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PubMed1989

Evaluation in rats of the somnogenic, pyrogenic, and central nervous system depressant effects of muramyl dipeptide.

Muramyl dipeptide increased sleep during the dark-phase, but not the light-phase of the rats' sleep-awake cycle. This circadian variation may be due to the inability of MDP to increase sleep over the high baseline levels of sleep that occur during the light-phase. However, MDP was pyrogenic during the light-phase, indicating it was pharmacologically active. In the dark-phase, MDP was not pyrogenic, but when compared to concurrent vehicle-treated rats, rats treated with MDP did not demonstrate as great a fall in body temperature. At approximately equisomnogenic doses, MDP produced less potentiation of ethanol-induced loss of righting reflex than triazolam, indicating it produces less non-specific central nervous system depressant effects. These data indicate the possibility of a new generation of hypnotic agents derived from muramyl peptides.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1984

Amino acid changes in regions of the CNS in relation to function in experimental portal-systemic encephalopathy.

Sustained hyperammonemia resulting from portocaval anastomosis (PCA) in the rat, is accompanied by neurological symptoms and reversible morphological changes in brain, the nature and distribution of which suggest selective vulnerability of certain brain structures. The present study was initiated to investigate the effects of increasing CNS ammonia on the distribution of amino acids in regions of the rat brain in relation to the degree of neurological impairment in PCA rats. Four weeks following PCA, rats were administered ammonium acetate (5.2 mmol/kg, i.p.) to precipitate neurological symptoms of encephalopathy which included diminished locomotor activity, loss of hindlimb extension and righting reflexes and ultimately coma. At various stages during the development of encephalopathy, rats were sacrificed and the amino acids glutamine, glutamate and aspartate measured simultaneously, using a sensitive double-isotope dansyl microassay. Homogenates of the following regions of the CNS were assayed: cerebral cortex, hippocampus, striatum, midbrain, hypothalamus, cerebellum, medulla-pons, spinal cord (gray matter) and spinal cord (white matter). Sustained hyperammonemia associated with PCA alone resulted in a non-uniform 2-4 fold increase of glutamine in all regions of the CNS. Glutamate, on the other hand, was selectively increased in striatum and cerebellum, two regions of brain shown to exhibit early morphologically-characterised astrocytic abnormalities in rats with PCA. Onset of severe neurological dysfunction was accompanied by significantly decreased glutamine and glutamate in striatum and cerebellum. Thus, sustained hyperammonemia in association with portocaval shunting results in region-selective effects with respect to glutamine-glutamate metabolism in the CNS.

Acetates↗

PubMed1985

GABA-transaminase and glutamic acid decarboxylase changes in the brain of rats treated with pyrithiamine.

Pyrithiamine, a thiamine phosphokinase inhibitor, was fed to rats on a thiamine-deficient diet, producing weight loss, ataxia and loss of righting reflex in 10 days. Some rats were then sacrificed; others were returned to a normal diet, to be sacrificed only when their weight had returned to pre-experimental levels. Rats were sacrificed for assay of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in homogenates of eight brain regions or were perfused for gamma-aminobutyric acid transaminase (GABA-T) histochemistry. GAD activity was significantly reduced in symptomatic rats in the thalamus greater than cerebellum greater than midbrain greater than pons/medulla. GABA-T staining was similarly reduced, with greatest losses in the thalamus greater than inferior colliculus greater than pons greater than medulla. ChAT activity was not significantly altered in any brain area. Following return to a normal diet. GAD activity was significantly recovered in all areas except the thalamus. GABA-T staining recovered, at least partially, in all areas affected.

4-Aminobutyrate Transaminase↗

PubMed1995

Regional alterations of dopamine and its metabolites in rat brain following portacaval anastomosis.

Hyperammonemia and changes in brain monoamine metabolism have been proposed to contribute to the pathogenesis of the neuropsychiatric symptoms characteristic of human portal-systemic encephalopathy (PSE) resulting from chronic liver disease. Portacaval anastomosis (PCA) in the rat leads to sustained hyperammonemia and mild encephalopathy. In order to evaluate the role of dopamine (DA) metabolism in PSE, levels of DA and its metabolites were measured by HPLC with electrochemical detection in brain regions of rats with PCA at various stages of encephalopathy precipitated by ammonium acetate administration. Following ammonium acetate administration, rats with PCA rapidly develop severe neurological signs of encephalopathy progressing through loss of righting reflex to coma; sham-operated control animals administered ammonium acetate showed no such neurological deterioration. Concentrations of the DA metabolites DOPAC and HVA as well as [DA metabolites]/[DA] ratios, an indirect measure of DA turnover in brain, were increased in caudate-putamen, in cingulate and pyriform entorhinal cortices as well as in raphe nucleus and locus coeruleus. Increased DA metabolites, however, did not worsen at coma stages of PSE. Increased DA turnover thus appears to relate to early neuropsychiatric and extrapyramidal symptoms of PSE.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Increased cerebrospinal fluid lactate reflects deterioration of neurological status in experimental portal-systemic encephalopathy.

