Effects of phencyclidine,secobarbital and diazepam on eye tracking in rhesus monkeys

Rhesus monkeys were trained to track a moving disk using a procedure in which responses on a lever were reinforced with water delivery only when the disk, oscillating in a horizontal plane on a screen at a frequency of 0.4 Hz in a visual angle of 20 degrees, dimmed for a brief period. Pursuit eye movements were recorded by electrooculography (EOG). IM phencyclidine, secobarbital, and diazepam injections decreased the number of reinforced lever presses in a dose-related manner. Both secobarbital and diazepam produced episodic jerky-pursuit eye movements, while phencyclidine had no consistent effects on eye movements. Lever pressing was disrupted at doses which had little effect on the quality of smooth-pursuit eye movements in some monkeys. This separation was particularly pronounced with diazepam. The similarities of the drug effects on smooth-pursuit eye movements between the present study and human studies indicate that the present method using rhesus monkeys may be useful for predicting drug effects on eye tracking and oculomotor function in humans.     

MCI-225, A Novel Thienopyrimidine Analog,Enhances Attentional Eye Tracking in Midpontine Pretrigeminal Preparation

The effects of MCI-225, a novel psychoactive compound, and reference drugs on attention behavior were studied using visual stimulus induced vertical eye tracking movements in midpontine pretrigeminal (PTG) feline preparation. Surgery was performed under ether anesthesia and subsequently switched to nitrous oxide-fluothane which was discontinued only during experimental sessions. In addition xylocaine was locally injected. Vertical eye movements were monitored by electrooculogram (EOG) and a TV camera. To compare the effects of drugs on eye movement, numbers of spontaneous and tracking eye movements exceeding a present amplitude in EOG were counted before and during the visual stimulation, respectively. MCI-225 (1 and 3 mg/kg, i.v.) enhanced tracking movements dose-dependently without an increase in spontaneous eye movements. No or little change of the electrocorticogram (ECoG) was seen with 1mg/kg MCI-225 and a slight increase in low voltage fast pattern was observed with 3mg/kg, i.v.. On the other hand, tacrine (0.3mg/kg, i.v.), physostigmine (0.03mg/kg, i.v.) and methylphenidate (0.3mg/kg, i.v.) enhanced both types of eye movement and induced ECoG arousal. Desipramine (3mg/kg, i.v.) slightly increased spontaneous eye movement without affecting tracking movements. Piracetam (100mg/kg, i.v.) decreased spontaneous eye movements only. These data clearly show that MCI-225 enhances attention to a moving object and suggest that MCI-225 could be useful in the treatment of attentional deficits and related congnitive dysfunctions in psychiatric disorders.     

Effect of amphetamine on saccadic and smooth pursuit eye movements

Healthy volunteers received single oral or intravenous doses of d-amphetamine sulphate (15 mg) and placebo in a double blind randomized design. Peak velocity of horizontal saccadic eye movements, saccade duration, saccade reaction time and smooth pursuit velocity were measured at intervals up to 1 h (IV) and 6 h (oral) after drug administration. Amphetamine produced no significant effect on saccadic and smooth-pursuit eye movements after oral administration. However, intravenous amphetamine abolished the effect of fatigue on saccadic movements and significantly (P less than 0.01) shortened saccadic reaction time.     

Behavioral effects of the isomers of pentobarbital and secobarbital in mice and rats

To determine what stereoselective differences there may be in the behavioral effects of the isomers of pentobarbital and secobarbital, the effect of each isomer was determined on the spontaneous motor activity (SMA) and multiple fixed-ratio 30, fixed-interval 600-sec (mult FR30 FI600) responding of mice, and on the variable-interval 60-sec (VI60) responding of rats. The S-(-) isomers of pentobarbital and secobarbital decreased SMA at lower doses than those required for the R-(+) isomers. At moderate to high doses of R-(+)-pentobarbital (30-42.5 mg/kg) and low to moderate doses of S-(-)-secobarbital (5.6-17.5 mg/kg) SMA was increased. An increase in SMA following R-(+)-secobarbital was only observed at 30 mg/kg, and no increases were observed with S-(-)-pentobarbital. No potency differences were observed between the isomers of pentobarbital and secobarbital on the responding of mice under the mult FR30 FI600 schedule over a dose range of 1-30 mg/kg. Increases in FI600 responding were only observed following moderate doses of the S-(-) isomer of pentobarbital (5.6-17.5 mg/kg). In rats responding under the VI60 schedule of food presentation, no qualitative stereoselective differences were observed in the behavioral effects of the isomers of pentobarbital (1-13 mg/kg) and secobarbital (1-13 mg/kg), but small differences in potency were observed. Thus, differences in the effects of the isomers were usually restricted to differences in potency, but in some cases differences in efficacy were observed.     

