Vasopressin: possible role of microtubules and microfilaments in its action.

Colchicine, vinblastine, podophyllotoxin, and cytochalasin B inhibit the action of vasopressin and cyclic adenosine monophosphate on osmotic water movement across the toad bladder. The findings suggest that microtubules, and possibly microfilaments, play a role in the action of vasopressin, perhaps through involvement in the mechanism of release of secretory material from the bladder epithelial cells.

Gammahydroxybutyrate: an endogenous regulator of energy metabolism.

Gammahydroxybutyrate is a naturally occurring metabolite of many mammalian tissues. Although its administration produces a wide range of pharmacological effects, its normal function has never been clearly defined. GHB can induce NREM and REM sleep, anaesthesia, hypothermia, and a trance-like state which has been considered a model for petit mal epilepsy. It markedly increases brain dopamine levels. It has been touted as a central neurotransmitter or neuromodulator, and high affinity brain receptors, as well as central mechanisms for its synthesis, uptake and release have been demonstrated in support of this. But GHB is also found in many peripheral tissues and in some of these in higher concentrations than in the brain. No explanation has been offered for its presence in these tissues. A number of studies indicate that GHB can reduce energy substrate consumption in both brain and peripheral tissues, and that it can protect these tissues from the damaging effects of anoxia or excessive metabolic demand. Indeed there is some evidence to suggest that endogenous GHB levels rise under these circumstances. GHB appears to act through the endogenous opioid system, since in the brain, at least, GHB raises dynorphin levels and its metabolic and pharmacological effects can be blocked by naloxone. These, and other observations detailed in this review, suggest that GHB may function naturally in the induction and maintenance of physiological states, like sleep and hibernation, in which energy utilization is depressed. GHB may also function naturally as an endogenous protective agent when tissue energy supplies are limited.

Narcolepsy: a family study.

We obtained medical and psychological assessments and 48-hr polysomnographic recordings on five sisters, three of whom had narcolepsy. Of the three, two were identical twins. All three narcoleptic sisters cited emotional stress and environmental demands for sustained performance as the major factors which aggravated their symptoms, and corresponding to this, the illness followed a different life course in each of the three. Most striking were the differences between the twin sisters in clinical symptoms and polysomnographic signs. One sister suffered from all the symptoms of narcolepsy and her sleep recording showed the typical sleep onset REM periods of the disease. Her twin suffered only from excessive daytime drowsiness and her sleep recording was normal--at least by the usual criteria. The sleep of all three narcoleptic sisters, however, was significantly more fragmented than that of their normal siblings. Our data suggested that excessive sleep fragmentation was a basic feature of narcolepsy and that it betrayed a constitutional predisposition for sleep to dissociate into its components and to become distributed around the nycthemeron. This process could be aggravated by emotional stress and by environmental demands for sustained vigilance, and this in turn, created the differences in symptoms and signs between individuals with identical genetic predispositions.

The effects of gamma-hydroxybutyrate on sleep.

Sodium gamma-hydroxybutyrate (GHB) is a remarkably safe and nontoxic hypnotic agent which is reported to be free of addicting properties. It is also a normal metabolite of the mammalian nervous system. We examined its effects on the sleep-EEG of eight patients with histories of impaired sleep, as a prelude to a more detailed study of its clinical potential. Sleep induced with GHB was indistinguishable subjectively from natural sleep as well as by behavioral and electroencephalographic criteria. Unlike most synthetic hypnotics, GHB increased delta sleep and did not suppress REM sleep. It shortened the REM sleep latency and shifted REM sleep into the first third of the night. On one occasion it induced a sleep onset REM period which was experienced as an attack of sleep paralysis. Withdrawal was simple; there was no REM sleep rebound and sleep patterns immediately returned to their pre-drug form. Its major clinical drawback was its short duration of action: its hypnotic effect lasting only 2 to 3 hr. We suggest that GHB may serve as the prototype for a new class of hypnotic compounds derived from natural sources and capable of activating the neurological mechanisms of normal human sleep.

Spectral EEG correlates of dream recall.

Recent studies have shown that dreaming is not limited to rapid eye movement (REM) sleep, but can be found to varying degrees in any stage of sleep. This study attempted to quantify the EEG correlations of dreaming during Stage 2 sleep. Six normal volunteers were studied for 24 nights in the sleep laboratory. Electroencephalogram (EEG) recording prior to awakening from Stage 2 sleep and from other stages without awakening were subjected to computer spectral analysis. Although awakenings associated with dream recall tended to have lower total power, mean frequency in the beta band proved to be the best correlate of mental activity in Stage 2 sleep. Mean frequency had its highest values in REM sleep and wakefulness and declined in Stage 2 and Stage 4 sleep, in keeping with the decline in mental activity reported from these stages. Implications of these findings are discussed with regard to models of dream recall and clinical states.

