidly, was more resistant to extinction, and was less susceptible to suppression by drugs. The stability of such behavior makes mice exhibiting this type of response advantageous for testing the effects of psychotropic drugs. The fact that chlorpromazine may be differentiated from pentobarbital by means of these technics supports this conclusion.Supported by a research grant from the National Institute of Neurological Diseases and Blindness (B-381), National Institutes of Health, U.S. Public Health Service.Portion of a thesis presented by Harold H. Wolf in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of Utah.Predoctoral Fellow 1960–61, National Institute of Mental Health, U.S. Public Health Service.     

Effects of chlordiazepoxide on the acquisition of avoidance learning and its transfer to the normal state and other drug conditions

Summary Rats trained after injection of chlordiazepoxide (CDP), 15 mg/kg, acquired the conditioned avoidance response significantly faster than saline controls. When tested in the undrugged state, CDP trained animals showed virtually no retention of the learned response. Conversely, normally trained rats showed a significant decrement in performance with CDP, whether or not they had received a series of CDP injections following the period of training. CDP trained animals performed much worse than controls on tests with chlorpromazine and amphetamine, despite continued perfect performance on intercurrent CDP tests. Both the rapid learning and the dissociation of learning are discussed with reference to the diminution by drug of the spectrum of behavioral responses to novel stimuli, as well as the elimination of the electrical response of hippocampus which normally accompanies these responses to novelty.Librium.This research was supported in part by funds made available by the National Institute of Mental Health under grants MY-2811 and MH-08519. awarded to Dr. E. R. John.     

A controlled comparison of drug effects on escape from conditioned aversive stimulation (“anxiety”) and from continuous shock

Squirrel monkeys were presented with two stimuli in alternation, separated by time out periods during which neither was present. One was white noise accompanied by irregularly spaced pulses of shock, the other continuous shock at a lower intensity. Following an interval of time which varied in an unpredictable sequence, the next depression of the response lever turned the stimulus off. The schedule on which termination was possible was identical for the two stimuli, and the intensity of the continuous shock was adjusted to a level that produced approximately equal frequencies of pressing, typically from 40 to 80 responses per minute.Doses of chlordiazepoxide ranging from 2.5 to 10.0 mg/kg, i.p., produced a significantly greater decrease in the rate of response in the presence of the continuous shock than in the presence of the noise. On the other hand, doses of chlorpromazine ranging from 0.25 to 1.0 mg/kg, i.p., produced no differential effect. Previous findings of selective action on behavior that terminates signals paired with shock (avoidance) may be related to differences in experimental contingencies or in the pre-drug strength of the two performances compared, rather than to the effect of chlorpromazine on an experimental analogue of human anxiety.This investigation was supported by PHS Grant No. MH 03648 from the National Institute of Mental Health. Portions of the data were reported at the annual meeting of the Eastern Psychological Association, New York City, 1966.     

Effects of chlorpromazine upon psychological development in the puppy

Summary Puppies were removed from the mother at three weeks of age and isolated through the seventh week. During the 8th–11th weeks (Phase I) one half received chlorpromazine daily before being removed for a training and observation session in an open arena. One half of each group were always rewarded; the remainder were punished for certain forms of behavior.During Phase II (weeks 12–15) all subjects were reversed on punishment, and half were reversed on drug. Observations in the arena were continued.In Phase III (weeks 16–17) drug was withdrawn and tests were conducted in a runway and in the arena to measure persistent effects. The results were as follows:During Phase I, both drug and punishment depressed the activity level of the animals and did so additively. Chlorpromazine did not impair the ability of the subjects to discriminate safe from dangerous situations in the Arena test and had no delaying effect upon the appearence of new responses; on the other hand, the drug did not alter the anxieties of the puppies in such a way as to enable them to enter new situations before non-drugged animals. Differences between drugged and non-drugged puppies were most evident in contacts with inanimate objects. In play with companion puppies, perhaps because of increased stimulus intensity, both groups were highly active and often indistinguishable. This would indicate the importance of stimulus context in interpreting behavioral effects from chlorpromazine.In Phase II, in animals changed from a non-punished regime, it was again evident that chlorpromazine has no deleterious effects upon learning a new avoidance pattern; dangerous versus safe phases of the Arena test were readily discriminated. In groups changed from punishment to non-punishment, the facilitating effect of chlorpromazine on extinction of avoidance behavior was apparent. Whether or not drug had been given to the prior punishment phase was inconsequential; the crucial fact was the presence of drug treatment during extinction.Phase III tests failed to demonstrate any significant differences between groups, either in arena behavior, willingness to run for handler contact, or in the runway dominance test.Supported in part by the Ford Foundation and by Grant MY-1775 from the U. S. Public Health Service.     

