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Biomedical subjects

J V Martin

Publications and source records attributed to J V Martin.

At least 37 records · Page 2Linked to original sources
PubMed1989

Behavioral and electroencephalographic effects of the adenosine1 agonist, L-PIA.

The effects of N6-(L-2-phenylisopropyl)-adenosine (L-PIA), an A1 agonist, were measured on both spontaneous locomotor activity and electroencephalographic (EEG) measures of sleep in rats. L-PIA strongly inhibited motor activity at 100 micrograms/kg intraperitoneally (IP), a dose which had no statistically significant effects on EEG-defined sleep. A higher dose of L-PIA (200 micrograms/kg) increased the latency to sleep initiation and inhibited later REM sleep. These results demonstrate that L-PIA can produce a state of apparent behavioral quiescence in the presence of EEG-defined arousal.

Adenosine↗
PubMed1989

Enhancement of sleep by microinjection of triazolam into the medial preoptic area.

A growing literature suggests that the basal forebrain may contain structures involved in the regulation of sleep. As part of a series of studies designed to locate the site(s) of hypnotic action of benzodiazepines, we have injected triazolam into the medial preoptic area (MPA) of the hypothalamus of rats. Total sleep time was increased, due primarily to an increase in non-rapid eye movement (non-REM) sleep and a trend toward a decrease in intermittent waking time. A previous study from this laboratory reported that injections into the raphe nucleus decreased sleep, whereas injections at adjacent sites were without effect. These studies indicate the selectivity with which different brain regions respond to triazolam in terms of actions on sleep.

Animals↗
PubMed1988

Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy?

High affinity recognition sites for benzodiazepines are part of the gamma-aminobutyric acid (GABA) supramolecular complex on the plasma membrane of neurons in the mammalian brain. Synthetic agonist benzodiazepines promote GABA-ergic neurotransmission, and hence the hypnotic and anxiolytic effects of this class of drugs, by binding to these sites. A normal physiological role for these binding sites is unknown, and an endogenous ligand for benzodiazepine receptors has not been definitely identified in normal animals. In animals and human beings with hepatic encephalopathy, however, benzodiazepine receptor antagonists have induced amelioration of the encephalopathy, and an endogenous substance that competitively binds to benzodiazepine receptors has been found in cerebrospinal fluid. These findings suggest that an endogenous ligand for the benzodiazepine receptor with agonist properties contributes to hepatic encephalopathy by promoting GABA-ergic neurotransmission.

Benzodiazepines↗
PubMed1988

Effects of flurazepam on sleep, arousal threshold, and the perception of being asleep.

This study examined the effects of flurazepam on arousal threshold and on quality of sleep during nights in which arousal threshold studies were performed. Ten patients with subjective insomnia received 30 mg flurazepam or placebo on nights in which arousal thresholds in response to electronic tones or a recording of the subjects' names were determined. Arousal thresholds differed across waking and sleep stages, but there was less difference in response to the subjects' names than to electronic tones. Flurazepam raised arousal thresholds to both stimuli, but did not selectively influence response in any individual sleep stage. Flurazepam did not alter subjects' estimates of elapsed time or duration of sleep between tests.

Adult↗
PubMed1988

Periodic cessation of respiratory effort during sleep in adult rats.

Using a noninvasive technique which measures respiration as a function of chest and abdominal movement, it was found that adults rats have periodic cessations of respiratory effort during the daytime. In a preliminary study, male Fischer-344 rats had respiratory pauses of 2.4-2.6 seconds duration, which tended to be more frequent in older (22-month) compared to young adult (3-month) rats. Respiratory rate was lower and respiratory volume greater in the 22-month-old animals. In a more detailed study of 3-month-old male Sprague-Dawley rats, respiratory pauses were divided into two types: those preceded by a large inspiration ("sighs") and those which were not. The latter, which appear to be most analogous to human apneas of clinical interest, occurred in all animals studied, with a frequency of 13 to 26 events during six hour recordings. These pauses varied in duration from 2.0 to 6.1 seconds and were most frequent and longest in REM sleep.

Aging↗
PubMed1987

Sleep induction by an adrenal steroid in the rat.

