LSD and tryptamine effects on sleep/wakefulness and electrocorticogram patterns in intact cats

Effects of intravenous infusions of LSD (3.75, 7.5, 15 g/kg over 5 min; crossover N=4) and tryptamine (0.04, 0.08, 0.12 mg/kg/min for 150 min; cross-over N=6) were compared to saline in intact cats through observation of five sleep/waking patterns. Electrocorticogram (ECoG) was analyzed for frequency band indices and mean amplitude and frequency. LSD increases wakefulness and drowsiness and decreases spindle sleep and rapid eye movement (REM) sleep during the first 75 min (period 1). The increase in active wakefulness and decrease in REM sleep persist during period 2, with an increase in spindle sleep thereafter. LSD increases delta index and ECoG amplitude, with a decrease in ECoG frequency; these effects peaked in period 2. Tryptamine increases wakefulness and drowsiness during period 1, with decreases in spindle sleep and REM sleep. The increase in quiet wakefulness and decrease in REM sleep persist during period 2, but no significant tryptamine effect is seen in sleep/waking patterns after infusion ceases. ECoG frequency increases during tryptamine infusion (periods 1 and 2), while ECoG amplitude increases during periods 2 and 3. Thus LSD and tryptamine both increase wakefulness, decrease spindle sleep, and decrease REM sleep.A summary of the results of this study was presented at the Fall Meeting of the American Society for Pharmacology and Experimental Therapeutics, August 19–23, 1973, East Lansing, Michigan, and published in The Pharmacologist 15, 161 (1975). A summary was also presented at the 17th annual meeting of the Association for the Psychophysiological Study of Sleep, April 17-May 1, 1977, Houston, Texas, and published in Sleep Research 6, 74 (1977)     

The effects of acutely administered low dose sarin on cognitive behaviour and the electroencephalogram in the common marmoset.

Previous studies have suggested that administration of a clinically sign-free dose of sarin to non-human primates gives rise to subtle changes in brain electrical activity as measured by electroencephalography (EEG) several months following exposure. The functional significances of such changes are unclear. The present study monitored EEG by using implantable radiotelemetry, and also assessed the performance of complex behavioural tasks, in non-human primates for up to 15 months following exposure to a low dose of sarin. Baselines of EEG and behaviour were shown to be stable over several months in control animals. The doses of sarin administered caused erythrocyte cholinesterase inhibitions of 36.4% to 67.1%. Overall, no significant changes in EEG patterns were observed although there were increases in beta 2 amplitude which approached significance (p=0.07). No deleterious effects on performance were seen on the touchscreen mediated discrimination tasks presented from the Cambridge Neuropsychological Test Automated Battery (CANTAB). This study illustrates the validity of the approach employed and makes an important contribution to the investigation of the long-term effects of organophosphorous compounds.     

The effects of estazolam on sleep, performance, and memory: a long-term sleep laboratory study of elderly insomniacs.

Insomnia, a common complaint among the elderly, is generally treated with benzodiazepines. Long-acting benzodiazepines (e.g., flurazepam) often produce daytime somnolence and performance deficits, whereas short-acting drugs (e.g., triazolam) have been associated with marked rebound insomnia and anterograde memory loss. The authors designed a pilot study to evaluate the efficacy of an intermediate-acting benzodiazepine, estazolam (e.g., ProSom), as well as its side effects. The parameters studied were sleep, daytime performance, and memory. Ten geriatric patients (greater than 60 years of age) with insomnia participated in the study. They received placebo nightly for 2 weeks (baseline), estazolam 1 mg nightly for the next 4 weeks (treatment phase), and placebo again for 2 weeks (withdrawal period). Sleep was monitored by polysomnography the first two nights of each week in a sleep laboratory. Estazolam significantly decreased sleep latency, nocturnal awakenings, and wake time after sleep onset. Total sleep time increased an average of 63 minutes the first night of treatment. Significant improvements in wake time after sleep onset and total sleep time also were observed in the fourth week of estazolam treatment. Rebound insomnia occurred on the first withdrawal night only for wake time and total sleep time. By the next night, these sleep parameters returned to baseline. Neither day-time performance nor anterograde memory was adversely affected by estazolam treatment or its withdrawal. A 1-mg dose of estazolam appears to be a safe and effective hypnotic for elderly patients with insomnia.     