Increased brain and CSF lactate have been described in human and experimental portal-systemic encephalopathy (PSE). Using a recently described cisterna magna catheter technique, CSF lactate was measured in relation to deterioration of neurological status in portacaval shunted rats administered ammonium acetate to precipitate severe PSE. Loss of righting reflex (precoma stage of PSE) was accompanied by 2-3 fold increased CSF lactate and onset of coma by 4-fold increases of lactate (p less than 0.001 compared to either sodium acetate treated portacaval shunted rats or sham-operated controls administered ammonium acetate). The most likely explanation for increased CSF lactate is ammonia-induced inhibition of malate-aspartate shuttle and/or inhibition of tricarboxylic acid cycle flux in brain. Similar mechanisms could be involved in the pathogenesis of PSE in patients with chronic liver disease.

Animals↗

PubMed1990

Flumazenil does not improve hepatic encephalopathy associated with acute ischemic liver failure in the rabbit.

The effect of flumazenil, a benzodiazepine antagonist, on hepatic encephalopathy was studied in rabbits with acute hepatic failure induced by a two-stage liver devascularization procedure. The rabbits were randomized for treatment with 5 mg/kg of flumazenil or the placebo. The drug was administered at two easily recognizable time points in the course of the encephalopathy: first, when the righting reflex was disturbed, and second, when the animal could no longer achieve to the sitting position. The response after flumazenil did not differ from that after the placebo, as measured by clinical evaluation and automated EEG analysis. Furthermore, the progression of the encephalopathy, as measured by the survival time after the first injection, was not affected by flumazenil.

Acute Disease↗

PubMed1993

Comparisons of subcolonies of selectively bred long-sleep and short-sleep mice.

The Albany subcolony of the selectively bred Long- and Short-Sleep mice was directly compared to the original Colorado colony. As expected from the additional selection applied to the Colorado colony, small differences in the selection phenotype, loss of the righting reflex duration following ethanol treatment, were observed in the Short-Sleep line. However, no colony differences existed in three other indices of ethanol effects. Clear line differences in the shape of the locomotor activity dose-response curve, thermoregulatory effects of ethanol, and ethanol elimination rate replicated earlier findings, but these differences were similar in the two colonies. These data argue for stability of the polygenic control system and provide a picture of remarkable similarity of the two sublines, which were separated by more than 30 generations.

Animals↗

PubMed1980

Antidepressant drugs and ethanol: behavioral and pharmacokinetic interactions in mice.

The interactions between ethanol and antidepressant drugs (both tricyclics and newer non-tricyclics) were studied in mice. The ability of these drugs to enhance the sedative effects of ethanol at two different doses (3.2 and 4.0 g/kg) was measured. The percentage of mice losing the righting-reflex was used for the lower dose, and the duration of ethanol-induced sleep was used at the higher dose. The relative order of potency was amitriptyline greater than or equal to imipramine > maprotiline = mianserin > desipramine greater than or equal to chlorimipramine > iprindole greater than or equal to alaproclate > norzimelidine greater than or equal to zimelidine. Amitriptyline (60 mg/kg) caused death in all mice when combined with 4.0 g/kg ethanol. Clinically established antidepressants which enhanced ethanol sedation only at doses considerably above therapeutic levels were zimelidine and iprindole. The relative potency of the antidepressants to enhance ethanol sedation is correlated with their inherent sedative properties which are in turn related to their ability to block central 5-HT, alpha-NA, muscarinic and H1-receptors. Amitriptyline (20 mg/kg) was found to increase ethanol plasma levels to 202, 167 and 132% of control values at 30, 60 and 90 min after ethanol administration, respectively. Desipramine, mianserin and alaproclate also increased ethanol plasma levels initially, but to a lesser extent. These findings suggest that in addition to their sedative effect, several antidepressants, particularly amitriptyline, are likely to interact with ethanol by increasing its concentration in plasma.