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.     

Addiction to secobarbital and chlordiazepoxide in the rhesus monkey by means of a self-infusion preference procedure

Monkeys were exposed to a 24 h continuous experimental procedure which provided a periodic forced choice between the self-infusion of secobarbital versus saline. Preference for secobarbital over saline was readily obtained using choice trials programmed approximately every 2 h at a dose of 9 mg/kg of secobarbital per infusion. Preference for self-infusion of chlordiazepoxide over saline was obtained using choice trials every 3 h, and a dose on the order of 1 mg/kg per infusion. In a subsequent experiment, two of the animals addicted to chlordiazepoxide were given a choice every 3 h between an infusion of chlordiazepoxide or secobarbital. Following a period of intake of both drugs, a gradual shift in preference from chlordiazepoxide to secobarbital was observed over a period of some 60 days. In general, this preference procedure provides a flexible technique with several dependent measures for single or multiple drug addiction studies.Supported in part by a contract from the Department of Justice, Bureau of Narcotics and Dangerous Drugs, J 69 15.     

Interaction of oxaprozin with acetaminophen,cimetidine, and ranitidine

Summary Twelve healthy male volunteers participated in a single-dose four-way crossover study to evaluate potential drug interactions with oxaprozin, a nonsteroidal antiinflammatory agent of the propionic class. The four modes of administration were:a. oxaprozin, 1200 mg alone;b. oxaprozin during concurrent acetaminophen, 500 mg 4 times daily;c. oxaprozin with cimetidine, 300 mg 4 times daily;d. oxaprozin with ranitidine, 150 mg every 12 hours. Acetaminophen, cimetidine, or ranitidine were begun 24 hours prior to oxaprozin dosage and continued for the 10-day duration of each trial. No significant differences existed among the four treatment conditions in peak plasma oxaprozin concentration (86 µg/ml), volume of distribution (0.23 l/kg), time of peak concentration (3.7 h after dosage), or elimination half-life (54 h). Oxaprozin oral clearance was significantly lower (by 20%) during both the cimetidine and ranitidine trials versus control (0.047 vs 0.047 vs 0.059 ml/min/kg), but clearance during acetaminophen was not significantly different from control. Thus acetaminophen, cimetidine or ranitidine has only a small influence on the pharmacokinetics of a single oral dose of oxaprozin. The reduction in oxaprozin clearance due to cimetidine or ranitidine is statistically significant but small in magnitude.Supported in part by Grants MH-34223 and AG-00106 and Biomedical Research Support Grant RR-05598 from the USPHS, and by a Grant-in-Aid from Wyeth Laboratories, Radnor, PA, USA     

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.     

Methamphetamine's effect on repeated acquisitions with serial discrimination reversals

Rats were trained through a series of discrimination reversals until they developed a stable, repeated acquisition baseline. Methamphetamine (0.5 mg/kg) accelerated acquisition measured from this baseline. The drug effect was demonstrated with successive cumulative records and with a graphic method using a distribution of error scores to develop a baseline. Generally, with low doses(0.25–0.50), methamphetamine reduced errors without affecting rewarded responding. This effect is dose dependent, although at 1.0 mg/kg the drug may disrupt operant behavior.Experiments I and II were conducted while the author was an NSF Science Faculty Fellow at Indiana University. Facilities were provided by the Psychopharmacology Laboratory supported by USPHS Grant MH-14658 to Dr. G. A. Heise. Experiment III was conducted at the University of Tennessee.     

The discriminative stimulus properties of barbiturate stereoisomers

Pigeons were trained to discriminate an IM injection of racemic pentobarbital sodium (5.0 mg/kg) from saline under a second-order color-tracking schedule of mixed grain presentation. In a time-course study, maximal pentobarbital-appropriate responding occurred 15 min after administration of 5.0 mg/kg racemic pentobarbital sodium, the pretreatment time used for subsequent experiments. Racemic pentobarbital sodium, the R(+) and S(-) isomers of pentobarbital, racemic secobarbital sodium, and the R(+) and S(-) isomers of secobarbital all produced dose-dependent increases in pentobarbital-appropriate responding. Racemic secobarbital sodium, the secobarbital isomers, and the R(+) isomer of pentobarbital were equipotent to each other and slightly less potent than racemic pentobarbital and the S(-)-pentobarbital isomer in this regard. Except for R(+)-pentobarbital, all barbiturates caused dose-dependent decreases in response rate over the dose range tested.     

