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.     

The effects of chlorpromazine and secobarbital on matching from sample and discrimination tasks in monkeys

Summary Monkeys were trained in the performance of a matching from sample task and in two simultaneous visual discrimination tasks differing in level of difficulty. In the case of the matching task, four doses each of chlorpromazine and of secobarbital were administered to the animals according to a balanced design. The procedure was then replicated. The results of the matching task indicated that chlorpromazine produced many errors of omission and few errors of commission. The latter kind of error as well as other measures of confused responding were seen primarily with secobarbital. In the case of the visual discriminations, secobarbital produced greater impairment of the more difficult (pattern) task than of the simpler (color) task; chlorpromazine had equivalent effects on the two tasks. The similarity between the secobarbital action and the behavioral consequences of certain cortical lesions in the monkey was discussed.This work was supported by the following grants from the National Institute of Mental Health, Public Health Service: Research Grant MH-12568; Special Fellowship 1-F3-25,128 (Dr. Bakay Pragay); Research Scientist Award 5-KO-5MH-14,915 (Dr. Mirsky); Predoctoral Fellowship 1-F2-NB-32-103 (Dr. Abplanalp).     

Male and female C57BL/6 mice respond differently to diazepam challenge in avoidance learning tasks

Benzodiazepines (BZ) impair learning and memory performance of animals. The goal of this study was to examine sex differences in the effects of diazepam on learning and memory of C57BL/6 mice in avoidance paradigms. Male and female C57BL/6 mice were tested in the one-way active avoidance, step-down passive avoidance, and foot-shock pain threshold tasks, following administration of vehicle or diazepam (1 mg/kg). No substantial sex or drug effects on the threshold of the pain response to shock were found. There were no significant differences in avoidance performance between vehicle-treated male and female mice while 1 mg/kg of diazepam produced opposite effects on performance of males and females in both tasks. Diazepam-treated females learned faster in the active avoidance task and showed stronger retention in the passive avoidance task. In contrast, diazepam impaired learning of males in the active avoidance task and had no effect on their performance in the passive avoidance task. Diazepam-induced impairment in males was not due to higher sensitivity to the sedative effect of diazepam as females were more sedated than males on the first trial of the passive avoidance task. Our data showed that sedative and amnesic effects of BZs are not tightly linked. This study also suggests that cognitive effects of BZs in rodents could be sex dependent and highlight the importance of using both sexes in studies on behavioral effects of psychoactive drugs.     

Strychnine sulfate and piracetam: Lack of effect on learning in the rat

Strychnine sulfate and piracetam: lack of effect on learning in the rat. The effects of post-trial administration of piracetam and strychnine sulfate were examined using learning tasks. In the first procedure, a discrimination task was employed. In terms of two parameters used to assess drug effects on the acquisition of the discrimination, neither strychnine nor piracetam facilitated learning. The second task used to assess learning was acquisition of a conditioned avoidance response. Rats were trained in a shuttle box to avoid electric shock upon the presentation of an auditory stimulus. Six experiments were performed in an attempt to demonstrate facilitation of learning by post-trial injection of strychnine. Drug-treated animals did not differ significantly from controls in their acquisition of the avoidance response in any of the six experiments. Because control groups from the individual experiments did not differ significantly among themselves, data from all experiments were combined. In all, 8 doses of strychnine were tested, ranging from 0.005 to 0.60 mg/kg. Analysis of variance showed no significant differences between any of the treatment conditions, nor was there evidence of a graded dose-effect relationship. The present results do not support the conclusion that strychnine or piracetam facilitate learning.Supported by Graduate Training Grant 5-T01-GM 00107 from the Division of Medical Sciences, National Institutes of Health (M.W.O.), and by Grant MH-15406 from the National Institute of Mental Health (J.C.W.).     

