The nature of performance deficit under secobarbital and chlorpromazine in the monkey

The effects of secobarbital and chlorpromazine were studied in monkeys trained on a continuous, rapidly presented successive discrimination task. The subjects were implanted with epidural electrodes to monitor EEG during drug-induced impairment of performance. The analysis was focussed on the phase of drug effect during which both drugs induced intermittent lapses of responding.EEG and behavioral analysis of events following stimulus onset lead to the conclusion that the mechanism of error occurrence is different under the two drugs. The effect of secobarbital was prominent both in correct and incorrect trials; input, integration and output processes seemed to be functional but slowed down. This was inferred from the presence of EEG arousal, late or abortive motor responses (in the case of errors) and prolonged reaction time of correct responses. In contrast to this general, even effect, CPZ affected the performance in an all-or-none fashion. Periods of normal functioning (i.e., correct responses with moderately increased average reaction time) alternated with complete absence of responsiveness including the EEG arousal reaction. These findings support the view that secobarbital suppresses the behavior by affecting the level of wakefulness and thus impairing the functional condition of the whole central nervous system; chlorpromazine on the other hand exerts its effect by selectively blocking input processes subserving the EEG and behavioral arousal.Supported by Grant MH-12568 from the National Institute of Mental Health, Public Health Service.Research Scientist Awardee (5-K-5-MH-14, 915) of 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 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).     

Contrasting effects of vasopressin,desglycinamide-vasopressin and amphetamine on a delayed matching to position task in rats

The effects of peripherally injected arginine vasopressin (AVP: 0–25 g/kg), its desglycinamide analogue (DGAVP: 0–25 g/kg), which is practically devoid of pressor activity, and d-amphetamine (AMP: 0–1.25 mg/kg) were studied using a delayed (0–32 s) matching to position task (Dunnett 1985). A limited hold for responding (20 s) was in operation. This task enables an accurate assessment of forgetting in rats. AVP reliably improved per cent correct performance, and this effect was substantiated by accuracy indices derived from signal detection theory (TSD). DGAVP, however, was inactive, suggesting that the parent peptide's pressor properties were responsible for its beneficial effects. AMP disrupted performance in a dose-related manner, and was the only substance to alter a TSD bias index (responsivity index, RI), indicating a degree of response repetition at the highest dose. These results are consistent with some earlier reports, and suggest that AVP may enhance memory by peripheral action, while AMP disrupts performance. Closer inspection of the data, however, suggested that the peptide reduced general responsiveness. A new index to measure bias (Sahgal 1987) suggested that AVP-treated subjects restricted their sample and choice responses to one side of the operant chamber, thereby achieving a spuriously high detection rate with few errors of commission (incorrect responses). It is concluded that AVP does not, after all, improve performance: on the contrary it has detrimental effects, and produces errors of omission (failure to respond).     

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.     

Dissociation between the attentional effects of infusions of a benzodiazepine receptor agonist and an inverse agonist into the basal forebrain

The effects of infusions of the benzodiazepine receptor (BZR) full agonist chlordiazepoxide (CDP) or the full inverse agonist -CCM into the basal forebrain on behavioral vigilance were tested. Vigilance was measured by using a previously characterized task that requires the animals to discriminate between visual signals of variable length and non-signal events. Measures of performance included hits, misses, correct rejections, false alarms, side bias, and errors of omission. Following the infusion of saline (0.5 µl/hemisphere), the relative number of hits varied with signal length. In response to shorter signals, the number of hits decreased over time, indicating a vigilance decrement. Infusions of CDP (20, 40 µg/hemisphere) initially decreased the relative number of hits in response to shorter signals and, later in the course of the test sessions, to longer signals as well. CDP did not affect the relative number of correct rejections. In contrast, infusions of the inverse agonist -CCM (1.5, 3.0 µg/hemisphere) did not affect the relative number of hits but decreased the relative number of correct rejections (i.e., increased the number of false alarms). These data suggest that the basal forebrain mediates the attentional effects of BZR ligands. As systemic or intrabasalis administration of BZR agonists and inverse agonists was previously demonstrated to decrease and augment, respectively, activated cortical acetylcholine (ACh) efflux, their effects on behavioral vigilance are hypothesized to be mediated via their effects on cortical ACh.     

