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Biomedical subjects

I K Ho

Publications and source records attributed to I K Ho.

At least 235 records · Page 13Linked to original sources
PubMed1982

Alterations of synaptic high and low affinity opiate binding sites after acute and chronic morphine administration in mice.

1. The opiate receptor binding to whole brain synaptic membranes obtained from mice subjected to acute and chronic morphine administration and precipitated withdrawal was investigated. 2. The number of high and low affinity binding sites was significantly higher in morphine tolerant group than in control; acute administration of morphine also induced an increase in the number of binding sites, though this increase was significantly lower as compared to tolerant group. 3. The affinity of both high and low affinity sites, however remained unchanged after acute or chronic treatment. In contrast, both the affinity and the number of binding sites were significantly reduced after precipitated withdrawal, compared to the tolerant group. 4. Sodium chloride enhanced the antagonist binding and inhibited the agonist binding in both tolerant and non-tolerant groups. 5. It is concluded that (a) the increase in the number of receptors during tolerance development is an extension of the acute effect of morphine, (b) the character of tolerant membrane is qualitatively same as that of non-tolerant membrane, (c) upon withdrawal, the receptor population is brought back to normal; the altered higher, affinity after withdrawal may be a compensatory effect as a corollary to the withdrawal-induced decrease in receptor population.

Animals↗
PubMed1982

Chlordecone-induced alterations in content and subcellular distribution of calcium in mouse brain.

The neurotoxic insecticide chlordecone was administered orally to "young" (4-6 wk old) and "old" (6 mo old) mice in a dose of 25 mg/kg X d in 10 ml/kg corn oil. Age-matched control mice received 10 ml/kg X d corn oil. The acute (24 h after a single dose) and subchronic (24 h after 8 daily doses) effects of chlordecone on content and subcellular distribution of Ca in the brain were studied. Significant differences in Ca content and subcellular distribution were found between the young and old control mice. Whole brains of old mice had significantly greater amounts of total brain Ca, protein-bound Ca, and mitochondrial Ca than did those of young mice, but significantly less nuclear and cytosol Ca. Acute exposure to chlordecone (no signs of neurotoxicity) increased significantly total brain, protein-bound, nuclear, mitochondrial, and myelin Ca in brains from young mice. However, under the same chlordecone exposure conditions, old mice had significantly decreased total brain, protein-bound, and mitochondrial Ca with significantly increased nuclear Ca content. It is suggested that aging caused altered biochemical responses to the neurotoxic agent, at least at subtoxic doses or exposure times. When young mice received chlordecone for 8 d and were suffering severe chlordecone-induced tremors, at the times of sacrifice, their brains were found to have significantly decreased total, protein-bound, myelin, and synaptosomal Ca. Nuclear Ca was increased. The increased excitation of the central nervous system evidenced as severe tremors induced by chlordecone might be due, at least in part, to chlordecone-induced Ca deficiency in brain synaptosomes. Such Ca deficiency may decrease the Ca-dependent release of the CNS inhibitory transmitters gamma-aminobutyric acid (GABA) and dopamine.

Animals↗
PubMed1982

An analysis of GABA receptor changes in the discrete regions of mouse brain after acute and chronic treatments with morphine.

The effects of morphine on the affinity and distribution of GABA receptors in the mouse regions (striatum, medulla, diencephalon, cortex, and cerebellum) were investigated in relation to: (a) acute administration, (b) chronic administration (tolerance), (c) precipitated withdrawal by naloxone, an opiate antagonist, and (d) abrupt withdrawal for 8 and 24 h. The alterations in the affinity as reflected by the dissociation constant (KD) and the number of receptors (Bmax) in the synaptic membranes obtained from controls and various treatments were determined by radioligand binding assay using [3H]muscimol as a ligand. Significant changes were observed in striatum, medulla, and diencephalon, whereas other regions including whole brain exhibited marginal changes. In general the number of GABA receptors increased after tolerance development, which upon abrupt withdrawal returned to control levels except in the case of naloxone-induced precipitated withdrawal. The affinity changes in different regions were diverse in nature and were not evident in the whole brain membranes. These results indicate that: (as) the regional alterations in the affinity and distribution of GABA receptors may play a role in the induction, maintenance, and regression of morphine tolerance; (b) abrupt withdrawal and antagonist precipitated withdrawal affect the GABA system differently, (c) chronic morphine treatment appears to influence the GABA receptors in the cerebellum, a region generally known for its lack of opiate receptors.

Animals↗
PubMed1982

Comparison of brain discrete area distributions of chlordecone and mirex in the mouse.