Animals↗

PubMed1979

Alteration of plasma ketamine levels in mice by probenecid.

Probenecid increases plasma ketamine levels in mice concurrently with an enhancement of duration of loss of righting reflex. The magnitude of these changes is directly related to the dose of ketamine and intervals between administration of compounds. Plasma levels of anesthetic are similar for all animals upon termination of hypnosis.

Animals↗

PubMed1986

Interaction studies in mice of SCH 29851, a potential non-sedating antihistamine, with commonly used therapeutic agents.

SCH 29851 was studied for its ability to interact with selected drugs used in man. The non-sedating antihistamine terfenadine and the sedating antihistamine diphenhydramine were also studied for comparison. SCH 29851 at 80 mg/kg po in mice, a dose about 50 times its ED50 for blocking histamine-induced paw edema in the same species, potentiated the anticonvulsant effects of diazepam. At the high dose of 320 mg/kg po, about 80 times its ED50 for antihistamine effects, SCH 29851 potentiated the ability of high doses of ethanol and hexobarbital to induce loss of righting reflexes (LRR). However, no potentiation was seen when SCH 29851 was studied with lower doses of ethanol or phenobarbital that had anticonvulsant effects but did not cause LRR. At this high dose of 320 mg/kg po, SCH 29851 also did not interact with the antihypertensive drugs propranolol and alpha-methyldopa, the anti-ulcer drug cimetidine, the nasal decongestant pseudoephedrine, or the CNS stimulant d-amphetamine. A nearly identical profile of interactions was seen with terfenadine, including potentiation of diazepam at 50 times its antihistamine ED50, potentiation of ethanol- and barbiturate-induced LRR at 80 times its antihistamine ED50, and lack of interaction effects at 320 mg/kg po with each of the other tested drugs. The demonstration in this study of the significant interactions between diphenhydramine and many of the tested drugs is consistent with the clinical experience in man that this drug does have sedating properties and significant interactions with drugs like ethanol and diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1975

Protective action of ascorbic acid and sulfur compounds against acetaldehyde toxicity: implications in alcoholism and smoking.

Acetaldehyde is a toxic substance common to heavy drinking of alcohol and heavy smoking of cigarettes. It has been implicated thereby in diseases of the cardiovascular, respiratory, and central nervous systems. Protection against acetaldehyde toxicity (i.e. anesthesia and lethality) was studied in rats by oral intubation of test compounds 30-45 minutes prior to oral intubation of a standardized oral LD 90 dose (18 millimoles/kilogram) of acetaldehyde. Animals were monitored for anesthesia (loss of righting reflexes) and lethality for 72 hours. A total of 18 compounds was tested. L-ascorbic acid at 2 millimoles/kilogram (mM/kg) showed moderate protection against anesthesia and marked protection against lethality. Greatest protection against anesthesia and lethality was obtained at 2 m M/kg with each of the following: L-cysteine, N-acetyl-L-cysteine, thiamin-HCl, sodium metabisulfite, and L-cysteic acid. A combination of L-ascorbic acid with L-cysteine, and thiamin-HCl at reduced dose levels (2.0, 1.0 and 0.3 mM/kg, respectively) gave virtually complete protection. A detailed literature review is presented of the rationale and significance of these findings. Our findings could point the way to a possible build-up of natural protection against the chronic body insult of acetaldehyde arising from heavy drinking of alcohol and heavy smoking of cigarettes.

Acetaldehyde↗

PubMed1990

Antagonistic effect of physostigmine on ketamine-induced anesthesia.

Effects of physostigmine on ketamine-induced anesthesia and analgesia were studied in male Sprague-Dawley rats using behavioral tests. Rats were divided into six groups. Immediately after loss of the righting reflex following an intraperitoneal injection of ketamine 75 mg/kg, each group of rats was given an intraperitoneal injection of either physostigmine 0.05, 0.1, 0.2, 0.4, 0.6 mg/kg or saline as the control, respectively. Physostigmine 0.1 mg/kg caused the greatest antagonistic effect on ketamine anesthesia as indicated by sleeping time, duration of ataxia and motor coordination. The antagonistic effects of physostigmine were reduced by a dose of physostigmine of greater than 0.1 mg/kg. However, at no dose did physostigmine antagonize ketamine analgesia as indicated by the tail-flick latency. Physostigmine (0.4 and 0.6 mg/kg) itself had analgesic and motor-suppressive actions. It can therefore be presumed that there is a limited threshold of the dose of physostigmine which develops an antagonistic effect on ketamine anesthesia due to the motor-suppressive action. It is also confirmed that physostigmine itself produces analgesia, and does not antagonize ketamine-induced analgesia.

