EEG correlates of impaired attention performance under secobarbital and chlorpromazine in the monkey

The effects of secobarbital and chlorpromazineupon behavior in a continuous, rapidly presented successive (go-no go) discrimination (attention) task were evaluated in six Macaca mulatta monkeys. Simultaneous monitoring of EEG activity from epidural and subcortical electrodes permitted an evaluation of the nature of altered central nervous system events during erroneous performance (errors of omission) on this task. The computer-assisted analysis of pre-stimulus and post-stimulus EEG frequency activity (baseline crossings) suggests that the best measure of attentive behavior from the pre-stimulus EEG is percentage of beta 2 (25–40 cps) activity. No difference could be observed between drugs or among cerebral placements in this regard. This was determined by comparing measures of EEG frequency, pooled for a given test period, with performance from the same test period. On a trial-by-trial basis, however, the beta 2 measure in the pre-stimulus epoch failed to distinguish correct responses from errors of omission.Separation between correct responses and errors of omission is possible if comparisons are made between the changes in percentage of beta 2 activity in the pre-stimulus vs. post-stimulus epochs. For both drugs, the largest absolute change in beta 2 pre- vs. post-stimulus occurs with correct positive trials and the smallest change with correct negative trials. For secobarbital, no difference could be detected between correct and incorrect positive trials. For chlorpromazine, however, there was significantly less change in beta 2 for incorrect positive than for correct positive trials. The results were interpreted in terms of the hypothesis that secobarbital produces errors by depression of the general level of activation whereas chlorpromazine acts by reducing the sensory input which is necessary for correct discrimination performance.Some of these results were presented to the IXth Meeting of the Collegium Internationale Neuropsychopharmacologicum, Paris, France, July, 1974. Supported by USPHS grant No. MH 12568 from the National Institute of Mental Health. The authors are grateful to Dr. Eva Bakay Pragay for her wise counsel.Research Scientist Awardee K05 14915 of the National Institute of Mental Health.     

Alpha chloralose and nocturnal physiological patterns

Summary Sleep physiological patterns were examined following a single oral dose (500 mg) of the hypnotic drug alpha chloralose. The drug increased SW sleep and decreased REM sleep without affecting total sleep time or the amount of stage 2. These changes were accompanied by a shift to slower frequencies and greater EEG synchrony, as well as a decrease in the number of spontaneous arousals in all stages of sleep, and throughout the night of medication. Except for a slight decrease in eye movement density, the drug had no systematic effects on phasic phenomena such as electrodermal or cardio-respiratory fluctuations, nor was there a systematic change in basal heart and breathing rates.On the night following medication a rebound increase in percent stage REM was associated with a sharp decrease in SW sleep, and increases in spontaneous arousals and waking time. Such findings suggest that sleep stages are controlled by homeostatic mechanisms whose function is to maintain equilibrium.A comparison of the effects of alpha chloralose with those of the barbiturate secobarbital revealed some striking differences. Although both alpha chloralose and the barbiturate reduced the amount of stage REM and the frequency of brief arousals, the latter compound enhanced EEG fast activity and desynchrony, and suppressed such phasic phenomena as rapid eye movements during stage REM, sigma spindles in stage 2, nonspecific electrodermal responses during SW sleep and cardio-respiratory variability in all sleep stages. For secobarbital, the decrease in percent stage REM was compensated by an increase in stage 2 rather than SW sleep.Several studies in the cat suggest that in subanesthetic doses, alpha chloralose acts primarily on cortical inhibitory processes, causing release of the reticular activating system from inhibitory influences. The results of this study show that moderate doses in man probably act on both cortical and subcortical systems involved in the mediation of SW sleep, REM sleep and arousal.This study was supported in part by USPHS grant No. MH 10844-04 of the National Institute of Mental Health.We thank Lawrence C. Cowden and Orvis H. Rundell for their technical assistance and management of subjects, and Rosa Coulter and Cindy Williams for their contributions to analysis of data.     

“Barbiturate Thresholds” in the rabbit

Summary As a step toward exploring mechanisms determining the sedation threshold, methods were devised for measuring barbiturate thresholds in the rabbit. These utilized the behavioral indicator of head drop and the effect of thiopental on the EEG. The reliability of these thresholds was studied and attempts were made to determine whether they were altered by experimental conflict and premedication with chlorpromazine. amphetamine, and adrenocorticotrophic hormone (ACTH). Results suggest that rabbit barbiturate thresholds resemble those in man. Specific effects of conflict were not demonstrated. Although amphetamine and ACTH produced no consistent effects, chlorpromazine caused a marked decrease in threshold.Supported in part by a grant (MY-2635) from the National Institute of Mental Health and a summer medical student Research training grant to R.M. Bittle from National Institutes of Health.     