Discrete area distributions of chlordecone or mirex in the brain at different times after a single oral administration of the compounds, 50 mg/kg, were investigated. Whole brain and plasma levels of these compounds also were compared. With the same dose of chlordecone or mirex administered to mice, both brain and plasma levels of chlordecone were significantly higher than those of mirex. Chlordecone appeared to distribute to specific discrete areas in the brain--the striatum and medulla/pons areas having higher chlordecone levels and retaining chlordecone longer. Mirex showed less specific distribution in discrete areas. Therefore, it appears that these structurally related analogs exhibited distribution and pharmacokinetic differences.

Animals↗
PubMed1982

Effects of oral administration of chlordecone and mirex on brain biogenic amines in mice.

Levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA) were determined in brains of mice after daily oral administration of 10, 25 or 50 mg/kg of chlordecone or mirex until mortality occurred. Significant decreases in whole brain and striatal DA levels were observed in chlordecone-treated mice exhibiting tremors. Mirex had no effect at the 3 doses tested. In mice treated with chlordecone or mirex, the 5-HT levels were elevated only in animals exhibiting severe tremors or diarrhea, respectively. NE levels were not altered by chlordecone or mirex. These results suggest that chlordecone-induced neurotoxicity may be due in part to a decrease in the inhibitory state of dopamine neurons.

Administration, Oral↗
PubMed1982

Effects of chlordecone and mirex on amino acids incorporation into brain and liver proteins in the mouse.

Effects of chlordecone and mirex on 3H-leucine or 3H-amino acids incorporation into mouse brain and liver proteins were investigated. In mice treated with chlordecone by oral intubation, 25 mg/kg/day for 3 days, a significant decrease in 3H-leucine incorporation into brain trichloroacetic acid (TCA)-precipitable proteins was observed. On the other hand, mirex significantly increased 3H-leucine incorporation into TCA-precipitable proteins in the liver but not in that of the brain. These phenomena also were confirmed by the data obtained from 3H-amino acids mixture incorporation into both brain and liver proteins in mice which were orally administered with chlordecone or mirex, 25 mg/kg/day for 4 days. These results are also substantiated by a single dose of chlordecone (125 or 200 mg/kg, p.o.) or mirex (250 or 350 mg/kg, p.o.). These results suggest that although structurally similar, these two analogs differ significantly in their effects on amino acids incorporation into brain and liver proteins.

Amino Acids↗
PubMed1981

Effect of chlorphentermine on the pulmonary disposition of norepinephrine in the isolated perfused rabbit lung.

Chlorphentermine (CP) has been noted to cause primary pulmonary hypertension both clinically and experimentally. It was postulated that CP might affect the pulmonary clearance of endogenous vasoactive substances such as norepinephrine (NE). The uptake and metabolism of 14C-NE were followed in artificially ventilated isolated perfused rabbit lung preparations using a constituted perfusate with initial NE concentration of 5 micrograms/100 ml. Perfusate samples were analyzed for total radioactivity, metabolites, and parent compound. Preloading the lungs with 0.25 mM CP significantly increased the concentrations of total radioactivity, deaminated products, and decreased the concentration of normetanephrine in the perfusate. In addition, the accumulation of total radioactivity in the lung tissue after 60 min of perfusion was significantly decreased in CP-treated lungs. The proportion of deaminated metabolites in the lung tissue was slightly decreased while the percent of normetanephrine, and parent compound were significantly increased by the CP treatment. CP (0.1 mM) also inhibited the in vitro metabolism of NE by 79%. These results provide experimental evidence in support of a hindered pulmonary clearance of circulating NE by CP.

Animals↗
PubMed1981

Assessment of neurotoxicity induced by oral administration of chlordecone (Kepone) in the mouse.

Neurotoxicity in the mouse was produced following oral administration of chlordecone at 10, 25 and 50 mg/kg/day in corn oil vehicle. Hyperexcitability and tremors were observed on the 1st, 4th and 9th day after the administration of chlordecone at 50, 25 and 10 mg/kg/day, respectively, and mortality occurred on the 5th, 7th and 13th day after daily administration of the respective doses. In all cases, the cumulative LD 50 for chlordecone was estimated between 180 and 200 mg/kg. Daily oral administration of chlordecone caused loss of body weight, and the loss of body weight was greatest at the onset of tremor. The effect of chlordecone on food and water consumption varied depending on the dose. A recovery in body weight, and food and water consumption were observed upon the termination of chlordecone treatment. In terms of neurotoxic responses, the effect of chlordecone on motor coordination in the mouse was dose-dependent, both during treatment and during recovery after terminating treatment. The threshold for pentylenetetrazol-induced seizures was significantly reduced in chlordecone treated animals. This study may provide essential basic information for studying the biochemical mechanisms of chlordecone-induced neurotoxicity in the mouse.