Anesthesia↗

PubMed1992

Differences in response to the aversive properties and activity effects of low dose ethanol in LAS and HAS selectively bred rats.

Rats selectively bred for high alcohol sleep times (HAS) and those that are less affected (LAS) by hypnotic doses (3.0-3.6 g/kg) of ethanol were tested for differential responses to the aversive effects of 1.0 g/kg ethanol in a conditioned place preference task. Likewise, the effects of 0.3-1.0 g/kg ethanol on spontaneous locomotor activity over a 30-min period, as well as the loss of righting reflex with a higher ethanol dose (3.0 g/kg), were determined in these animals. The LAS rats reacted more aversively to 1.0 g/kg during conditioned place aversion testing than the HAS animals and also had a shorter mean sleeping time following 3.0 g/kg ethanol. Furthermore, dose-related depression of spontaneous motor activity was seen in the HAS animals and not in the LAS animals over a 30-min period using doses of 0.3, 0.6, or 1.0 g/kg (10% w/v) ethanol. Taken together, the results indicate that the intoxicating sequelae of high ethanol doses, such as ataxia and sedation, may not be correlated with the aversive effects of low ethanol doses.

Animals↗

PubMed1995

Sedative potency and 2-[125I]iodomelatonin binding affinity of melatonin analogues.

Melatonin (5-methoxy N-acetyltryptamine), the hormone synthesized and released from the pineal gland each night, has sedative and sleep-promoting effects in experimental animals and man. In the present study, the sedative effect of melatonin and a number of analogues was determined by examining their ability to extend the duration of the loss of righting reflex ("sleeping time") in mice injected with pentobarbitone (50 mg/kg i.v.). All of the analogues tested produced a dose-related (5-20 mg/kg) potentiation of pentobarbitone sleeping time. In radioligand binding assays using 2-[125I]iodomelatonin in chicken brain membranes, all of the analogues were competitive inhibitors. There was no correlation between their ability to inhibit 2-[125I]iodomelatonin binding in chick and sedative potency in the mouse. Potentiation of pentobarbitone sleeping time by diazepam (1 mg/kg i.p.), but not melatonin (10 mg/kg i.p.), was blocked by pretreatment with the benzodiazepine antagonist, flumazenil (10 mg/kg i.p.). Similarly, an increase in pentobarbitone sleeping time produced by the aminoalkylindole cannabinoid receptor agonist, WIN 55212-2 (0.5 mg/kg i.p.), but not that produced by melatonin (10 mg/kg i.p.) was reduced by the cannabinoid receptor antagonist WIN 56098 (5 mg/kg i.p.). These studies confirm that melatonin has sedative activity and show that this action is shared by several structurally-related analogues but does not appear to be mediated by an interaction with benzodiazepine or cannabinoid receptors.

Animals↗

PubMed1986

Mechanism of anesthesia: the potency of four derivatives of octane corresponds to their hydrogen bonding capacity.

The anesthetic potency of four derivatives of n-octane was measured by tadpole righting reflex and expressed as effective millimolar concentration of drug in membrane, EDM50. Potency diminished (ED50 increased) in this order: 1-octanol, EDM50 = 5.5; 1-(2-methoxyethoxy)octane, EDM50 = 28; 1-methoxyoctane, EDM50 = 61; and 1-chlorooctane, EDM50 greater than 100. Since the aliphatic chain length was kept constant it is concluded that the differences in anesthetic potency are a consequence of the differences in head group structure. This result is predicted by a theory (Lipids 17, 1001-1003 [1982]) which holds that anesthesia is the result of a drug-induced restructuring of the hydrogen belts, those strata of the membrane that contain the hydrogen bond receiving and donating CO and OH groups of the membrane lipids and the adjoining proteins. The Meyer-Overton rule for anesthetics should be modified: chemicals induce anesthesia at equimolar in-membrane concentration provided their hydrogen-bonding parts are identical.

Anesthesia↗

PubMed1998

Immediate-early gene expression in the brain of the thiamine-deficient rat.