The role of catecholamines in behavioral arousal during ontogenesis

Effect of catecholamine depletion on normal hyperactivity in the neonatal rat was examined. Both -methyl-para-tyrosine and reserpine significantly depressed behavioral arousal at 15 days postpartum, the age of greatest excitability. Heightened activity could be restored in drug-treated animals by administration of l-Dopa. These results indicate that the ontogenetic hyperactivity effect is a result of accelerated catecholamine function.This work was supported in part by National Institute of Mental Health Grants MH01562 and MH08501 to Byron A. Campbell.     

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).     

Influence of secobarbital and chlorpromazine on precentral neuron activity during attentive behavior in monkeys

Precentral motor cortex neurons were studied under non-drug and drug conditions in three trained monkeys during the performance of a go-no go visual attention task. The two drugs studied, secobarbital and chlorpromazine, produced differing patterns of effect on components of the motor sequence involved in reaction time. The following components were considered: The SF interval or the period from stimulus onset to change in neuronal firing; the FR interval, which is the period from change in firing to the beginning of the task response; and MT or movement time, which is the time necessary to complete the response. Secobarbital produced an increase of 80% in SF and a relatively small average change in FR although there was considerable variability in the latter. MT was decreased in most secobarbital experiments. Anatomical factors relating to the FR variability were considered, and the MT decrease was discussed in terms of possible excitatory effects of the drug.Chlorpromazine produced small increases in SF, FR and MT, alternating with periods of complete abolition of performance. The results were discussed in terms of theories of attention deficit following administration of secobarbital and chlorpromazine.Part of the costs of this work were supported by Grants MH-12568 (N.I.M.H.) and DA-00257 (N.I.D.A.) from the United States Public Health Service. Some of these results were presented at the 1974 Meeting of the Federation of Societies for Experimental Biology and were published as an abstract by Otero and Mirsky (1974) in the proceedings of that meeting.Supported by a John E. Fogarty International Center, N.I.H. P.H.S. Fellowship No. 5-F05-TWO-1668-01/02, and by Grant Foundation Award, F.A.E.S., N.I.M.H.Supported by Research Scientist Award PHS 5 K05 MH14915-08 from N.I.M.H.     

Effects of drugs on “augmenting/reducing” in averaged visual evoked responses in man

Summary The averaged visual evoked response (VER) amplitude in some subjects at the greatest depths of modulation of sine wave light is the same or less than at lesser depths of modulation. This phenomenon is referred to as reducing and is measured by computing the slope of VER amplitudes as a function of the four greatest modulations. Previous studies reported that reducing varies between test and retest sessions, possibly due to changes in the subjects' level of arousal. In order to test this hypothesis, various drugs were employed to alter level of arousal. It was found that the two depressants (sodium pentobarbital and ethyl alcohol) both significantly decreased the slope of the VER amplitude at the four highest depths of modulation, i.e. subjects reduce more. Stimulants (methamphetamine and caffeine) and placebo, on the other hand, had no effect on the slopes. The lack of change in slope after the stimulants is discussed and possible explanations are advanced. It is concluded that level of arousal is one factor in determining the augmenting/reducing level of subjects.Supported by PHS Training Grant No. NB-5270 from N.I.H., Office of Naval Research Contract NONR 2931(00), National Institutes of Health Interdisciplinary Training Program MH 7082, California Department of Mental Hygiene grant 67-1-49. Reproduction in whole or in part is permitted for purposes of the United States Government.     

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.     

Electrophysiological correlates of the behavioral effects of tubocurarine in conscious cats

The effects of tubocurarine on behavior, electrical activity, and auditory evoked potentials were studied in restrained conscious cats. Tubocurarine hydrochloride (doses of 0.05–1 g intraventricularly) produced various central stimulatory effects characterized by EEG desynchronization, decrease in both low (7–9 Hz) and high (10–14 Hz) alpha waves, and decrease in the amplitude and area of the surfacepositive (P₁) wave of auditory evoked potentials. Concomitant with the alterations in brain electrical activity tubocurarine hydrochloride produced generalized behavioral arousal phenomena and the cats became restless and exhibited miaowing and increased movement of the head and ears. Almost all parameters except behavior showed a distinct dose-response relationship. A correlation between the behavioral effects and the EEG analog was thus demonstrated.     