Correlation of brain catecholamines with cortical acetylcholine outflow, behaviour and electrocorticogram

The effects of changes in the brain DA/NA ratio were correlated with cortical acetylcholine outflow, behaviour and E.Co.G. in unanaesthetized, unrestrained guinea pigs. The prevailing reduction in DA content determined by α-methyl-p-tyrosine and the increase in NA levels caused by d,1-dihydroxyphenylserine, were associated with reduced acetylcholine outflow, sedation and E.Co.G. synchronization. Conversely, the predominance of DA over NA, obtained with L-dopa and Fla-63, was associated with increased acetylcholine outflow and desynchronized E.Co.G., although sedation occurred after Fla-63. The results are in agreement with the concept that DA enhances and NA restrains the functional level of the cholinergic telecenphalic structures.     

Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep

AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100?mg, 300?mg and 1000?mg) and placebo were studied in 16 healthy male volunteers (18-45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000?mg dose. Analysis of the recovery sleep showed that CX717 1000?mg significantly reduced stage 4 and slow-wave sleep (p?≤?0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000?mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep.     

Effects of beta-blockers and nicardipine on oxotremorine-induced tremor in common marmosets

Effects of beta-blockers (propranolol, arotinolol and nipradilol) and a Ca2+ channel blocker (nicardipine) on oxotremorine-induced tremor were studied in common marmosets. Generalized tremor was elicited by an intraperitoneal administration of 0.25 mg/kg oxotremorine. Intensity of the tremor was classified into 7 degrees, and it was evaluated every 10 min. The total intensity of oxotremorine-induced tremor for each drug was expressed as "points", which were the sum of tremor intensity scores evaluated every 10 min up to 190 min following the administration of oxotremorine. Beta-blockers significantly suppressed the tremor. On the other hand, the Ca2+ channel blocker exacerbated the tremor.     

Effects of ropinirole on motor behavior in MPTP-treated common marmosets

The effects of ropinirole (4-[2-(dipropylamino)ethyl]-2-indolinone monohydrochloride), a nonergoline dopamine receptor agonist with a high affinity for native dopamine D(2)-like receptors, on Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2.5 mg/animal in common marmosets were examined and compared to the effects of bromocriptine. Ropinirole (0.1-3 mg/kg, PO) increased motor activity dose dependently and reversed akinesia or uncoordinated movement in MPTP-treated marmosets. The activities for ropinirole were very similar to those of bromocriptine. Ropinirole had, however, several properties that differed from those of bromocriptine. Ropinirole caused a more rapid onset of anti-Parkinsonian activity compared to bromocriptine, and had a potency more than five times greater than that of bromocriptine in the improvement of motor deficits. The combination of ropinirole and L-DOPA increased the effectiveness of ropinirole or L-DOPA alone, and produced a more marked additive effect on motor activity than did bromocriptine and L-DOPA. Chronic administration of ropinirole for 21 days produced a statistically significant increase in motor activity compared to the initial administration, and akinesia scores, measured through rating the quality of movements, were also improved without obvious dyskinesia. This study suggests that ropinirole is a dopamine D(2)-like receptor agonistic drug of potential use in the treatment of Parkinson's disease.     