The effects of several barbiturates on lithium chloride induced taste aversion

The effects of single doses of five barbiturates on LiCl induced saccharin aversion were examined. Twenty three hour fluid deprived rats were offered a novel 0.125% saccharin solution and then were injected with either 3.0 mEq/kg LiCl or 0.9% saline. On the first test day after conditioning the animals were injected with either 60 mg/kg sodium phenobarbital, 80 mg/kg sodium barbital, 30 mg/kg sodium amobarbital, 20 mg/kg sodium secobarbital, 9 mg/kg sodium pentobarbital or 0.9% saline, 15 min prior to the drinking session. Results indicate that only 9 mg/kg pentobarbital, 60 mg/kg phenobarbital, and 80 mg/kg barbital were effective in attenuating the LiCl induced saccharin aversion on the day of administration. In addition, dipsogenic effects for only 60 mg/kg phenobarbital and 30 mg/kg amobarbital were observed in the saline treated control groups. A synergistic interaction between the effects of LiCl and sodium phenobarbital, barbital, and secobarbital was also observed. Lithium chloride plus these barbiturates resulted in a longer term aversion to saccharin than LiCl alone and no barbiturate produced saccharin aversion when administered without LiCl.     

Comparison of progressive-ratio performance maintained by cocaine,methylphenidate and secobarbital

Cocaine, methylphenidate and secobarbital were compared on a drug maintained progressive-ratio procedure in baboon subjects. Trials, scheduled throughout the day, occurred at a minimum interval of 3 hrs after completion of the preceding trial. A ratio response requirement on the initiate lever was required during each trial which terminated in a single intravenous infusion of drug. A drug was introduced on the progressive-ratio procedure with a low ratio requirement in order to obtain a baseline performance of a high stable frequency of trial completion. The ratio requirement was systematically increased every 7 days until the breaking point when the rate of completing trials fell below a criterion level. Within-subject comparison revealed that cocaine produced higher breaking points than methylphenidate at the same absolute dose, 0.4 mg/kg. At the range of doses studied, manipulation of doses of methylphenidate (0.1–0.8 mg/kg) and cocaine (0.4–1.6 mg/kg) had little effect on breaking point. In contrast, increasing doses of secobarbital (6.0 and 12.0 mg/kg) produce higher breaking points within the same subjects.     

A research note on some of the critical factors on the dissimilar effects of chlorpromazine and secobarbital on the digit symbol substitution and continuous performance tests

Summary The effects of single doses of chlorpromazine and secobarbital on performance of normal subjects on four behavioral tests were compared. The tests were the Continuous Performance Test (CPT), an experimenter-paced test requiring continued vigilence on the part of the subject; the Digit Symbol Substitution Test (DSST), a self-paced, cognitive test; the Subject-Paced Test (SPT), a test designed to include the same visual stimuli as those used in the CPT with the subject having control over the speed of presentation of the visual stimuli: and the Symbol Copying Test (SCT), a test designed to have all the motor, visual, and self-pacing components of the DSST with the cognitive aspect removed.The results support the hypothesis that chlorpromazine causes more decrement in performance than does secobarbital on experimenter-paced tests where sustained attention is necessary. However, on self-paced tests where sustained attention is not necessary, secobarbital causes more decrement in performance than does chlorpromazine. A self-paced test that is sensitive to barbiturates ceases to be a sensitive indicator of barbiturate effects when the cognitive aspect of the test is removed.This research is supported by USPHS Grant MH-03312-04 and GM-K3-1759-C3-A.The authors wish to thankHarold Lee, M. D., Assistant Superintendent at Medfield State Hospital, for his co-operation in both obtaining the subjects and for assuming medical responsibility for the subjects.     