Chlorpromazine and amphetamine effects on three operant and on four discrete trial reinforcement schedules

Several doses of chlorpromazine (CPZ) and amphetamine (AMP) were given to rats trained on one of three operant schedules of reinforcement (VI 60, FI 60, or FR 100) or one of three discrete trial schedules (conditioned approach, CA; conditioned discrimination, CD; or stimulus self selection, SSS). The discrete trial procedures were more resistant to disruption by CPZ than were the operant schedules. AMP facilitated behavior only in the VI and FI schedules and had differential effects in the CD schedule (milk reward showed much greater resistance to disruption than water rewarded behavior). AMP was also given to Ss trained to respond on one of three response levers for milk, water or food reinforcement. Food responding was most disrupted while milk responding was least disrupted. It is concluded that depressants—like CPZ—can be studied equally well in many behavioral procedures while compounds which activate—like amphetamine—require a variety of behavioral procedures to show their many different effects.Portions of this paper were presented at the Symposium on Methods in Drug Evaluation, Milan, Italy, 1965. This research is supported in part by Grant MH 08111 from the National Institute of Mental Health.     

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 intrinsic effects of sarmazenil on sleep propensity and performance level of sleep-deprived subjects

The effect of two dosages of sarmazenil (RO 15-3505) on sleep propensity and performance was investigated in a double-blind, placebo-controlled paradigm. The design included three 24-h testing periods, separated by at least one 7-day rest period, commencing after 24-h of sleep deprivation. Twelve normal, healthy, adult males (mean age 27±2.8 years) were paid to participate. During the experimental periods, they came to the sleep laboratory at 2100 hours and spent the night awake under close supervision. At 0700 hours, a schedule of 7 min attempting sleep in bed, 13 min awake outside the bedroom, began. This schedule was maintained for 24 h. Repeated administrations of 1 mg and 2 mg sarmazenil significantly reduced the 24-h levels of total sleep. This was particularly evident during the period 0700–2300 hours. Sarmazenil also significantly improved reaction time and tended to increase the number of correct responses in the categories search task. Sarmazenil tended to improve reaction time in the Stroop test but this was significant only for the easy version of the test during the night.     

The effects of intravenous epinephrine and norepinephrine on a conditioned response in the cat

Summary Epinephrine and norepinephrine were infused continuously into the superior vena cava of the cat during the performance of an instrumental response. Both drugs depressed performance, epinephrine at 2 g/kg/ minute and norepinephrine at 4 g/kg/minute. Smaller doses produced no effect. With larger doses, the effect was practically idistinguishable from that obtained with intraventricular injections. It is concluded that the rates of infusion required to produce behavioral depression probably exceed the maximum rates of secretion of the adrenal medulla under physiological conditions, although the necessary level might be attained by endogenous catecholamines from other sources, including the brain itself. The possible sites of action are discussed.This work was reported at the Twenty-Ninth Annual Meeting of the Eastern Psychological Association, April, 1958. It was supported by National Science Foundation Grant G-4459, and carried out while the author was a senior postdoctoral fellow on Interdisciplinary Grant 2M-6418, National Institute of Mental Health, U. S. Public Health Service.     

The effects of certain psychotropic agents on the conditioned emotional response behavior pattern of the albino rat

Summary The conditioned emotional response (CER) testing procedure was utilized as a drug screening test. Two control compounds, chlorpromazine and reserpine, and one experimental compound 5-(O-methoxyphenoxy-methyl)-2-oxazolidinone, were tested in various doses in the CER program. None of the drugs produced an attenuation of the anxiety response in the rat. It would appear that the CER program, as presented in this study, is not suitable as a screening procedure for the evaluation of potential ataractic agents.This work was supported by research grant MY-3029, National Institutes of Mental Health.     

Pharmacodynamic characterization of the electroencephalographic effects of thiopental in rats

We have developed a chronically instrumented rat model that uses changes in electroencephalographic waveforms to estimate continuously the degree of central nervous system (CNS) depression induced by thiopental. Such changes were subject to aperiodic signal analysis, a technique that breaks down the complex EEG into a series of discreet neurologic events which are then quantitated as waves/sec. We thus obtained a continuous measure of CNS drug effect. In addition we continuously recorded central arterial blood pressure and heart rate and monitored ventilatory status using arterial blood gas determinations. We also determined, with frequent arterial blood sampling, the distribution and elimination of thiopental in individual animals. The time lag occurring in the curve representing arterial concentration of thiopental vs. EEG effect suggests that arterial plasma is not kinetically equivalent to the EEC effect site. Application of semiparametric pharmacodynamic modeling techniques enabled us to estimate equilibration rate constant (K_eo for concentrations of thiopental between arterial plasma and the effect site. The half-life for equilibration of thiopental with the EEG (CNS) effect was less than 80 sec. Knowledge of the rate of equilibration permitted characterization of the relationship between the steady state plasma concentrations and CNS effect of thiopental, as measured by activation and slowing of the EEG. At concentrations of thiopental below 5 gmg/ml, EEG activity was 180% higher than during the baseline awake state. Thiopental produced an activated EEG over more than 20% of the concentration-effect relationship. Further increases in the concentration of thiopental at the site of effect depressed EEG activity progressively until complete suppression of the EEG signal occurred (at which time, the concentration was approximately 80 g/ml). This report describes our model and its application to the assessment of the pharmacodynamics of thiopental as manifested by changes on the EEG.Supported by grant RO1-AGO4594 from the National Institute on Aging, National Institute of Health; and the Anesthesia/Pharmacology Research Foundation.     