Inhibition by 8-hydroxy-2-(di-n-propylamino) tetralin and SM-3997, a novel anxiolytic drug,of the hippocampal rhythmical slow activity mediated by 5-hydroxytryptamine1A receptors

Summary Electrophysiological studies using spectral analysis techniques were undertaken in rabbits to determine whether or not hippocampal rhythmical slow activity (RSA, theta wave activity) was affected by the 5-hydroxytryptamine_1A (5-HT_1A) agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 3 , 4 , 7 , 7 -hexahydro-2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-4, 7-methano-IH-isoindole-1,3(2H)-dione dihydrogen citrate (SM-3997, a newly synthesized anxiolytic drug). Intravenous administration of 8-OH-DPAT and SM-3997 induced a desynchronized pattern with low-amplitude slow wave activity in the hippocampal EEG and inhibited RSA generation following stimulation of the midbrain reticular formation. RSA was also inhibited by 5-HT_1A related anxiolytics such as buspirone, gepirone, and ipsapirone. The effects of 8-OH-DPAT and SM-3997 on the hippocampal RSA were blocked by pindolol, which has 5-HT_1A antagonistic activity. Direct microinjection of these 5-HTIA selective agonists into the hippocampus inhibited generation of the hippocampal RSA. These findings indicated that 8-OH-DPAT and SM-3997 inhibited the hippocampal RSA by acting on hippocampal 5-HTIA receptors. Send offprint requests to A. Hirose at the above address     

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.     

Drug effects on discrimination performance at two levels of stimulus control

The effects of several doses of d-amphetamine, chlordiazepoxide (CDP), chlorpromazine (CPZ), LSD, pentobarbital, and scopolamine were examined in rats trained to respond to the brighter of two keys. On each of the 100 trials during a daily session, the rat pressed the key that was brighter (correct key) and received a food pellet, or pressed the incorrect key and terminated the trial without food, or pressed neither key for 10 s, allowing the trial to terminate. Within a session, trials were mixed randomly such that on 50 trials the incorrect key was not lit (easy trials,) and on 50 trials the incorrect key was dimly lit (difficult trials). Amphetamine (0.5–2.0 mg/kg) reduced percent correct responses, with a greater effect of difficult than on easy trials. CDP (4.0–16.0 mg/kh) and pentobarbital (2.0–16.0 mg/kg) reduced percent correct responses on the difficult trials at the highest doses tested. Scopolamine (0.12–1.0 mg/kg) reduced both percent correct (more so on the difficult trials) and percent of trials on which a response was made, in a dose-related fashion. CPZ (1.0–4.0 mg/kg) reduced trial responding at 2.0 and 4.0 mg/kg and reduced percent correct on the difficult trials at 4.0 mg/kg. LSD (0.08–0.32 mg/kh) did not significantly alter behavior in this study.A preliminary report of these data was presented at the Rocky Mountain Psychological Association Annual Convention, Denver, Colorado, April, 1978     

An observational study of intravenous medication errors in the United Kingdom and in Germany

Objectives: To investigate the incidence and the severity of intravenous (i.v.) drug preparation and administration errors in two countries and three pharmacy services. Method: A disguised observational method was used to record details of the preparation and administration of prescribed i.v. drugs on two wards in each of three teaching hospitals: one with a traditional British ward pharmacy service (TBP) and two hospitals in Germany, one with a traditional ward stock supply (TGP) and one with a satellite pharmacy service (GSP) with unit dose system. Main outcome measures: Errors in i.v. drug preparation and administration and their potential significance. Results: The number of observed preparations/administrations were: TBP 77/63, TGP 126/109 and GSP 134/106. The preparation error rates were: TBP 22% (95% confidence interval: 1331%), TGP 23% (1630%) and GSP 31% (2339%). The administration error rates were TBP 27% (1638%), TGP 49% (3958%) and GSP 22% (1430%). The percentage of administration errors on the wards with TGP was statistically significantly higher than in the other two services. Common errors at the study sites with TBP and GSP were omissions. Wrong rate of administration occurred most frequently on the wards with TGP. The majority of errors were likely to be of 'moderate' to 'severe' outcome. Careful drug chart reading could possibly reduce omission errors on the wards with TBP. A change of the German nursing law ('Krankenpflegegesetz') to legally entitle nurses to administer i.v. drugs could probably result in better training, national guidelines and standards. Conclusion: This study found a high rate of i.v. medication errors of moderate to severe significance. Changes in practice should be considered to make i.v. therapy safer for patients.     

