Biomedical subjects
Publications and source records attributed to W B Mendelson.
Electroencephalographic sleep recordings were compared in patients with panic disorder and normal controls. Correlation coefficients of standard sleep parameters versus ratings of anxiety, depression, and panic attack frequency were calculated in the panic-anxious patients. Overall findings are discussed in the context of previous sleep studies in patients with depressive, anxiety, and obsessive-compulsive disorders.
Four 51-year-old monozygotic quadruplets concordant for schizophrenia, originally studied at the National Institute of Mental Health 25 years ago, were restudied with topographic electroencephalography (EEG), evoked potentials (EPs), computed tomography (CT scans), polysomnographic sleep recordings, and positron emission tomography (PET) with 18F-2-deoxyglucose. EEG and EP findings were consistent with those from other groups of patients with schizophrenia and showed great similarity within the quadruplets. CT scans revealed uniformly small lateral ventricles. PET scans replicated earlier findings of relatively low glucose use in the frontal lobes but did not show strong familial concordance.
Basal growth hormone levels were measured every 20 minutes over 24 hours in eight long-term survivors of acute lymphoblastic leukemia and in 13 age- and pubertal stage-matched normal children. Among the patients, the median total basal growth hormone output (AUC) was 43 units, compared with 341 units in the normal control group (P less than 0.001). In the patients, mean pulse amplitude (6.9 ng/ml) and frequency (4.6) over 24 hours also were reduced, compared with the control values (32 ng/ml and 8.5, P less than 0.001 and P less than 0.05, respectively). In addition, normal children secreted more GH at night (median AUC 280) than during the day (113, P less than 0.001). However, this diurnal pattern was absent in three of the patients studied. These data suggest that perturbations of spontaneous pulsatile GH secretion are common after standard therapy for ALL and may be a sensitive means of detecting therapy-related neuroendocrine damage. Blunting of spontaneous pulsatile GH secretion may contribute to the abnormalities in growth seen in children with ALL.
Previous studies have implicated the benzodiazepine receptor in the sleep-inducing effects of these widely used hypnotics, but the effector mechanism of this process is poorly understood. There is also in vitro evidence that benzodiazepines enhance calcium entry into synaptosomal preparations, leaving open the possibility that altered calcium flux may be involved in their actions. In order to explore this hypothesis, we administered intraventricular nifedipine, a calcium blocking agent. It was found that pretreatment with a dose of nifedipine which by itself does not affect sleep will prevent sleep induction by flurazepam in rats. Effects on anticonvulsant properties of flurazepam or anxiolytic effects of diazepam were not apparent. This suggests that changes in calcium channel function may be involved in the hypnotic action of benzodiazepines.
The discovery of high affinity, stereoselective binding sites for benzodiazepines (BZ) was a major step in understanding the molecular mechanism by which these widely used sedative/hypnotics exert their various pharmacologic effects. It has become clear that the BZ receptor complex has functional significance in terms of the anxiolytic, anticonvulsant and muscle relaxant properties of these widely used compounds. Until recently its role in the sleep-inducing properties has been unclear. This paper reviews a series of studies indicating that the BZ receptor complex does indeed mediate the hypnotic effects of flurazepam, and that these effects may involve alterations in calcium flow across neuronal membranes. Preliminary evidence also suggests that some pharmacologic properties of barbiturates may involve interactions with portions of the benzodiazepine receptor complex. Lethality from pentobarbital in mice, for instance, can be greatly reduced by treatment with IPPO, a compound which binds in relation to the chloride ionophore. The implications of sub-types of BZ receptors are discussed. Experience with some compounds which bind at the BZ receptor suggests that in the future drugs may become available which are much more specific for individual desired effects.
Explore the source record for details and available documents.
Patients should be aware of alterations in sleep with age, and they should not have unrealistic expectations. Drinking or taking sleeping pills is not likely to be a long-term solution to a sleep problem. Chronic difficulty in sleeping raises the possibility of sleep apnea, nocturnal myoclonus or depression, all of which commonly appear after 40. In the absence of these and other, less common disorders, sleep can often be improved by exercise, regular habits and removal of any disturbing elements from the bedroom.