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.     

The effects of long term administration of psychotropic drugs on human sleep: I. Methodology and the effects of placebo

These six papers present the effects on human sleep of long-term administration of reserpine (0.50 mg/day), amitriptyline (50 mg/day), chlorpromazine (50 mg/day), chloral hydrate (500 mg/day), and chlordiazepoxide (50 mg/day).This initial paper describes in detail the methodology of the entire study which involves six 60-day drug periods for each subject completing the protocol-one period on each of the five drugs and one period on placebo, in a balanced design. Measures of laboratory sleep, home sleep, and mood were obtained throughout the study.Comparisons between the long placebo-only period of this study and the more usual baseline period-laboratory nights 4-6-revealed a significantly higher total desynchronized sleep time (D-time) and D-time per cent in the placebo period. Other variables were not significantly different. Some clear changes over time within the long placebo period are also described.This work was supported in part by National Institute of Mental Health Grant # MH 14520.     

Pharmaco-EEG study of 6-azaianserin (ORG 3770): Dissociation of EEG and pharmacologic predictors of antidepressant activity

The effects of a single oral dose of 6-azamianserin (2 mg) were compared to those of mianserin (6 mg), flurazepam (10 mg), and placebo in 11 healthy male volunteers, in a crossover design. Quantitative EEG, heart rate, blood pressure, task performance, and subjective state were measured. EEG and behavioral measures distinguished the substances from placebo. 6-Azamianserin was similar to mianserin in type and duration of effects. In a separate study in 12 volunteers, 0.5 and 1.0 mg of the (+) and (-) enantiomers of 6-azamianserin elicited dose-related EEG and behavioral effects, distinguishable from placebo. These effects were similar to those elicited by racemic 6-azamianserin and mianserin. Clinical trials of 6-azamianserin in depressed patients, particularly the elderly and those with cardiovascular disease, are warranted. Dosages selected should be onethird those of mianserin. The stereospecific properties of the enantiomers in preclinical tests predict that any clinical antidepressant activity will reside in the (+) isomer only, while the pharmaco-EEG trials predict that both enantiomers will be clinically antidepressant. Clinical testing of the isomers, particularly the (-) isomer, is indicated as a test of the predictive value of pharmacologic and pharmaco-EEG models of clinical antidepressant activity.     

The effects of long term administration of psychotropic drugs on human sleep: VI. The effects of chlordiazepoxide

This paper reports on the effects of long-term administration of chlordiazepoxide (CDX) (50 mg per day at bedtime) on normal young males. The effects on laboratory sleep, home sleep, and mood were investigated.CDX produced an immediate increase in sleep time, but this returned to placebo levels after 2–3 days. Slow-wave sleep (stages 3 and 4) was normal for the first few days, but then showed a great decrease and remained significantly low throughout the period of drug administration, and for the first week after discontinuation. D-time similarly is not greatly affected for the first days, but is then decreased for the remainder of the four weeks on medication. During the period when both slow-wave sleep and D-time are decreased, stage 2 sleep is greatly increased. CDX produced little effect on mood; subjective quality of sleep was judged better on CDX than on placebo by these subjects.This work was supported in part by National Institute of Mental Health Grant # MH 14520.     

Effect of chlorpromazine on the interaction between phasic and tonic electrocortical arousal mechanisms

The effect of chlorpromazine on the rate of habituation of phasic arousal responses has been studied in cats carrying permanently implanted cortical recording electrodes. In the sleeping animal repeated presentation of an auditory stimulus (1 sec duration, 3000 Hz) at intensities which only produced a localised, phasic electrocortical change in the auditory cortex, resulted in the rapid habituation of this latter response. Once habituation had occurred the intensity of the stimulus was increased until a similar change in electrocortical activity once again appeared in the auditory cortex. The habituation procedure was then repeated. In this way it was possible to habituate the animal gradually to successively higher intensities of auditory stimulation without ever inducing behavioural arousal or tonic, generalised changes in electrocortical activity. Indeed, it was possible to reach a level of stimulation which previously would have induced overt behavioural effects and tonic arousal. It may be concluded that alterations in the activity of the mechanisms responsible for phasic electrocortical responses leads to changes in the responsiveness of the animal even during sleep.Following chlorpromazine phasic electrocortical responses were still elicited but their rate of habituation was significantly increased. Thus the overall effect of chlorpromazine was a marked shortening in the time taken to train the animal while still asleep, not to respond behaviourally or with tonic electrocortical changes to a particular auditory stimulus.