Pyrithiamine-induced thiamine deficiency (PTD) in the rat is associated with neuronal loss in the thalamus and inferior colliculus. Recently, we were able to demonstrate the occurrence of apoptosis in the thalamus of these animals. Given that immediate-early genes (IEGs) participate in signal transduction pathways that mediate programmed cell death, the present study utilized in situ hybridization and immunohistochemistry to examine the expression of four IEGs (c-fos, c-jun, fos-B, and NGFI-A) during the progression of PTD. Elevated c-fos mRNA levels were initially observed in the posterior medial thalamus on d 12 of the deficiency. At the acute symptomatic stage (characterized by a loss of righting reflex on d 16-17), the posterior-medial thalamus exhibited increased mRNA for all genes examined, whereas the inferior colliculus demonstrated mRNA induction for c-fos, c-jun, and NGFI-A. Immunohistochemical analysis revealed that elevations of IEG mRNA associated with the acute symptomatic stage were consistently translated into protein in the thalamus. In contrast, whereas elevated Fos- and Jun-like immunoreactivity were detected in the inferior colliculus at this stage, NGFI-A-like immunoreactivity declined significantly below basal levels, suggesting a translational block. These results are consistent with our recent findings of apoptotic cell death, and indicate that differential patterns of IEG expression occur in the thalamus and inferior colliculus during PTD, which may contribute to the pathogenesis of this disorder.

Animals↗

PubMed1995

Decreased hypothalamic prostaglandin D2 and prostaglandin E2 contents during isoflurane anaesthesia in rats.

This study was undertaken to evaluate the effect of isoflurane anaesthesia on the hypothalamic contents of both prostaglandin D2 and E2 which affect the sleep-wakefulness cycle. Sixty-three Wistar rats were divided into three equal groups, control, isoflurane and recovery groups. Twenty-one rats of the control did not receive isoflurane. In the other groups 21 rats received isoflurane 2% for 30 min and 21 received isoflurane 2% for 30 min and were allowed to recover their usual behaviours, including righting reflex, spontaneously. The hypothalamus was removed and the contents of PGD2 and PGE2 were measured by enzyme immunoassay. The PGD2 content in the hypothalamus was 397.9 +/- 226.0 pg.g-1 for the control group, 134.2 +/- 41.2 pg.g-1 for the isoflurane group and 269.1 +/- 124.6 pg.g-1 for the recovery group, respectively. The hypothalamic PGE2 contents were 381.4 +/- 139.0 pg.g-1 for the control group, 183.3 +/- 26.4 pg.g-1 for the isoflurane group and 312.2 +/- 96.0 pg.g-1 for the recovery group, respectively. The hypothalamic PGD2 and PGE2 contents in the isoflurane group were lower (P < 0.05) than those in the control and recovery groups, while both the PGD2 and PGE2 contents of the control and the recovery groups were similar. We conclude that decreased hypothalamic PGD2 and PGE2 contents may be related to some manifestations of general anaesthesia with isoflurane.

Anesthesia Recovery Period↗

PubMed1997

Magnesium deficiency increases ketamine sensitivity in rats.

PURPOSE: Inhibition of the NMDA receptor likely contributes to ketamine's neurodepressive properties. Magnesium also inhibits the NMDA receptor by binding to a site associated with the ketamine-binding domain. Electrophysiological studies suggest that magnesium prevents ketamine from binding to the NMDA receptor and thereby prevents ketamine inhibition. We undertook an in vivo study to determine if magnesium deficiency was associated with an increased sensitivity to ketamine. METHODS: Weanling rats were maintained on a Mg(2+)-deficient or control diet for 14 days. In Study I, rats were anaesthetized then sacrificed and the Mg2+ concentrations in the brain and plasma were measured. In a second prospective study, experimental animals were rendered hypomagnesaemic and the potency of 125 mg.kg-1 ip ketamine was evaluated. Animals were then were fed a Mg(2+)-containing diet and ketamine sensitivity was re-examined 14 days later. RESULTS: The Mg(2+)-deficient diets rendered the rats hypomagnesaemic as indicated by the brain and plasma concentration of Mg2+. In Study 2, the time to loss of righting reflex was shorter; 1.9 +/- 0.3 min (n = 12) and 2.6 +/- 0.2 min (n = 16, P < 0.05), whereas the latency to toe pinch was prolonged: 25.0 +/- 5.8 min (n = 12) vs 3.1 +/- 2.1 min (n = 16, P < 0.05) in the Mg(2+)-deficient compared with age-matched control animals, respectively. The hypomagnesaemic animals had a higher death rate following ketamine injection. The increased sensitivity to ketamine was no longer apparent when the animals were re-tested following replenishment of Mg2+. CONCLUSION: Hypomagnesaemia is associated with an increased sensitivity to ketamine.

Anesthetics, Dissociative↗