Both the methyl ester of beta-carboline-3-carboxylic acid and the 6,7-dimethoxy-4-ethyl derivative of this compound are potent convulsants in rodents, while the ethyl ester of beta-carboline-3-carboxylic acid does not cause convulsions, even when administered at very high doses. The rate of degradation of these compounds by rat plasma (in vitro) parallels their potencies as convulsants. In contrast, 3-carboethoxy-beta-carboline was found to potently elicit tonic and clonic convulsions in the squirrel monkey (Saimiri sciureus). Furthermore, the rate of degradation of 3-carboethoxy-beta-carboline in monkey plasma (in vitro) is negligible compared with rats. No significant differences were observed in either the potency or efficacy of GABA to inhibit [3H]beta-carboethoxy-beta-carboline binding in rat and monkey brain. These data strongly suggest that pharmacokinetic, as well as pharmacodynamic, factors may determine the pharmacologic profile of these beta-carboline-3-carboxylic acid esters.
Intravenous administration of 3-carboethoxy-beta-carboline (beta-CCE, 10 mg/kg) to rats resulted in multiple bursts of rhythmic waves (2-4 second duration, 5-7 Hz) with amplitudes of 100-250 microV. Pretreatment of animals with the benzodiazepine receptor antagonists CGS 8216 prevented the electroencephalographic seizures elicited by beta-CCE. This dose of CGS 8216 did not produce any electroencephalographic abnormalities when administered alone. These observations suggest that the electroencephalographic seizures elicited by beta-CCE are mediated via an interaction with benzodiazepine receptors. An in vitro study of the rate of degradation of beta-CCE and 3-carbomethoxy-beta-carboline (beta-CCM) in rat plasma demonstrated that the rate of degradation of the former compound was three times more rapid than the latter. These observations, taken together with previous studies demonstrating that parenteral administration of beta-CCM elicits tonic and clonic seizures, suggests that pharmacokinetic factors may be involved in defining the pharmacologic profile of beta-carboline-3-carboxylic acid esters.
The effects of the benzodiazepine antagonist CGS 8216 (2-phenylpyrazolo[4,3-c]quinoline-3(5H)-one) were examined in a thirsty rat conflict test in the presence and absence of pentobarbital. CGS 8216 (2.5-10 mg/kg i.p.) did not affect nonpunished responding, but doses of 5 and 10 mg/kg significantly reduced the rate of punished responding (i.e., the number of 3 second drinking episodes in a "shock" contingency). However, a dose of CGS 8216 which did not significantly alter punished responding (2.5 mg/kg) antagonized the anticonflict actions of pentobarbital. These observations suggest that while high doses of CGS 8216 may elicit an "anxiogenic" response in rodents, lower doses of CGS 8216 antagonize the anticonflict actions of a compound which has been shown to enhance benzodiazepine affinity in vitro. These data imply that the anticonflict actions of pentobarbital may be mediated through benzodiazepine receptors.
The benzodiazepine receptor antagonist 3-hydroxymethyl-beta-carboline, which blocks several of the pharmacological actions of benzodiazepines, induces a dose-dependent increase in sleep latency in the rat. Furthermore, at a low dose that by itself does not affect sleep, 3-hydroxymethyl-beta-carboline blocks sleep induction by a large dose of flurazepam. The benzodiazepine receptor may play a role in both the physiological regulation and pharmacological induction of sleep.
Parenteral administration of the adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) results in a profound decrease in spontaneous motor activity in mice and rats. The inhibition of cortical ADA activity measured ex vivo parallels the decrease in spontaneous motor activity in a time-dependent manner. Nonetheless, a marked reduction in electroencephalographically defined sleep was observed in rats during a period when both spontaneous motor activity and ADA activity were profoundly inhibited. These data suggest that EHNA produces in rats a state of 'quiescent waking', which may be related to the observed inhibition of brain ADA activity.