Facilitating effects of some chlorpromazine-d-amphetamine mixtures on avoidance learning

The effects of several chlorpromazine-d-amphetamine mixtures on discriminated avoidance learning in rats have been studied and compared with the effects of d-amphetamine alone, and it has been found that some of these mixtures increase shock avoidance very significantly. The different mixtures cannot be compared on the basis of the same dose ratio, but some of the observed effects can probably be explained in terms of more or less sustained brain levels of d-amphetamineThe combined treatment of 1 mg/kg chlorpromazine and 1 mg/kg d-amphetamine is one of the most effective and an increase of conditioned responses and a decrease of interresponses is observed in this group as compared with the corresponding d-amphetamine 1 mg/kg group. The significance of these findings and the possible sources of this especial behavioural interaction of the two drugs are discussed.A preliminary report of this study was presented at the 7th International C.I.N.P. Congress, Praha, August 1970.With the technical assistance of Miss M^a Luz de Toro.     

How do tranquilizing agents selectively inhibit conditioned avoidance responding?

A number of tranquilizing agents have been shown to inhibit conditioned avoidance responses (CAR) at doses that do not interfere with escape responses (ER). To test the hypothesis that this selective action may be due to differential response strengths of the two responses, rats were trained to press retractable levers in an operant chamber either to avoid a 0.5 mA shock during a 5.0-s warning period or to escape from a low-intensity shock within 5.0 s. The intensity of the latter shock was adjusted for each animal so that CAR and ER were comparable in terms of probability of occurrence and latency. While doses of chlorpromazine, clonidine, diazepam, and morphine that reduced CAR by 30%–50% did not significantly affect high-shock ER, i.e., ER on CAR trials where no CAR occurred, they interfered with low-shock ER to the same degree as CAR. These and other results suggest that the selective blockade of the CAR by these drugs in the CAR paradigm is primarily due to differential strengths of the CAR and ER. They also support studies concluding that tranquilizing drugs reduce avoidance because of a deficit in the ability to initiate motor responses, rather than interfering with associative processes or reducing situation-induced emotional reactions. However, the finding of a small differential effect, at least with chlorpromazine, on CAR and low-shock ER across trials within sessions indicated that different mechanisms may be involved in the suppression of these two responses.     

Social influence on the response to drugs. II

Summary Rats were treated with saline, chlorpromazine, or iproniazid and observed in either a solitary condition or in a condition where stimulus rats were present behind a wire mesh barrier. Five categories of behavior were observed and recorded. These included locomotion, barrier-directed behavior, sniffing, grooming, and inactivity. The number of times an animal shifted from one category of behavior to another (behavior shifts) was also obtained. Results showed that the behavior of iproniazid treated rats was most modified by the presence of stimulus rats. Animals in this group spent significantly more time engaged in barrier-directed behavior than rats in the other groups.This investigation was carried out during the tenure of a Postdoctoral Fellowship (MF-8654-C2) from the National Institute of Mental Health, U.S. Public Health Service and supported by research grant MY-5981 (A) from the game organization. The author wishes to express his appreciation to David Rumelhart for his assistance during the study.Chlorpromazine used in this study was furnished by Smith, Kline, and French Laboratories, Philadelphia. Iproniazid was furnished by Hoffmann-LaRoche Inc., Nutley, New Jersey.     

The mechanism of fixation prevention and “Dissociation” learning with chlordiazepoxide

Summary This experiment investigated the possibility that chlordiazepoxide (CDP) has unique properties that account for state dependent learning, and prevention of conflict-induced behavior fixations.One group of rats were given a discrimination problem on a Lashley jumping stand, but on even days all responses were punished. Another group were treated the same way except than on even days all responses were rewarded. Each of these groups were subdivided, half of the Ss were given CDP on even days, the other half no drug. The results showed that punishment on even days for the response to be learned disrupted learning more than reward for responses that were to be avoided. CDP practically eliminated these disruptive effects and aided learning for the punishment group, but led to a slower rate of learning for the reward group. These findings confirmed the hypothesis that CDP attenuates the effects of negative incentives, and that this property accounts for the drug's cue value in discrimination learning and for its fixation prevention characteristics.This experiment was supported by Research Grant MH-01061, United States Public Health Service. Chlordiazepoxide was generously supplied by HoffmannLaRoche Inc., Nutley, New Jersey. The animals were run by Pieper Toyama and Nancy F. Feldman. The statistical analysis was done by Dennison Smith. Nancy F. Feldman also composed and drew the figures.     

Effect of amobarbital and chlorpromazine on punished behavior in the pigeon

Summary The effects of amobarbital and chlorpromazine were studied on punished behavior in the pigeon. Key-pecking responses, maintained by a variable-interval schedule of food reinforcement, were punished by brief electric shocks. Under this simultaneous food and punishment schedule, responding is suppressed and occurs at a fairly uniform rate that is inversely related to the punishment intensity. Amobarbital partially restores responding suppressed by punishment, but chlorpromazine has no tendency to attenuate suppression by punishment.This work was supported by grants MH 02904 and MH 07658 from the U.S. Public Health Service and by a research career program award 5-K3-GM-15, 530 from the Institute of Mental Health.     

Effects of chlorpromazine on avoidance and escape responding in humans

The effects of chlorpromazine on shock avoidance and escape responding were determined using four human subjects lever pressing on a modified free operant avoidance schedule. Doses of chlorpromazine ranging from 50 to 100 mg and shock levels ranging from 0.35 to 3.0 mA were used. In general, the results showed that chlorpromazine suppressed avoidance responding at doses which did not suppress escape responding.     