Animals↗
PubMed1981

Correlation between neurotoxicity and chlordecone (Kepone) levels in brain and plasma in the mouse.

The brain and plasma levels of chlordecone were monitored after daily oral administration of chlordecone at 10 to 50 mg/kg/day. At a low dose, the plasma level of chlordecone increased steadily and the brain level showed a steady increase and then a plateau. However, at the higher dose the brain and plasma concentrations of chlordecone decayed biphasically. The data also revealed that chlordecone-induced neurotoxicity correlated closely with both brain and plasma concentration of chlordecone. Brain and plasma concentrations required for low and high dose for induction of the loss of motor coordination were estimated to be 10 to 65 ug/g and 10 to 25 microgram/ml, respectively. In addition, the chlordecone levels in the brain at time of death were 0.10 and 0.41 mg/g in groups receiving 10 and 50 mg/kg/day, respectively. However, the cumulative lethal dose of chlordecone in animals treated with different doses was about the same. This study established the threshold levels of chlordecone in plasma and brain for motor incoordination and mortality in the mouse.

Animals↗
PubMed1981

Pharmacological responses to pentobarbital in different strains of mice.

This study was designed to assess the strain differences in pentobarbital toxicity, narcosis, the development of tolerance and physical dependence, the half-life of pentobarbital and the activities of hepatic microsomal electron transfer chain in DBA/2J, C57BL/6J and ICR mice. The comparisons of responses to acute pentobarbital-induced narcosis with two different doses revealed that DBA was most sensitive among these strains. When continuous administration of pentobarbital by pentobarbital pellet implantation is concerned, four criteria were used to assess strain differences: 1) determination of the duration of the loss of righting reflex during pentobarbital pellet implantation; 2) cumulative mortality after pentobarbital pellet implantation; 3) degree of tolerance development after 3 days of s.c. implantation of a 75-mg pentobarbital pellet by the relative decrease in the pentobarbital sleeping time; and 4) assessment of hyperexcitability by pentylenetetrazol- and audiogenic-induced seizures after pellet removal. The order of susceptibility to continuous pentobarbital pellet implantation was found to be as follows: DBA/2J > C57BL/6J > ICR. The biochemical data also revealed that the half-life of pentobarbital in DBA/2J mice was significantly longer than that of C57BL/6J or ICR mice in both brain and serum. Further studies also showed that DBA/2J mice have lower hepatic cytochrome P-450 and cytochrome b5 levels and NADPH dehydrogenase and NADPH-cytochrome c reductase activities as compared with the other strains of mice. However, these parameters were markedly induced in DBA/2J mice after the development of tolerance to pentobarbital. It appears that the differences in genetic variation could be of importance for further studies in gaining insight of the mechanism of barbiturate tolerance and dependence.

Animals↗
PubMed1980

Continuous administration of barbital by pellet implantation.

Mice were continuously administered with barbital by the sc implantation of 16 mg barbital pellet (acid form). Serum and brain barbital levels were assessed at different times after pellet implantation. After 3 days of implantation the barbital pellet was removed and the mice were observed for a 96 hr period. A 30% decrease in sleeping time was observed 72 hr after pellet removal when mice were challenged with 400 mg/kg of barbital ip. Brain and serum barbital levels upon awakening were also assessed with a dose of sodium barbital, 400 mg/kg ip, administered 72 hr after removal of either a barbital or placebo pellet. It was observed that serum and brain barbital concentrations were significantly higher in barbital treated animals than in controls. The effect of barbital pellet implantation on pentobarbital (75 mg/kg, ip) sleeping times was also assessed. Cross tolerance to pentobarbital was observed 24, 48, and 72 hr after barbital pellet implantation. The results demonstrated that barbital pellet implantation enhanced hepatic drug metabolism as evidenced by significant increases in hepatic microsomal N-demethylase and hydroxylase activities. CNS hyperexcitability, an indication of dependence, was assessed by the method of pentylenetetrazol (PTZ) induced convulsions (60 mg/kg, sc). At 48 and 72 hr after pellet removal, PTZ induced convulsions increased by 41% and 35%, respectively, over control values. Index of dependence was also substantiated by a decrease in threshold for electroshock. These studies substantiate the validity of this experimental model for the assessment of the development of tolerance to and physical dependence on barbiturates.

Animals↗