CNS side effects of centrally-active antihypertensive agents: A prospective,placebo-controlled study of sleep,mood state,and cognitive and sexual function in hypertensive males

A prospective, placebo-controlled, comparative evaluation was conducted on two widely prescribed, sympatholytic antihypertensive agents with known CNS effects. In order to separately assess these effects in younger and older male hypertensives, patients were assigned to either of two treatment studies based on age. For study I, 24 males aged 31–59 (mean=49.8; SD=7.4) with mild hypertension (mean DBP=100.2 mm Hg; SD=8.0) received 3 months of treatment with propranolol (20–80 mg bid), clonidine (0.1–0.3 mg bid), or double-blind placebo in a counterbalanced, crossover design. For study II, 23 elderly hypertensive males (mean DBP=102.6 mm Hg; SD=8.2) aged 60–78 years (mean=65.1; SD=4.6) were randomized to propranolol (20–40 mg bid) or double-blind placebo therapy. Patients received cognitive testing, mood assessments, and all-night polysomnographic evaluations before and after each treatment period. Multivariate analysis of EEG sleep data was statistically significant for study I, with significant univariate effects on four of the six primary sleep variables: total sleep time was reduced, sleep maintenance decreased, REM latency increased, and percent total REM time was reduced. A similar MANOVA analysis for the effects of treatment on the sleep of older patients (study II) was not significant. However, propranolol administration was found to be associated with a significant decline in cognitive performance in these patients. Significant mood effects were observed with each of the study drugs, and nocturnal penile tumescence (NPT) was significantly decreased in both younger and older patients. Overall, this research suggests that distinct patterns of CNS effects are associated with each of the antihypertensive agents studied.     

Acute effects of hydroxyzine on nocturnal sleep and sleep tendency the following day: A C-EEG study

The acute hypnotic effects of hydroxyzine 25 mg and 50 mg nocte, were examined in six male and six female volunteers. Continuous electrophysiological measures (C-EEG) were taken to assess both nocturnal sleep and sleep tendency the following day. Both doses produced significant reductions in sleep onset latency and decreases in waking during sleep; reciprocal increases in sleep duration were also seen. Female subjects demonstrated a greater hypnotic response, including a dose-dependent decrease in sleep onset latency. Increases in sleep duration following both doses were significant for the female group alone. C-EEG measures of increased drowsiness the following day failed to achieve significance; although the largest effects on daytime sleepiness, including dose-dependent increases, were again seen with the female subject group and corresponded with subjective ratings. These results demonstrate the hypnotic efficacy of hydroxyzine whilst failing to detect significant C-EEG hangover effects. However, variability in response to antihistamines, registered here as differences between the sexes, requires further consideration.     

A comparative study on the effects of brotizolam and flurazepam on sleep and performance in the elderly

This study was undertaken to compare the effects of 0.25 mg of brotizolam, 15 mg of flurazepam, and placebo on the sleep and performance of elderly subjects with chronic insomnia during a 2-week period of administration. Thirty-six male and female subjects who ranged in age from 60-72 years were divided into three treatment groups. All groups received placebo on the first three study nights, the active drug or placebo on the next 14 nights, and placebo again on the two following withdrawal nights. Sleep was assessed by means of questionnaires, and residual effects during the day were studied by means of the multiple sleep latency test and a variety of memory, performance, and vigilance tests. Sleep improved with all treatments. Rebound insomnia was noted on brotizolam withdrawal; flurazepam withdrawal had a milder impact. At the end of this 19-night study, only the placebo-treated group was sleeping significantly longer than at baseline. Both drug treatments increased daytime sleepiness and impaired performance on the first day after their administration. These effects waned after 2 weeks of treatment with brotizolam, but not flurazepam. The results of this study affirm the increased sensitivity of elderly subjects to benzodiazepine hypnotics and their indication for acute or intermittent insomnia, rather than for the more chronic forms of this disorder.     