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.     

Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition

Rationale The nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signal transduction pathway has been implicated in some forms of learning and memory. Recent findings suggest that inhibition of phosphodiesterase (PDE) enzymes that degrade cGMP may have memory-enhancing effects. Objectives We examined whether treatment with sildenafil citrate, a PDE type 5 inhibitor, would attenuate a learning impairment induced by inhibition of NO synthase [60 mg/kg N ^ω-nitro-l-arginine methyl ester (l-NAME), i.p.]. Methods Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and, on the next day, received 15 training trials in a 14-unit T-maze, a task that has been shown to be sensitive to aging and impairment of central NO signaling systems. Combined treatments of l-NAME or saline and sildenafil (1.0, 1.5, 3.0, or 4.5 mg/kg, i.p.) or vehicle were given 30 and 15 min before training, respectively. Behavioral measures of performance included entries into incorrect maze sections (errors), run time from start to goal (latency), shock frequency, and shock duration. Results Statistical analysis revealed that l-NAME impaired maze performance and that sildenafil (1.5 mg/kg) significantly attenuated this impairment. Control experiments revealed that administration of l-NAME alone did not significantly increase latencies in a one-way active avoidance test and that different doses of sildenafil alone did not significantly alter complex maze performance. Conclusions The results indicate that sildenafil may improve learning by modulating NO–cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease. M. Jimenez and D. Sierra-Mercado, Jr., were supported by Minority Access to Research Careers grants NIGMS 08253 and NIGMS 07717.     

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.     

Generalization of behavioral history across responses in the reversal of the effects of cocaine and d-amphetamine on the punished behavior of squirrel monkeys

Previous research has demonstrated that the effects of d-amphetamine on punished lever pressing of squirrel monkeys are modified by an avoidance history in which lever pressing postpones shock. In the present experiment generalization of behavioral history across responses was assessed by determining the effects of d-amphetamine and cocaine on punished lever pressing of squirrel monkeys before and after exposure to an avoidance procedure in which a chain-pulling response postponed shock. The punishment schedule consisted of a fixed-interval 5-min schedule of food delivery in which every 30 lever presses produced a 5-mA electric shock. During avoidance sessions each chain pull postponed shock delivery for 25s; in the absence of chain pulling, shocks occurred every 5s. Only a single response manipulandum was present in each phase. Punished lever pressing was initially unaltered or decreased by d-amphetamine and cocaine. Following the chain-pull avoidance history, however, d-amphetamine produced dose-dependent increases in the punished lever pressing of all three monkeys at several doses that formerly did not alter or reduce responding; a similar pattern of results was obtained when cocaine was administered to two of the subjects. The effects of d-amphetamine and cocaine on punished lever pressing were subsequently determined within the context of a multiple schedule of lever-press punishment and chain-pull avoidance, with both manipulanda present simultaneously. The effects of the drugs on punished lever pressing within the multiple schedule were similar to their initial, pre-avoidance effects for the two monkeys whose responding was increased by both drugs in the preceding, post-avoidance phase. Chain pulling during the punishment component was dose-dependently increased, suggesting that chain pulling during punishment reduced the opportunity to exhibit increases in punishing lever pressing. The remaining monkey's punished lever pressing was increased by both drugs within the context of the multiple schedule. This experiment demonstrates that avoidance-dependent upward shifts in the dose-response curves of d-amphetamine and cocaine can occur when the punishment and avoidance responses differ, and that original effects can be partially restored when both responses are available simultaneously. The results suggest that generalization across responses of the effects of a critical behavioral history may be a general property of behavioral history phenomena within behavioral pharmacology. These findings underscore the generality and importance of behavioral history as a modulatory influence on the effects of abused drugs.     

Effects of triazolam on conditioned behavior in rats (author's transl)]

Effects of triazolam on various types of conditioned behavior were investigated and compared mainly with diaepam in rats. The active conditioned avoidance response of the rat in a Shuttle box was inhibited by triazolam and diazepam only at large doses. The passive avoidance response in a step-down method was not affected by either triazolam or diazepam, but was markedly suppressed by chlorpromazine. The low rate response of hypothalamic self-stimulation behavior was markedly increased by triazolam at doses ranging from 2 to 40 mg/kg p.o., but was suppressed at doses over 80 mg/kg p.o. The high rate response was unaffected by triazolam even at doses of 40 approximately 180 mg/kg p.o. The low rate response was increased by diazepam at doses of 1 approximately 10 mg/kg p.o. and was suppressed at 80 mg/kg p.o. The high rate response was reduced by diazepam at 180 mg/kg p.o. In the conflict situation of the rat subjected to food reward and foot-shock punishment, the lever press response in the unpunished period was reduced by triazolam at doses of 1 approximately 5 mg/kg p.o., whereas that in the punished period was markedly increased. Similar effects were observed with diazepam at doses of 15 approximately 20 mg/kg p.o. Triazolam appeared to be 10 approximately 15 times more potent than diazepam in this anticonfluct effect. Thus, triazolam appears to be a potent antianxiety agent.     

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.