Effect of destruction of the 5-hydroxytryptaminergic pathways on the acquisition of temporal discrimination and memory for duration in a delayed conditional discrimination task

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on the acquistion of a temporal discrimination and on memory for duration, using a delayed conditional discrimination task. In phase I, rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and shamlesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset, a response on a panel placed midway between the two levers was required in order to intiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a correct response, reinforcer delivery. Both groups gradually acquired accurate discrimination, achieving >90% correct choices within 20–30 sessions; the lesioned group acquired accurate performance significantly faster than the control group. In phase II, delays were interposed between stimulus offset and lever presentation in 50% of the trials (2, 4, 8, 16 and 32 s; 10% of trials in each case). Accuracy declined as a function of post-stimulus delay in both groups, and there was no significant difference between the performances of the two groups. Both groups showed an increasing tendency to respond on lever A following longer post-stimulus delays (choose-short effect); this effect was somewhat enhanced in the lesioned group. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered.     

“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.     

Dependence of the cardiovascular effects of pindolol on the individual sympathetic nervous activity

Summary To investigate the mechanism of the relative beta-antagonist and agonist properties of pindolol, the cardiovascular effects of i.v. pindolol 0.01 mg/kg were studied in 23 subjects with different baseline levels of cardiac beta-adrenergic function. Baseline cardiac beta-adrenergic activity was assessed by the decrease in heart rate following intravenous propranolol 0.2 mg/kg (HR) after parasympathetic blockade with intravenous atropine 0.04 mg/kg. Cardiac beta-adrenergic sensitivity was defined by the positive chronotropic effect of a three minute infusion of isoprenaline 0.005 µg/kg/min. The chronotropic effect of intravenous pindolol was negatively correlated with resting beta-adrenergic activity (R=–0.81, p<0.001). The traditional point of HR, at which pindolol shifted from beta-antagonist to beta-agonist action, was 17 beats/min, i.e. pindolol decreased heart rate in subjects with HR greater than 17 bpm, and increased heart rate in those with HR less than 17 bpm. The chronotropic effect of intravenous pindolol, however, was positively correlated with beta-sensitivity (R=+0.73, p<0.001). Thus subjects with the greatest increment in heart rate with isoprenaline had an increased heart rate with pindolol, while those with the lowest increment in heart rate with isoprenaline had a decreased heart rate with pindolol. Intravenous pindolol decreased cardiac index and increased total peripheral resistance in the group with HR more than 17 bpm, and it had the contrary actions in the group with HR less than 17 bpm. Blood pressure in both groups was not significantly changed by pindolol. Compared to endogenous catecholamines, pindolol was considered to possess higher beta-adrenocepter affinity and weaker beta-adrenoceptor stimulating action. Therefore, pindolol produced a net beta-blocking action in subjects with elevated cardiovascular sympathetic nervous activity and beta-stimulating action in subjects with reduced sympathetic nervous activity.     

Enhancement of Solubility and Bioavailability of β-Lapachone Using Cyclodextrin Inclusion Complexes

Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with -lapachone (-lap) to overcome solubility and bioavailability problems previously noted with this drug. Methods. Inclusion complexes between -lap and four cyclodextrins (-, -, -, and HP-CD) in aqueous solution were investigated by phase solubility studies, fluorescence, and ¹H-NMR spectroscopy. Biologic activity and bioavailability of -lap inclusion complexes were investigated by in vitro cytotoxicity studies with MCF-7 cells and by in vivo lethality studies with C57Blk/6 mice (18-20 g). Results. Phase solubility studies showed that -lap solubility increased in a linear fashion as a function of -, -, or HP-CD concentrations but not -CD. Maximum solubility of -lap was achieved at 16.0 mg/ml or 66.0 mM with HP-CD. Fluorescence and ¹H-NMR spectroscopy proved the formation of 1:1 inclusion complexes between -CD and HP-CD with -lap. Cytotoxicity assays with MCF-7 cells showed similar biologic activities of -lap in -CD or HP-CD inclusion complexes (TD₅₀ = 2.1 M). Animal studies in mice showed that the LD₅₀ value of -lap in an HP-CD inclusion complex is between 50 and 60 mg/kg. Conclusions. Complexation of -lap with HP-CD offers a major improvement in drug solubility and bioavailability.     