Some effects of muscarinic cholinergic blocking drugs on behavior and the electrocorticogram

Summary Results are presented for the effects of drugs with muscarinic cholinergic blocking actions, both central and peripheral (scopolamine and 1-hyoscyamine) and primarily peripheral (methyl atropine and methyl scopolamine), on conditioned avoidance behavior, spontaneous motor activity, and the ECG in the rat. Low doses of the agents with central actions retarded acquisition of conditioned avoidance, while high doses virtually abolished it. Both low and high doses were essentially ineffective in altering retention of conditioned avoidance. Agents with primarily peripheral actions had no effect on acquisition or retention. Most of the agents produced an increase in spontaneous activity although there was a definite suggestion that higher doses depress activity. All of the agents used provoked a high amplitude, slow frequency ECG. This phenomenon was dose-related; scopolamine appeared to be most effective. It is suggested that the disruption of the acquisition, but not retention, of conditioned avoidance is due to a deficit of recent memory. A possible site of action of cholinergic blocking drugs is proposed. This work was supported in part by USPHS Grant MY-02653. United States Public Health Service Postdoctoral Fellow MPD-12, 702-C2.     

Multiple vaccine and pyridostigmine interactions: effects on EEG and sleep in the common marmoset

Following active service during the 1990/1991 Gulf conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans' Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that long-term health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated using a non-human primate model, the common marmoset. This paper reports the results from two aspects of the study, brain electrical activity (EEG, collected during performance of a touchscreen mediated discrimination task) and sleep. There were no marked long-term changes in EEG or sleep patterns that could be attributed to vaccines and/or PB administration. The changes that were detected were predominantly time related and independent of treatment. Where statistical differences were detected between treatments, the magnitudes of the difference were relatively minor and therefore not regarded as having long term biological significance.     

Evaluation of the efficacy of metaclazepam and its effects on sleep,psychomotor performance and cognitive function in anxious patients

The effects of single and multiple doses of metaclazepam were investigated in 60 anxious patients. A 15 mg nocturnal dose of metaclazepam was compared to two daily doses (5 mg in the morning and 10 mg at bedtime) in terms of efficacy and effects on various aspects of sleep, cognitive function and psychomotor performance. Anxiolytic efficacy was assessed by means of questionnaires, including the Self Rating Anxiety Scale of Zung, State Trait Anxiety Inventory of Spielberger, and a modified version of the Hamilton Anxiety Rating Scale. Hypnotic activity was evaluated using a clinical rating of insomnia questionnaire. The psychometric battery consisted of tests of Critical Flicker Fusion, Choice Reaction Time and Digit Span. In terms of clinical efficacy, metaclazepam administered in either dosage regimen demonstrated a good anxiolytic activity profile. Both dosage regimens were effective in improving the quality and quantity of sleep, however the number of intermittent awakenings were significantly higher with the daily divided dose. In addition, the nocturnal administration of metaclazepam did not appear to be associated with any undesirable side effects or decrements in psychomotor performance the following morning. In conclusion, it appears that a 15 mg bedtime dose of metaclazepam is efficacious in relieving anxiety without impairing psychomotor performance the following morning. © 1998 John Wiley & Sons, Ltd.     

A double-blind,placebo-controlled study of the effects of eptastigmine on scopolamine-induced cognitive deficits in healthy male subjects

This double-blind, placebo-controlled, crossover study examined the effects of two single doses of eptastigmine, a novel cholinesterase inhibitor, on scopolamine-induced cognitive deficits in 24 healthy male volunteers. Each subject received the following treatment sequences, separated by at least 1 week, in a randomly assigned order:

Sex- and histamine-dependent long-term cognitive effects of methamphetamine exposure.

As prenatal methamphetamine (MA) exposure results in long-term hippocampus-dependent cognitive deficits, the increased MA use in women of childbearing age is of great concern. As mice are most commonly used in genetic models, we started to study the potential effects of neonatal MA exposure in female and male mice on brain function 3 months later. As histamine (HA) might mediate some effects of MA in adulthood, we also tested whether in neonates HA might mediate the long-term effects of MA using HA H(3) receptor agonists and antagonists. Stimulation of HA H(3) receptors by H(3) agonists inhibits HA synthesis and release, whereas inhibition of H(3) receptors by H(3) receptor antagonists increases HA release. MA (5 mg/kg), the H(3) receptor antagonist thioperamide (5 mg/kg), and the H(3) receptor agonist immepip (5 mg/kg) alone or in the presence of MA (5 mg/kg) were administered once daily from postnatal days 11 to 20 and the mice were tested at 3 months of age. Here we show that in mice exposure to MA early in life causes sex-dependent impairments in object recognition, spatial learning, and memory in the water maze, and pre-pulse inhibition in adulthood. HA mediates these impairments. Increasing HA release mimicked, whereas inhibiting HA release blocked the long-term detrimental MA effects. This model could be used to determine the role of genetic and environmental factors in MA-dependent cognitive impairments and to develop therapeutic strategies to inhibit them.     