丁螺环酮对小鼠主动和被动回避反应的影响

应用小鼠一次性被动回避和穿箱主动回避行为法 ,观察抗焦虑剂丁螺环酮 (Bus)对学习获得和记忆保持的影响 .结果发现 ,训练前 ip Bus0 .3- 1 0mg·kg-1不影响小鼠一次性被动回避反应的获得 ,但训练后立即 ip Bus 0 .3- 1 mg· kg-1时损害其保持 ,缩短小鼠进入暗室的潜伏期 .每天训练前 ipBus 0 .3- 1 0 mg· kg-1时 ,小鼠 d 1穿箱主动回避反应率显著提高 ,但随后的 d2 - 4,1 ,3,1 0 mg·kg-1组小鼠主动回避反应率显著降低 .Bus 0 .3-3.0 mg· kg-1不影响小鼠自发活动 ,1 0 mg· kg-1使小鼠活动性降低 ,这些结果表明 Bus不影响或促进学习获得 ,对记忆的保持具有损害作用     

Substance P enhancement of passive and active avoidance conditioning in mice

In a series of seven experiments we explored the effects of peripherally administered substance P on passive and active avoidance conditioning in mice of two genotypes. The peripheral post-trial administration of substance P significantly enhanced the retention of a single-trial passive avoidance task. This effect was dose dependent; 1 ng/g of substance P enhanced the retention of this habit, whereas higher and lower doses were either less effective or ineffective. In heterogeneous strain (HS) mice, substance P administered before training on an active avoidance task did not alter the rate at which these animals learned this habit. However, animals that had been trained with substance P were significantly more resistant to extinction than were animals that had been injected with vehicle. Similarly, C57Bl/6J mice that had been treated with substance P immediately after active avoidance training were more resistant to extinction than were mice that had been given control injections. The enhancement of retention of the passive avoidance habit with substance P was reversed in animals that had been pretreated with naltrexone. Substance P enhancement of the retention of the passive avoidance habit, and its reversal with naltrexone, was observed in both sham operated and adrenalectomized mice.     

Effects of delta9-tetrahydrocannabinol on active avoidance acquisition and passive avoidance retention in rats with amygdaloid lesions.

Delta9-Tetrahydrocannabinol was administered to rats with basolateral amygdaloid lesions, control rats, and normal rats in doses of 0.75, 1.5, and 3.0 mg/kg i.v. They were trained in a one-session two-way active avoidance task. Delta9-Tetrahydrocannabinol increased the percentage of avoidance and the intertrial crossing rates in all groups, regardless of lesion treatment. Rats with basolateral amygdaloid lesions were not different from controls on any measure. In a second experiment, delta9-tetrahydrocannabinol was administered to rats with basolateral amygdaloid lesions and control rats in doses of 0.75 and 3.0 mg/kg 24 h after learning of a one-trial passive avoidance task, and retention was measured. No differences were found as a function of drug treatment or lesion condition. It was concluded that the basolateral amygdala is not a necessary condition for the action of delta9-tetrahydrocannabinol on active avoidance acquisition, that the drug has no effect on passive avoidance retention, and the basolateral amygdala is not necessary for two-way active avoidance acquisition or passive avoidance retention. Active avoidance results are discussed in terms of a possible relationship between delta9-tetrahydrocannabinol, ACTH, and avoidance learning.     

Avoidance enhancement and discriminative response control by anxiolytics with drugs acting on the GABA system

Two types of conditioned behaviors were investigated for the purpose of evaluating anxiolytic drugs. A conditioning procedure used was an active avoidance in poorly-performing mice. Chlordiazepoxide, diazepam, chlorazepate and meprobamate increased the avoidance rate, while chlorpromazine, haloperidol and nortriptyline did not produce such an effect. The effect of diazepam was potentiated by gamma-aminobutyric acid (GABA) and aminoxyacetic acid (AOAA) and antagonized by picrotoxin and thiosemicarbazide, but was influenced little by spiroperidol, alpha-methyltyrosine, phenoxybenzamine and levallorphan. In addition, the effect of other anxiolytics was potentiated by AOAA and antagonized by picrotoxin. Biperiden, methamphetamine, caffeine and morphine also induced an avoidance enhancement, which was not influenced by AOAA. A drug discrimination experiment was also performed using a milk-reinforced two-lever operant method. In the rats trained to discriminate phenobarbital from saline, diazepam produced a dose-related phenobarbital-lever selection, which was potentiated by AOAA and antagonized by picrotoxin. Chlordiazepoxide, chlorazepate and meprobamate also elicited responses on the phenobarbital-lever. On the other hand, haloperidol, nortriptyline, biperiden, methamphetamine, caffeine and morphine produced a saline-lever selection, at the doses tested. These results suggest that, among several drugs tested, the avoidance enhancement and discriminative response control by anxiolytics may be closely linked with the GABA system.     