The effect of gammahydroxybutyrate on the H-reflex: pilot study.

Gammahydroxybutyrate (GHB) promotes cataplexy when given during the day, but decreases the incidence of daytime cataplexy when given at night. To understand the effects of GHB on this form of motor inhibition, we studied its actions on the H- and F-responses. The H-response is attenuated or abolished during cataplexy. GHB markedly inhibited the H-reflex response in normal and narcoleptic subjects, whether or not sleep was induced. It had no effect on the F-response. Prolonged motor inhibition at night by GHB may raise the threshold for inhibition during the day, accounting for the decrease in daytime cataplexy. The failure to affect the F-response suggests that GHB has a presynaptic site of action.

Brain neurotransmitter changes in human narcolepsy.

We measured the concentrations of the three major monoamine neurotransmitters noradrenaline, dopamine, and serotonin, their metabolites, and receptor binding sites in autopsied brain of three patients with narcolepsy. As compared with the controls, concentrations of the noradrenaline and serotonin metabolites MHPG and 5-HIAA, respectively, were markedly elevated in cerebral cortical subdivisions of the narcolepsy patients together with a trend for above-normal neurotransmitter/metabolite "turnover" ratio. A moderately reduced number of alpha 1-adrenoceptors, as judged by the reduced levels of 3H-prazosin binding, was observed in cerebral cortex of two of the three patients with narcolepsy. Mean striatal levels of dopamine and its metabolite homovanillic acid were normal, whereas the concentration of dopamine's second metabolite, dihydroxyphenylacetic acid, was markedly reduced by 50% or greater. This was accompanied by a marked increase (+125%) in mean 3H-spiperone binding to the D2 dopamine receptor in both caudate and putamen; in contrast, the levels of 3H-SCH 23390 binding to the striatal D1 dopamine receptor were in the normal range. Our data provide evidence for altered brain monoaminergic neurotransmitter function in human narcolepsy.

Treatment of narcolepsy and sleep apnea with gammahydroxybutyrate: a clinical and polysomnographic case study.

Gammahydroxybutyrate was administered to a patient who experienced narcolepsy associated with central sleep apnea. The treatment relieved the major symptoms of narcolepsy, and significantly decreased the number of apneic periods. Gammahydroxybutyrate did not cause the prolonged and potentially fatal apneic periods associated with the use of other hypnotic agents.

Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings.

Previous studies on the effects of gamma-hydroxybutyrate (GHB) on the sleep and clinical response of patients with narcolepsy are reviewed. New information on 48 patients treated with GHB for as long as 9 years is presented. These studies indicate that 2.25 to 3.00 g of GHB, taken in conjunction with a low dose of a stimulant during the day, rapidly alleviate the symptoms of narcolepsy in most patients. Tolerance does not develop to this treatment regimen; neither have any patients discontinued the treatment because of side effects. In poor responders, daytime drowsiness and not cataplexy has been the most common residual symptom. Sleep studies reveal that GHB induces REM followed by slow wave sleep. Although total sleep time at night may be unchanged, sleep is less fragmented. GHB appears to be effective because it can induce the symptoms of narcolepsy and contain them at night. It is noteworthy, therefore, that the central biochemical changes induced by GHB also appear comparable to those found naturally in narcolepsy.

Effects of flurazepam and zopiclone on the performance of chronic insomniac patients: a study of ethanol-drug interaction.

Three groups of ten middle-aged insomniac patients were treated with placebo, flurazepam, or zopiclone for 12 consecutive days in a study designed to compare the residual daytime effects of long-acting flurazepam and short-acting zopiclone on a variety of cognitive and motor tasks. These effects were examined independently and in combination with ethanol effects. The effects of the drugs on sleep parameters were also subjectively assessed by means of questionnaires during treatment and withdrawal. The study demonstrated persistent performance effects with flurazepam. Testing at the end of the treatment period showed that movement time was impaired in the flurazepam treated group. Flurazepam also enhanced the increment of movement time produced by ethanol. One subject became severely confused when given ethanol after using flurazepam for 12 days. None of these effects were found with zopiclone. The rapid elimination of zopiclone may account for these findings.

The effects of a single night's dosing with triazolam on sleep the following night.