By using Vogel's method to test the anxiolytic action of benzodiazepines and reducing the intensity of the current delivered to the drinking tube, it is possible to distinguish the pharmacological activity of three types of ligands for the benzodiazepine recognition site. An anticonflict action typical of anxiolytic benzodiazepines, a proconflict action typical of many beta-carbolines, including FG 7142 (beta-carboline-3-carboxylic acid ethyl ester methyl amide), and an antagonistic action of the proconflict and anticonflict actions typical of RO 15-1788 (ethyl-8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-alpha]-[1, 4]-benzodiazepine-3-carboxylate) and CGS 8216 (2-phenylpyrazolo[4,3-c]quinolin-3-(5H)-one). Pentylenetetrazole, which causes convulsions by interacting with a subunit of the gamma-aminobutyric acid receptor that is different from the benzodiazepine recognition site, also induces a proconflict action that is antagonized by anxiolytic benzodiazepines but not by RO 15-1788.
Previous studies have demonstrated that injections of growth hormone (GH) can blunt subsequent GH secretory responses to daytime pharmacological stimulation. The current study was undertaken to determine whether GH administration to normal subjects would suppress sleep-related secretion. GH (2 U im) was given nine times over 5 days to each of six subjects, and sleep studies with blood sampling were performed 6 h after the last injection. Secretion during the first 2 h of sleep was decreased by 62.4%, indicating that sleep-related GH secretion may be responsive to a negative-feedback mechanism.
Fourteen patients with obsessive-compulsive disorder (OCD) were studied with all-night sleep EEG recordings. Nine of these patients reported abnormal sleep patterns before the polygraphic study. Analysis of the sleep records disclosed significantly decreased total sleep time with more awakenings, less stage 4 sleep, decreased rapid-eye-movement (REM) efficiency, and shortened REM latency compared with those of a group of age- and sex-matched normal subjects. These abnormalities generally resembled those of an age-matched group of depressed patients, although significant differences remained. These findings suggest that such sleep abnormalities as shortened REM latency may not be entirely specific for primary affective illness. They also point to a possible biological link between OCD and affective illness.
The effects of clorgyline, a type A monoamine oxidase (MAO) inhibitor, on the sleep of the rat were examined after subacute and lifetime administration. When 2 mg/kg 24 hours were given for 60 hours, type A MAO was inhibited by 92% and a significant reduction in REM sleep time was noted. When fetal rats were exposed to maternal dosage of 1 mg/kg/24 hours and then received this dose from one to 6 weeks postnatally, type A MAO was inhibited by 99%, but there were no alterations in the EEG sleep stages. In summary, subacute administration of clorgyline resulted in decreases in both Type A MAO and REM sleep; during chronic administration in a developing animal, Type A MAO was again decreased, but there was no corresponding change in REM sleep.
Cortical EEG analysis of the effects of cholecystokinin (CCK) on sleep were performed in rats treated intraperitoneally with 1,10, or 20 micrograms/kg CCK8. Latency to the first episode of non-REM sleep was significantly reduced from 29 minutes to 16 minutes. No change in total waking time, total non-REM sleep, or total REM sleep was seen at any dose over the first hour after CCK administration. Locomotor activity was significantly reduced by 10 micrograms/kg CCK8 during the first ten minutes only. The temporal separation between the sleep-latency reduction and the behavioral inactivity induced by CCK indicate that these effects are distinguishable phenomena. Sleep does not appear to be a primary cause for the satiety-related behavioral effects of CCK.
Naloxone produced improvement in abnormal thought content in medicated chronic schizophrenic patients, but not in drug-free patients. In contrast, drowsiness and increases in plasma prolactin concentrations were seen only in drug-free schizophrenic patients. Although growth hormone concentrations increased in drug-free and medicated schizophrenic patients, the time course was different in the two groups. Neuroleptics appear to alter naloxone's clinical and neuroendocrine effects in chronic schizophrenic patients.