Effects of ZK 93426 on muscarinic and nicotinic antagonist or nucleus basalis lesioning-induced electrocortical slowing

The present study investigated the effects of a benzodiazepine receptor antagonist, -carboline ZK 93426 (1, 3 and 10 mg/kg, IP), on scopolamine and nucleus basalis (NB) quisqualic acid lesion-induced neocortical electrocortical activity slowing in rats. Scopolamine induced a dose dependent increase in EEG spectral values and slow delta waves (0.3<0.9=2.7 mg/kg IP). ZK 93426 partially reversed EEG slowing induced by the smallest scopolamine dose (0.3 mg/kg), but had no effect on the EEG changes induced by higher doses. A combination of scopolamine at 0.3 mg/kg and mecamylamine (a centrally active nicotinic antagonist) at 10 mg/kg induced an EEG slowing that was not reversed by ZK 93426. NB lesions markedly decreased cortical choline acetyltransferase (ChAT) activity (–77%) and increased EEG slow waves. ZK 93426 had no effect on the NB lesion-induced slow wave activity increase. The present results support the idea that -carboline ZK 93426 may increase cortical cholinergic activity by disinhibiting the NB cholinergic neurons. However, if the activity of NB to cortex cholinergic system is greatly decreased by either a marked reduction in NB cell number (in NB-lesioned rats), a near complete cortical post-synaptic muscarinic receptor blockade (large scopolamine dose) or by a combination of nicotinic (decrease acetylcholine release) and muscarinic receptor blockade, the effects of -carboline ZK 93426 on EEG slowing may be negligible.     

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.     

Metabolic fate of mescaline in man

Summary Human subjects given C¹⁴-mescaline by mouth excrete an average of 87% of the dose during the first 24 hours and an average of 92% during the first 48 hours. Average half-life of mescaline in six hours.The composition of the urine in respect to the various metabolites of mescaline from hour to hour has been determined. The concentration of mescaline and its metabolites in the plasma and the cerebrospinal fluid at the various times has also been determined.Mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetyl--(3,4-dimethoxy-5-hydroxyphenyl) ethylamine and N-acetyl-mescaline have been identified in human urine after mescaline administration in the following amounts: mescaline 55–60%, 3,4,5-trimethoxyphenylacetic acid 27–30%, N-acetyl--(3,4,dimethoxy-5-hydroxyphenyl) ethylamine 5% and N-acetylmescaline less than 0.1%. Five other metabolites have been partially characterized.Chromatographic evidence is presented for the presence of mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetylmescaline and N-acetyl--(3,4-dimethoxy-5-hydroxyphenyl) ethylamine in the cerebrospinal fluid in man after oral mescaline administration.This investigation was supported in part by Public Health Service Research Grant, MH-10777, from the National Institute of Mental Health.     

The contribution of the time locking of EEG waves to the generation of the auditory P300

OBJECTIVES: To study the time locking of the 'natural' (delta, theta, slow alpha, fast alpha and beta) EEG waves during the generation of the P300 in passive (P300a) and active (P300b) auditory oddball paradigms in order to obtain insights into the generation of the P300 and into the transitions between background and evoked activity. METHODS: Tone burst stimuli (standard and deviant) were delivered to normal young adult subjects in passive and active oddball paradigms. The time distributions of EEG waves were analyzed in several frequency bands during background and post-stimulus periods. RESULTS: The ongoing background activity was modified by the deviant stimulus, producing the time locking of the positive delta, theta and alpha EEG deflections in the time range of the P300. This involved prolongation of the positive component of negative-positive wave complexes so that the positive wave was delayed into the time period of the P300. The time locking effects were more prominent in the delta and theta ranges, and differed in frequency components and scalp topography between the two paradigms. Not all deviant stimulus trials contributed deflections to the P300. The contributing trials can be selected, providing the basis for single trial analysis. CONCLUSIONS: The study of the time locking of the EEG waves in different frequency bands provides improved analysis of the P300 and an approach to single deviant stimulus trial analysis, that in turn can enhance signal-to-noise ratios. The results show that the time reorganization of EEG can be considered in the generation of P300 separately from the amplitude factor. SIGNIFICANCE: This can lead to improved analysis of normal and abnormal brain function in individual subjects.     