This study was undertaken to determine whether a single night's use of triazolam by normal healthy sleepers leads to withdrawal insomnia on the subsequent night, and whether there is a dose response relationship to this phenomenon. Thirty normal sleepers of both sexes were randomly assigned to three parallel treatment groups. All subjects were studied for five consecutive nights by means of pre- and post-sleep questionnaires and all night polysomnography. Multiple sleep latency tests were conducted on the days following the second, third, and fourth nights in the laboratory. All subjects received placebo capsules on the first, second, fourth, and fifth nights in the laboratory and either placebo, 0.25 mg triazolam or 0.5 mg triazolam according to their assigned group on the third night. Both doses of the drug increased subjective estimates of sleep duration, but no objective increase was found. Neither dose altered daytime measures of sleepiness. No changes were found in any of the sleep parameters on withdrawal of the 0.25 mg dose of triazolam. However, discontinuation of the 0.5 mg dose did lead to significant objective and subjective withdrawal effects. It was concluded that higher doses of triazolam could lead to withdrawal effects in normal sleepers even when this drug was used for only a single night.

A comparative 25-night sleep laboratory study on the effects of quazepam and triazolam on chronic insomniacs.

The short- and intermediate-term actions, as well as the carryover and withdrawal effects, of quazepam , a new benzodiazepine hypnotic with a half-life of 60 to 100 hours, were compared with those of triazolam, a triazolodiazepine hypnotic with a half-line of 2 to 3 hours. Both the subjective effects of these drugs as well as their objective actions on the sleep EEG were sought. The study was conducted on two groups of six subjects with chronic insomnia who ranged in age from 32 to 56 years. Each subject was studied for 25 consecutive nights. Placebo was administered at bedtime on the first four nights, followed by 30 mg quazepam or 0.5 mg triazolam on the next 14 nights and by placebo again on the ensuing seven withdrawal nights. Both drugs increased the total sleep time during their administration and improved the subjective quality of sleep. Major differences, however, were observed on withdrawal. A significant and marked decrease in the total sleep time occurred with triazolam on the first withdrawal night. With quazepam , rebound insomnia was not observed at any time during the seven-day withdrawal period.

Serum and quantitative electroencephalographic pharmacokinetics of loprazolam in the elderly.

This study was undertaken to determine the serum pharmacokinetic parameters of loprazolam, a new benzodiazepine hypnotic, in elderly subjects and to compare these with the kinetics of the drug as determined by quantitative EEG analysis. In addition, a 14-day study was undertaken to determine the steady-state serum levels achieved in this population with repeated drug administration. The study was conducted on 16 male and female subjects between the ages of 62 and 72 years, randomly assigned to two groups treated with 0.5 or 1.0 mg of loprazolam. The serum half-life of loprazolam was found to be 5 hours, and the peak serum concentration was reached after 2 hours. Quantitative EEG changes were observed after 30 minutes suggesting rapid access of the drug into the nervous system. Quantitative EEG changes were evident for 9.5 hours, suggesting the persistent effects of an active metabolite. The 14-day study indicated that loprazolam did not accumulate with continued use.

High- and low-affinity states of dopamine D1 receptors in schizophrenia.

Using SKF-38393/[3H]SCH-23390 dopamine D1 receptor agonist/antagonist competition binding technique, we showed that schizophrenics distinguished from the neuro-psychiatric and normal controls by exhibiting a significant increase in the density of the low-affinity state, and a concomitant enhancement in the binding affinity of the high-affinity state of D1 dopamine receptors in caudate nucleus. The results suggest that perturbation in dynamic equilibrium of high- and low-affinity states of D1 receptors underlies the pathogenesis of schizophrenia.

Brain adenylate cyclase activity in the amphetamine sensitized rat.

Behaviour was augmented in rats by treatment with 10 mg/kgm d-amphetamine twice a day for 10 days. A greater activation of adenylate cyclase was found in dopamine rich areas of these rats brains than in normal controls when the enzyme was tested with sodium fluoride and quanylimidodiphosphate. These results parallel similar findings in the brains of schizophrenics obtained at post mortem and support the use of amphetamine sensitization in rats as a model for schizophrenia.

Neurodegeneration, sleep, and cerebral energy metabolism: a testable hypothesis.