Postnatal alpha-methylphenylalanine treatment effects on adult mouse locomotor activity and avoidance learning

Neonatal mice were injected for five days with a combination of alpha-methylphenylalanine and phenylalanine to determine the influences of excess phenylalanine during development upon the behavior of these mice as adults. Spontaneous activity, bolus production, passive avoidance learning, simple active avoidance learning and complex active avoidance learning were tested in mice treated at two different postnatal periods. The results show that the treatments during development produced adult behavioral alterations compared to controls. The effects were most pronounced in mice treated in the postnatal period immediately after birth. The behavioral effects can be summarized as increased emotionality and generalized, stimulus-induced activity as well as decreased passive avoidance performance and complex active avoidance performance. These behavioral deficits are consistent with those usually reported in various models of human phenylketonuria.     

Pharmacological distinctions between “active” and “passive” avoidance memory formation as shown by manipulation of biogenic amine active compounds

Female CF-1 mice were trained either in a passive step-through avoidance or in an active one-way escape avoidance task. The apparent memory for either task (measured 8 days later) was reduced by reserpine dosage immediately after training. Five-hydroxytryptophane, given along with the reserpine, eliminated memory reduction for the passive training; Dopa, given along with the reserpine, did not eliminate memory deficit for the passive training. Five-hydroxytryptophane given along with reserpine did not eliminate the memory deficit for the active training; Dopa given along with the reserpine did eliminate memory reduction for the active training. Implications are discussed.     

Chlorpromazine and avoidance: A genetic analysis

Chlorpromazine exerts a significantly higher impairment on the performance of C57BL/6By than on BALB/cBy inbred mice pretrained in an active avoidance task. The effects of the drug on this measure assessed in these two strains, their reciprocal F₁ hybrids, their recombinant inbred strains, and two C57BL/6By congenic lines indicate that at least two genes modulate the action of chlorpromazine on avoidance behavior. It was possible to characterize one of the loci modulating the effect of chlorpromazine on avoidance performance. We assign the symbol Cpz. The locus is in chromosome 9, Linkage Group II.The Jackson Laboratory is fully accredited by the American Association for Accreditation of Laboratory Animal Care.This study was supported by a grant from the Italian and French National Research Councils, in part by NIH Research Grant HD 05860 from the National Institute of Child Health and Human Development, and in part by NIH Research Grant GM 15574 from the National Institute of General Medical Sciences.     

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment.

Methods: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10?mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals’ locomotor activity was also studied.

Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p?p?p?p?Discussion: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).     

Stimulus significance and chlorpromazine-induced impairment of avoidance learning in mice

It is suggested that chlorpromazine may reduce the significance of stimuli to an animal, and that if this were so, it would follow that the effects of chlorpromazine might be offset by arranging for stimulus significance to be increased. The effects of 0–075 mg/kg of chlorpromazine on the acquisition of one-trial passive avoidance learning in mice are described; when the experimental subjects were given prior experience, in a T-maze, of the black-white discriminanda used in establishing one-trial learning, the extent of the drug-induced suppression of learning was reduced. The results are discussed as being consistent with a chlorpromazine induced reduction of stimulus significance.     

The effects of chlorpromazine on the decay and consolidation of short-term memory traces in mice

Summary F₁ hybrids of two highly inbred strains of mice were trained in a one-trial passive avoidance learning situation. Chlorpromazine, in doses of 0.5, 2.0 and 3.5 mg/kg, was administered at one of four injections times, 10 min before and 0.5, 2 and 10 min after learning. Pre-learning drug administration completely blocked acquisition of a learned avoidance response. Post-learning drug effects were more complex, involving reduced expression of avoidance learning but less rapid extinction of the learned response. The results were related to effects of the drug on short-term memory trace decay and consolidation.     

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.     