The ring A reduced metabolites of deoxycorticosterone and progesterone, 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) and 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-DHP) have been shown to be potent barbiturate-like ligands of the benzodiazepine receptor complex. The former has also been reported to have anxiolytic effects in mice and rats. In the present study, sleep recordings were obtained on rats given 5 and 10 mg/kg of these steroids alone and in combination with flurazepam. THDOC, but not 3 alpha-OH-DHP, had potent dose-dependent sleep-inducing properties and increased nonREM sleep. Flurazepam had similar hypnotic effects and also reduced REM sleep. There were no significant interactions between THDOC and flurazepam, except in the case of REM latency, which tended to increase when the two compounds were given together. In summary, THDOC, a mineralocorticoid metabolite found in brain, has sedative properties and could conceivably play a role in stress responses.

Animals↗
PubMed1987

Sleep and benzodiazepine receptor sub-types.

CL 218,872, which preferentially binds to benzodiazepine (BZ) type 1 receptors, and flurazepam, which is thought to bind to both types 1 and 2, were given alone and in combination to rats. CL 218,872 had little effect on sleep latency, but significantly increased total sleep time. As expected, flurazepam both shortened sleep latency and prolonged total sleep. Pretreatment with CL 218,872 had no effect on these alterations in sleep induced by flurazepam. The implications for possible significance of sub-typing of BZ receptors are discussed.

Animals↗
PubMed1987

Frequency analysis of the sleep EEG in depression.

Eight patients with major depressive disorder (seven bipolar and one unipolar) and matched controls had sleep studies, on which frequency analysis of the electroencephalogram (EEG) was performed. Total sleep and sleep efficiency were decreased in the patients, but there was no significant difference in rapid eye movement (REM) latency between the two groups. Frequency analysis revealed no group differences in power in the delta band (0.23-2.5 Hz) or the whole EEG spectrum (0.23-25 Hz). These findings suggest that mean REM latencies are not always shorter in major depression. The results are discussed in light of a previous report of decreased delta energy in the sleep EEG of unipolar patients.

Adult↗
PubMed1987

Arousal induced by injection of triazolam into the dorsal raphe nucleus of rats.

In order to explore the possible sites at which benzodiazepines alter sleep, we have performed sleep studies following administration of 0.5 microgram of triazolam into the dorsal raphe nucleus of rats. Triazolam significantly increased sleep latency and decreased non-rapid eye movement (REM) sleep, with an effect greatest in the first 2 hours after injection. Total REM sleep time was not significantly affected, although there was a modest trend toward reduction in the first 2 hours. In contrast to the decreased sleep resulting from injection into the dorsal raphe nucleus, triazolam did not significantly alter sleep in animals in whom it was injected into surrounding areas. Similarly, the low dose employed in this study did not significantly affect sleep when injected into the lateral ventricle. These data are reminiscent of studies showing transient decreases in sleep following lesions of the dorsal raphe nucleus.

Animals↗
PubMed1986

Cholinergic induction of seizures in the rat prefrontal cortex.

Intracerebral microinjection of the cholinergic agonist, carbachol, into the medial prefrontal cortex of the rat, induced a profound behavioral syndrome consisting of repetitive, stereotyped forepaw treading in an upright posture. Electroencephalographic analysis revealed multiple bursts of sharp waves, 200-300 microV, accompanying the carbachol-elicited motor behavior. Pretreatment with intraperitoneal doses of three anticonvulsant drugs, clonazepam, diazepam, and pentobarbital, blocked the manifestation of the motor behavior. These observations suggest that activation of cholinergically innervated regions of the rat medial prefrontal cortex induces an atypical form of seizures.

Animals↗
PubMed1985

Are the toxicities of pentobarbital and ethanol mediated by the GABA-benzodiazepine receptor-chloride ionophore complex?