Varying degrees of metabolic arrest are used by many living species to survive in a harsh environment. For example, in hibernating mammals, neuronal activity and cerebral metabolism are profoundly depressed in most regions of the brain and limited energy resources are deployed to maintain vital cell functions. Gathering evidence suggests that energy resources are also limited in both Alzheimer's and Parkinson's diseases, and that this promotes metabolic stress and the degenerative process. Key steps in this process are energy requiring, and this further compromises cell energy reserves. It may be possible to slow the progress of these diseases by inducing slow-wave sleep (SWS) at night with gammahydroxybutyrate. Patients with these diseases sleep poorly and generate little SWS. SWS and hibernation are thought to be on a continuum of energy conservation. Thus, the induction of SWS may retard the degenerative process by depressing cell metabolism and by directing energy utilization to vital cell functions. In this way, GHB-induced SWS may duplicate the effects of hibernation and extend biologic time.

Psychological, topographic EEG, and CT scan correlates of frontal lobe function in schizophrenia.

This study examined frontal lobe function in a group of 20 patients with schizophrenia, on and off medication, compared to 20 normals matched for age, sex, handedness, intelligence, and educational level. Schizophrenic patients generally did not perform as well as normals on the Wisconsin Card Sorting Test (WCST). Patients off medication performed less well on this test than those on medication. Those on medication did not perform as well as those off medication on the design and word fluency tests, which suggested that medications may affect various aspects of frontal lobe function differently. During the WCST, normal subjects demonstrated an increase in beta mean frequency of the electroencephalogram in frontal and centrotemporal regions which was not statistically significant in either schizophrenic group. This shift in beta mean frequency was found to correlate positively with performance on the WCST in normals, but not in patients. Patients with more negative symptoms tended to show a smaller increase in beta mean frequency during the WCST. Performance on the WCST was correlated negatively with ventricle-brain ratio in all subjects, suggesting that frontal lobe function might be related to computed tomographic measures in the normal population as well as in schizophrenic patients. There was no correlation with performance on the WCST and length of illness.

The treatment of narcolepsy-cataplexy with nocturnal gamma-hydroxybutyrate.

Sixteen patients with narcolepsy and cataplexy were treated with gamma-hydroxybutyrate (GHB) given at night and tailored to achieve as continuous a night's sleep as possible. The dosage usually consisted of 1.5-2.25 gm orally at bedtime and then one or two further 1.0-1.5 gm doses with awakenings during the night, and totaled about 50 mg/kg. Apart from one patient who took only the bedtime dose, the subjective quality of night sleep improved in all patients and the number of irresistible daytime attacks of sleep and cataplexy substantially diminished. Some residual daytime drowsiness remained and this usually responded well to low doses of methylphenidate. Improvement has been maintained for up to 20 months without the development of tolerance. Two patients experienced adverse side effects necessitating withdrawal of GHB treatment, but no serious toxic effects have occurred.

Effects of nocturnal gamma-hydroxybutyrate on sleep/waking patterns in narcolepsy-cataplexy.

Continuous 48-hour polygraphic recordings of sleep/waking patterns were performed on 14 patients with narcolepsy-cataplexy before and after 7-10 days of treatment of their nocturnal sleep with gamma-hydroxybutyrate (GBH). GBH improved the quality of night sleep by increasing the amount of slow wave sleep, reducing stage I, increasing sleep efficiency (percentage of time in bed spent asleep), and reducing the number of periods of short sleep under 15 minutes. Also nighttime REM sleep was reduced in latency and became less fragmented. The daytime period contained less slow wave sleep and REM sleep, and fewer episodes of prolonged sleep. Patients experienced reduction or loss of daytime attacks of irresistible sleep, cataplectic attacks, and other auxiliary symptoms. Residual daytime drowsiness subsequently improved on low doses of methylphenidate. Tolerance did not develop and there were no serious toxic side-effects. Four of the patients had been refractory to previous combinations of antidepressants and high doses of stimulants.

Clinical recovery and sleep architecture degradation.

We achieved a unique and timely recording of cerebral activity in a 70 year old woman immediately pre- and post-stroke, while studying the effect of acute cerebral infarction on sleep-electroencephalogram (EEG) patterns. Normal patterns, except for increased wakefulness, were recorded during two pre-infarct polysomnograms. Immediately following cerebral infarction increased delta activity was recorded from the infarcted hemisphere only. Initially, REM sleep could not be recorded from either side; however, on the third post infarct day REM sleep returned. Background EEG levels from both hemispheres became progressively slower, flatter and simpler. In addition, sleep spindles and the distinctive saw-tooth wave forms of sleep almost disappeared. At one year post-stroke sleep-EEG rhythm recordings from both hemispheres became more similar except for persisting delta activity from the left hemisphere. Unexpected deterioration of sleep-EEG pattern recordings from the undamaged hemisphere taken during the patient's clinical recovery remains unexplained. Serial sleep recording may facilitate the study of brain recovery, activity and reorganization following stroke.