Stabilizing and Solubilizing Effects of Sulfobutyl Ether β-Cyclodextrin on Prostaglandin E1 Analogue

Purpose. Parent cyclodextrins are known to accelerate the degradations such as dehydration and isomerization of E-type prostaglandins in neutral and alkaline solutions. The objective of this study was to attempt the stabilization and solubilization of E₁-type prostaglandin analogue in aqueous solution by biocompatible cyclodextrin derivatives. Methods. The interaction of an E₁-type prostaglandin, methyl 7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-4-(m-methoxymethylphenyl)1-butenyl]-5-oxocyclopentyl]-5-thiaheptanoate (MEester) with cyclodextrins (CyDs) was studied by spectroscopies and the solubility method. The degradation of MEester was monitored by high-performance liquid chromatography. Results. ¹H-nuclear magnetic resonance spectroscopic studies indicated that MEester forms 1:1 inclusion complexes with -, -, and -CyDs in solutions, where -CyD interacts with the -side chain containing methyl ester moiety of the drug, whereas - and -CyDs preferentially include around the five-membered ring and both side chains of the drug. Parent -CyD and hydrophilic derivatives, such as 2-hydoxypropyl-- and --CyDs, sulfobutyl ether -CyD (SBE--CyD) and maltosyl -CyD showed higher solubilizing abilities against MEester over parent - and -CyDs. SBE--CyD and 2,6-dimethyl--CyD (DM--CyD) significantly decelerated the degradation of MEester, particularly the base-catalyzed dehydration, in neutral and alkaline solutions, whereas other CyDs accelerated the degradation. The acid-catalyzed degradation of MEester (pH < 3) was decelerated by the addition of CyDs, especially -CyD. Conclusions. SBE--CyD with low hemolytic activity and low toxicity is useful as a pharmaceutical carrier for the preparation of injectable MEester, because of its higher stabilizing and solubilizing effects on MEester. Furthermore, SBE--CyD can be useful as a stabilizing agent for drugs, that are subject to base-catalyzed degradations, probably because of the electric repulsion between anionic charges of the sulfobutyl moiety and catalytic anionic species such as hydroxide ion.     

Single and repeated administration of neuroleptic drugs to rats: Effects on striatal dopamine-sensitive adenylate cyclase and locomotor activity produced by tranylcypromine and L-tryptophan or L-dopa

Injection of tranylcypromine and L-tryptophan results in rats displaying behavioural changes including hyperactivity, probably due to stimulation of post-synaptic 5-hydroxytryptamine (5-HT) receptors. Increased locomotor activity of a different type is elicited by injection of tranylcypromine and L-dopa, a procedure which increased dopaminergic function in the brain. It has now been demonstrated that the neuroleptic drugs, chlorpromazine, -flupenthixol, haloperidol and spiroperidol block both syndromes. The inhibition produced by these drugs on 5-HT-induced hyperactivity is probably because a dopaminergic system is involved in the behavioural expression of the 5-HT induced hyperactivity. The structurally related drugs with no neuroleptic activity (ethopropazine, promethazine and -flupenthixol) are without effect on these hyperactivity syndromes. Also ineffective were the neuroleptics pimozide and clozapine.Striatal dopamine sensitive adenylate cyclase activity in vitro was inhibited by the administration of chlorpromazine (100 mg/kg) in vivo.Rats treated for 4 or more days with chlorpromazine, -flupenthixol, spiroperidol and haloperidol subsequently showed enhanced locomotor activity in response to tranylcypromine and L-Dopa. Administration of those drugs which did not block hyperactivity acutely did not result in enhancement. Only chlorpromazine, when given for 4 days, enhanced the hyperactivity response following tranylcypromine and L-tryptophan, probably because the drug also blocks 5-HT receptors.In rats displaying enhanced behavioural responses no evidence was found for enhanced sensitivity of striatal adenylate cyclase to dopamine.