Both barbiturates and ethanol have been reported to interact with the GABA-benzodiazepine receptor-chloride ionophore 'supramolecular complex'. These observations raise the possibility that some of the pharmacologic actions of barbiturates and ethanol may be mediated through this complex. In this study we have administered a series of drugs which bind to various components of the complex in an attempt to antagonize the lethality of sodium pentobarbital, and ethanol-induced loss of righting reflex in mice. It was found that isopropylbicyclophosphate (IPPO), a cage convulsant which binds at or near the chloride ionophore, greatly reduces the overall mortality (and increases latency to death) of animals pretreated with a lethal dose of pentobarbital. Picrotoxin also decreases pentobarbital lethality, but only at doses which were usually lethal when given alone. Picrotoxin shortened, rather than increased, latency to death. Strychnine did not prevent pentobarbital lethality, suggesting that the IPPO effect is not shared by convulsants in general. IPPO did not prevent ketamine-induced deaths, which supports the notion that the protective actions of IPPO are specific for depressant drugs which act at the chloride ionophore. IPPO also significantly reduced the duration of loss of righting reflex induced by ethanol. These observations suggest that the use of compounds which have a high affinity for the chloride ionophore in vitro might be fruitful in developing a clinical treatment for barbiturate or ethanol toxicity.

Animals↗
PubMed1984

Diazepam-stimulated increases in the synaptosomal uptake of 45Ca2+: reversal by dihydropyridine calcium channel antagonists.

Pharmacologically relevant concentrations of benzodiazepines have previously been reported to increase 45Ca2+ uptake into synaptosomes. This observation, coupled with the recent report that nifedipine may block the hypnotic effect of flurazepam, led us to study the effects of nifedipine and nitrendipine on 45Ca2+ uptake into synaptosomes. Diazepam (1 microM) significantly increased the uptake of 45Ca2+ to a crude synaptosomal fraction (P2) prepared from rat cerebral cortex and depolarized with 55 mM K+. Nifedipine (1 microM) did not alter the uptake of Ca2+, while nitrendipine (1 microM) reduced uptake by 37%. Both nifedipine and nitrendipine completely antagonized the ability of diazepam to increase 45Ca2+ uptake following K+ depolarization. These observations support the notion that the pharmacologic actions of benzodiazepines may be mediated through effects on a calcium channel.

Animals↗
PubMed1984

Nifedipine blocks sleep induction by flurazepam in the rat.

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.

Animals↗
PubMed1984

Lipid abnormalities in workers exposed to dioxin.

Ten years after an incident in which workers were exposed to tetrachlorodibenzodioxin (TCDD) a controlled biochemical study showed statistically significant increases in the serum cholesterol and triglyceride concentrations of workers both with and without chloracne. Urinary excretion of D-glucaric acid was significantly higher for all workers.

Acne Vulgaris↗
PubMed1983

Pharmacokinetic and pharmacodynamic factors contributing to the convulsant action of beta-carboline-3-carboxylic acid esters.

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.

Animals↗
PubMed1983

3-carboethoxy-beta-carboline (beta-CCE) elicits electroencephalographic seizures in rats: reversal by the benzodiazepine antagonist CGS 8216.

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.

Animals↗
PubMed1983

Effect of liposomes containing various divalent cations on the release of acetylcholine from synaptosomes.

The effect of increasing the cytoplasmic levels of various divalent cations on the release of [3H]acetylcholine ([3H]ACh) from synaptosomes was investigated. Synaptosomes prepared from rat brain and prelabeled with [3H]choline were incubated with liposomes containing Mg2+, Ca2+, Mn2+, Co2+, Sr2+, or Ba2+. This treatment allows the transfer of the aqueous contents of the liposomes to the cytoplasm of the synaptosomes. The efflux of radioactivity subsequent to this treatment was measured, and the relative proportions of [3H]ACh and [3H]choline were determined. The release of radioactivity from synaptosomes incubated with liposomes containing Mg2+, Mn2+, or Co2+ was not altered when compared with synaptosomes incubated either without liposomes or with liposomes containing isotonic K+/Na+. Synaptosomes incubated with liposomes containing Ca2+, Sr2+, or Ba2+, however, released significantly more radioactivity than did controls. Moreover, the released radioactivity consisted almost entirely of [3H]ACh. Liposomes containing either Ca2+ or Sr2+ were equally effective in promoting the release of [3H]ACh from synaptosomes, whereas liposomes containing Ba2+ were 2.5 times more effective in promoting the release of [3H]ACh than were liposomes containing either Ca2+ or Sr2+. Since liposomes introduce their aqueous contents into cytoplasm via a mechanism not involving plasma membrane channels, the increased release of [3H]ACh caused by liposomes containing Ca2+, Sr2+, or Ba2+ is attributable to an increase in the intrasynaptosomal concentration of these ions, and not to their passage through calcium channels.

Acetylcholine↗