Effects of the antidepressant drug moclobemide on learning and memory in rats

Moclobemide is a well known drug with antidepressant action. The aim of this study was to investigate the effects of moclobemide on learning and memory processes in Sprague Dawley rats. Over a 5-day period, learning sessions with 30 trials per day and memory retention tests were performed. The conditioned responses (avoidances), the unconditioned responses (escapes) and the intertrial crossings were observed. An active avoidance test was carried out using a shuttle box. Two passive avoidance tests were used: step-through (using a light chamber) and step-down (using a platform). In the step-through passive avoidance test, the learning and retention sessions consisted of three trials each and the latency of reaction times (the rat remaining in the light chamber for more than 180 sec) was used as criterion. In the step-down passive avoidance test, learning and retention sessions consisted of two trials and the latency of reaction times (the rat remaining on the platform for 60 sec) was used as criterion. In the active avoidance tests, moclobemide dose-dependently increased the number of avoidances during learning sessions and maintained this number in memory retention tests. Moclobemide did not alter the number of escapes, but did increase motor activity. In the passive avoidance tests, moclobemide also increased the latency of reaction times in learning and short memory retrieval tests. These findings suggest that moclobemide improves learning and memory processes in active and passive avoidance tests and has a cognition-enhancing effect.     

True and apparent side effects in a controlled trial of chlorpromazine and imipramine in depression

Five hundred and fifty-five acutely depressed patients receiving chlorpromazine and imipramine, were studied to determine the incidence and severity of drug-related side effects. The ability of clinicians to distinguish between drug-related side effects and symptoms considered natural to the depressive illnesses was also investigated. The results indicated that side effects were minimal for both active drug groups and that among the dropouts for serious side effects (31 cases) the majority were receiving chlorpromazine. Skin rash and hypotension were the most frequent reasons cited for side effect terminations from the study.It appeared that clinicians were generally able to distinguish drug-related side effects from symptoms usually associated with depression. There was some indication, however, that they tended to rate as non-medication related, certain symptoms which were actually drug-induced. The latter included muscle rigidity, edema, and dry mouth on chlorpromazine and tremulousness on imipramine.This study was supported by grants numbered MH-10445, MH-10420, MH-10546 MH-10295, MH-10331, MH-10812, MH-10330, MH-10889, MH-10495 and MH-10892 from the National Institute of Mental Health.     

Extinction of fear II: Effects of chlordiazepoxide and chlorpromazine on fear and exploratory behaviour in rats

Rats avoided a distinctive environment in which they had previously received inescapable electric shocks; the amounts of passive avoidance were taken as indices of the levels of conditioned fear on repeated unpunished tests. Chlordiazepoxide, 7.5 and 15.0 mg/kg tended to reduce fear, but did not accelerate its extinction; 30.0 mg/kg however, retarded the extinction of fear by making the rats inactive and thus reducing the number of unpunished entries into the fear-evoking environment. The effects of chlordiazepoxide on locomotor activity were complex; entries were increased by all three doses of chlordiazepoxide on the first trial only, and following this, activity was markedly depressed by 30.0 mg/kg. Chlorpromazine on the other hand, consistently reduced locomotor activity and at the same time it increased avoidance, possibly by augmenting fear. As a result of this increased avoidance, the extinction of fear tended to be retarded by 1.5 mg/kg of chlorpromazine. The slowing of the free extinction of fear by both of these drugs was critically dependent on the doses used, but in no case was there a beneficial effect, indicating hastened extinction of fear.     

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.     

Impairment of passive avoidance performance in SART-stressed mice and the action of drugs

In order to investigate the behavioral characteristics of the SART-stressed (repeated cold-stressed) animal, a model of dysautonomia, step-down passive avoidance performance was examined in SART-stressed mice. SART-stressed mice exhibited a shortened test trial latency and a decreased incidence of maximum latency of 300 sec, but no change in the training latency. These alterations were blocked by single administration of chlorpromazine or carpipramine prior to the training trial. Repeated, but not single treatments with neurotropin and hopantenate improved the impaired performance due to SART stress. On the other hand, alprazolam and diazepam were ineffective by either mode of administration. Thus, SART-stressed mice appear to have impairment in the process of acquisition of a passive avoidance task.