Electroencephalographic study of the effects of tetrahydrocannabinols on sleep in the rat

This study examined the effects of tetrahydrocannabinols on sleep-wake states, and especially on paradoxical sleep (PS), in rats bearing chronically implanted EEG and EMG electrodes. Greatest attention was given to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), but Δ⁸-tetrahydrocannabinol and marihuana extract distillate were also studied. These agents in i.p. doses of 5 and 10 mg/kg reduced PS in rats non-deprived (ND) of PS, caused an apparent dissociation of phasic and tonic events of PS in PS-deprived (PSD) rats, and tended to decrease slow-wave sleep and increase wakefulness. No PS rebound was detected during 5 post-drug days in ND rats. In PSD rats the normal PS rebound was replaced by a form of “incomplete PS” characterized by tonic hippocampal theta rhythm, absence of muscle activity and continuous cortical spindling in the absence of normal phasic activity. The effect of 10 mg/kg of Δ⁹-THC administered daily for 20 days was initially to suppress PS; this was followed by rapid development of tolerance to effects on both sleep and behavior. Partial tolerance remained upon retesting at the 13th withdrawal day. When Δ⁹-THC was withdrawn no PS rebound occurred in rats. In preliminary experiments in cats, single doses of Δ⁹-THC (10 mg/kg i.p.) caused a clear-cut inhibition of PS in both ND and PSD cats which was followed by a significant PS rebound on the first post-drug day.     

The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice

When mice are exposed to harmless objects such as marbles in their cage they bury them, a behaviour sometimes known as defensive burying. We investigated the effect of an acute dose of MDMA (èecstasy') and other psychoactive drugs on marble burying and also examined the effect of a prior neurotoxic dose of MDMA or p-chloroamphetamine (PCA) on burying. Acute administration of MDMA produced dose-dependent inhibition of marble burying (EC50: 7.6 micro mol/kg). Other drugs that enhance monoamine function also produced dose-dependent inhibition: methamphetamine PCA paroxetine MDMA GBR 12909 methylphenidate. None of these drugs altered locomotor activity at a dose that inhibited burying. A prior neurotoxic dose of MDMA, which decreased striatal dopamine content by 60%, but left striatal 5-HT content unaltered, did not alter spontaneous marble burying 18 or 40 days later. However, a neurotoxic dose of PCA which decreased striatal dopamine by 60% and striatal 5-HT by 70% attenuated marble burying 28 days later. Overall, these data suggest that MDMA, primarily by acutely increasing 5-HT function, acts like several anxiolytic drugs in this behavioural model. Long-term loss of cerebral 5-HT content also produced a similar effect. Since this change was observed only after 28 days, it is probably due to an adaptive response in the brain.     

Immediate and long-term effects of opiate antagonists on postictal behaviour following amygdala kindling in the rat

Male Wistar rats implanted with bipolar electrodes in the amygdaloid complex were kindled. Subcutaneous injection of naloxone or naltrexone in low doses--0.12 and 0.24 mg/kg, respectively--dramatically reduced the postictal behavioural depression (BD) at 10 or 60 min. Remarkably, the BD was still reduced one day later. It would appear that the brain mechanisms involved in postictal BD use mu-receptors since BD is quite sensitive to low doses of the preferential antagonists naloxone and naltrexone. The long-term effects, the most novel aspect of these studies, are probably related to immediate effects but could be produced through slow genomic processes or alteration of the response to endogenously released enkephalins.