Secobarbital and nocturnal physiological patterns

Summary Sleep patterns of 14 male Ss were examined following a single oral dose (200 mg) of the barbiturate secobarbital. Compared to baseline, medication caused definite changes in the amount and distribution of the EEG stages of sleep. With the drug, a decrease in percent stage REM and an increase in percent stage 2 were accompanied by fewer body movements and a trend toward less waking. A more striking effect was the drug-induced redistribution of EEG stages with slow-wave sleep potentiated during the first half of the night but virtually eliminated during the last half. Stage REM, on the other hand, was inhibited in the first half but returned to baseline levels in the last half of the night. Recent evidence suggests that such effects could result from modulation of brain levels of the monoamines.Within the stages of sleep the amount of fast EEG activity was increased by the drug, with a tendency toward desynchrony. Pre-central beta activity became especially prominent in stages REM and 2 (low-voltage phases), and this change was associated with inhibition of such phasic events as eye movements during REM sleep, sigma spindles during stage 2 and spontaneous electrodermal responses in slow-wave sleep. Thus, it appears that secobarbital potentiates tonic and suppresses phasic phenomena during sleep. A possible interpretation of these results is that secobarbital enhances electrical activity in forebrain structures (Routtenberg's arousal system II) while inhibiting the reticular activating system (arousal system I) causing a reduction of phasic variability in all stages of sleep.We wish to thank O. H. Rundell and Joe Gold for their assistance in data acquisition and management of the experiment, and Rosa Coulter, Cindy Williams and Maria Chan for their invaluable contributions to data reduction and statistical analysis.     

Comparison of the effects of morphine,pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their lateral hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3–10 mg/kg), pentazocine (1.0–30 mg/kg), cyclazocine (0.03–3.0 mg/kg) and d-amphetamine (0.1–3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine>morphine>pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates were reduced at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.Publication No. 1303 of the Division of Basic Health Sciences of Emory University. This investigation was supported by USPHS Grant DA-00541.Recipient of Research Scientist Development Award K02-DA00008.     

Effects of acute ethanol intoxication combined with secobarbital abuse on hemostasis

Male Sprague-Dawley rats were treated with 0.5 ml of 46% ETOH, 2.8 mg/kg of secobarbital or 14.3 mg/kg secobarbital or combinations thereof. Twenty-four hours following treatment, blood clotting data was determined. The data indicated that either ethanol or secobarbital alone is just as detrimental to hemostasis as is the combined abuse of both. Likewise, a lesser concentration of alcohol was just as disruptive on hemostasis as was the greater concentration of ethanol.     

Convulsant versus typical barbiturates: effects on locomotor activity

The present studies examined the effects of a typical (secobarbital) and a convulsant (cyclohexylideneethyl-5-barbituric acid [CHEB]) barbiturate on spontaneous locomotor activity in rats. Administered alone, secobarbital produced a mild stimulation of activity at a low (2.5 mg/kg) dose, and a dose-dependent depression of locomotor activity at higher (5-20 mg/kg) doses. Surprisingly, the convulsant barbiturate CHEB produced a depression of locomotor activity at all subconvulsant doses tested (2.5-20 mg/kg). IP administration of CHEB was also observed to produce abdominal muscle contractions (writhing). In a second experiment, it was found that the writhe-inducing compound para-phenyl-quinone (PPQ) did not affect locomotor activity, indicating that the depression of activity produced by CHEB was not secondary to its writhe-producing effects. In a third experiment, the "barbiturate antagonist" potential of CHEB was examined. Treatment with 10 mg/kg CHEB did not significantly alter the depression of locomotor activity produced by 10 mg/kg secobarbital. These data suggest that (1) typical and convulsant barbiturates are not strict opposites in terms of all of their behavioral actions and (2) CHEB may not be effective as a "barbiturate antagonist."     

Effect of dopaminergic stimulation or blockade on morphine-withdrawal aggression

The effects of morphine (10 mg/kg), nalorphine (1 and 10 mg/kg), and naloxone (1 mg/kg) were studied on the neocortical release of acetylcholine (ACh) in midpontine pretrigeminal transected rats. Morphine and, to a lesser extent, nalorphine decreased ACh release. Naloxone was ineffective alone but antagonized the action of morphine.Predoctoral fellow with scholarships from Laval University and Province of Quebec, Canada.This research was supported in part by USPHS grant MH-11846.     

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.     

Effects of secobarbital on human aggressive and non-aggressive responding

This study examined the effects of secobarbital on human aggressive responding in a controlled laboratory setting. Sixty minutes prior to experimental sessions, male subjects were administered either placebo or 50, 100 or 200 mg per 70 kg of body weight doses of secobarbital double-blind. During these sessions, subjects could press a button to accumulate points exchangeable for money (non-aggressive response) or press another button ostensibly to subtract points from a fictitious person (aggressive response). Aggressive responding was occasioned by subtracting points from the subject. Subjects were instructed that points were subtracted by another person. Aggressive responding was maintained by contingent presentation of periods free of point subtractions, i.e., provocations. Acute secobarbital administration produced dose-dependent decreases in non-aggressive responding, and increases in aggressive responding.