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Biomedical subjects

I K Ho

Publications and source records attributed to I K Ho.

At least 145 records · Page 8Linked to original sources
PubMed1991

In vivo and in vitro metabolic studies of N3-benzyluridine which exhibits hypnotic activity in mice.

The metabolism of N3-benzyluridine (N3-ByUd), which possesses hypnotic activity, was studied in mice. The decrease in brain concentration of N3-ByUd was faster than that of uridine (Ud) after intracerebroventricular (i.c.v.) and intravenous (i.v.) administration. Liver and plasma concentrations of N3-ByUd were also lower than those of Ud after both i.c.v. and i.v. administrations. N3-Benzyluracil (N3-ByU) was identified as a metabolite of N3-ByUd in urine after i.c.v. administration. However, N3-ByUd was not metabolized in brain until 3 hr after i.c.v. administration. It was also not metabolized in the in vitro metabolic studies of N3-ByUd (brain and liver). The possible metabolites, e.g. Ud, uracil (U), N3-ByU and D-ribose, did not possess any hypnotic activity following i.c.v. administration. These results indicate that N3-ByUd itself, but not its metabolites, produced central nervous system (CNS) depressant activity.

Animals↗
PubMed1990

Barbiturates and the GABAA receptor complex.

The GABA synapse plays an important role in the pharmacologic effects of barbiturates and the mechanisms involved in barbiturate tolerance and dependence. A synopsis of the effects which have been reported to date is found in Tables 1 and 2. Although the acute changes in neurotransmitter uptake and release are nonselective, a lag in the ability of the GABA synapse to compensate for discontinuation of barbiturate exposure may be important in the symptoms of withdrawal. Barbiturates cause changes in the properties of many receptors, but manipulations of the GABAA receptor in vivo correlate with changes in the therapeutic and toxicologic responses to barbiturates, indicating that the GABAA receptor complex plays a pivotal role in the effects of barbiturates. Experiments done in several laboratories show that barbiturate tolerance and dependence cause subtle changes in the properties of the GABAA receptor complex. These observations suggest that decreased GABA-stimulated chloride channel activity and reduced ability to modulate it may be important in causing barbiturate tolerance and the symptoms observed in withdrawal. Selection of drug-resistant rodent strains suggests that there may be genetic factors involved in drug tolerance and dependence. The complexity of the responses of the GABA synapse to both acute and prolonged exposure to barbiturates indicates that it is a valuable model for understanding how the central nervous system responds to drugs and the mechanisms involved in drug addiction.

Animals↗
PubMed1990

Effects of GABA antagonists, SR 95531 and bicuculline, on GABAA receptor-regulated chloride flux in rat cortical synaptoneurosomes.

Synaptoneurosomes isolated from cerebral cortices of male Sprague-Dawley rats were used for studying GABAA receptor-regulated chloride influx. The in vitro effects of GABA antagonists, SR 95531 (a pyridazinyl GABA derivative) and bicuculline, on pentobarbital-stimulated, muscimol-stimulated or flunitrazepam-enhanced, muscimol-stimulated chloride uptake were studied. The chloride uptake was determined at 30 degrees C, for 5 sec. Pentobarbital and muscimol produced a maximal stimulation of chloride uptake in cortical synaptoneurosomes at 500 microM and 50 microMs, respectively. SR 95531 as well as bicuculline had no effect on the basal uptake of chloride. Whereas, SR 95531 (0.3 - 30 microM) and bicuculline (0.1 - 100 microM), when added 5 min before muscimol (50 microM), produced a significant concentration-dependent inhibition of muscimol (50 microM)-stimulated chloride uptake (IC50S of 0.89 +/- 0.11 microM and 13.45 +/- 2.10 microM, respectively). In studies of the inhibitory effects of SR 95531 and bicuculline on pentobarbital (500 microM)-stimulated chloride uptake, the IC50S were 0.81 +/- 0.12 microM and 3.86 +/- 1.14 microM, respectively. SR 95531 exhibited a more potent inhibitory effect than bicuculline on flunitrazepam-enhanced, muscimol-stimulated chloride uptake. The results revealed that SR 95531 has a more potent antagonistic effect than bicuculline on GABAA-regulated chloride flux.

Animals↗
PubMed1990

Effects of acute and subacute cocaine administration on the CNS dopaminergic system in Wistar-Kyoto and spontaneously hypertensive rats: I. Levels of dopamine and metabolites.

Effects of acute and subacute cocaine administration on dopamine (DA) and its metabolites in striata and nucleus accumbens of nine week-old Wistar-Kyoto and spontaneously hypertensive rats were studied. Levels of DA,3,4-dihydroxphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC-EC. There were no differences in DA levels in striata and nucleus accumbens between control WKY and SHR. Levels of DA in two brain regions were unaffected in groups treated acutely with cocaine. Both strains showed a significant increase in striatal HVA 2 hr after cocaine injection. Seven day treatment declined DA levels in striatum of WKY and in nucleus accumbens of SHR. However, only WKY treated subacutely with cocaine showed significantly increased HVA either with or without changes in DOPAC in nucleus accumbens and striatum, respectively. Increased DOPAC/DA and HVA/DA ratios appeared only in striatum of WKY and in nucleus accumbens of SHR following subacute treatment. These results suggest that subacute cocaine administration affects DA levels in striata and nucleus accumbens differently between WKY and SHR.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Effects of acute and subacute cocaine administration on the CNS dopaminergic system in Wistar-Kyoto and spontaneously hypertensive rats: II. Dopamine receptors.

The characteristics of D-1 and D-2 dopamine receptors after acute and subacute cocaine administration were determined in striata and nuclei accumbens from WKY and SHR. In striata from acutely treated rats, significant increases in D-2 receptor density were observed at 30 min, 2 or 24 h following cocaine injection in both strains without changes in affinities. The density of D-1 receptors was significantly decreased 30 min after the injection in WKY, but not in SHR. In striata from subacutely treated rats, the density of D-1 receptors was significantly increased in 3- and 7-day treated WKY, but not in SHR. The affinities of both binding sites remained unchanged. In nuclei accumbens, the change in both D-1 and D-2 receptors after cocaine administration were similar to those observed in the striatum. The results suggest that cocaine administration alters dopamine receptor binding characteristics. Furthermore, D-1 and D-2 dopamine receptors appear to be differently regulated.

Animals↗
PubMed1990

Effects of acute and subacute cocaine administration on the CNS dopaminergic system in Wistar-Kyoto and spontaneously hypertensive rats: III. Dopamine uptake.

The characteristics of dopamine uptake after acute and subacute cocaine administration were determined in striata from WKY and SHR. In acutely-treated (40 mg/kg, s.c.) rats, significant increases in the Vmax of dopamine uptake were observed 30 min after the cocaine injection in both strains, without changes in Km values. The in vitro IC50 for cocaine was significantly decreased at 30 min in WKY and at 2 h in SHR. However, the in vitro IC50 for GBR-12909 was significantly increased at 30 min and at 2 h in both strains following cocaine administration. In both strains, the density (Bmax) of the [3H]GBR-12935 binding site was significantly increased at 30 min and at 2 h with no changes in Kd. In subacutely-treated (20 mg/kg, twice daily for 3 or 7 days) rats, a significant increase in the Km for dopamine uptake was observed in 7 day treated SHR. The in vitro IC50 for GBR-12909 was significantly increased in 3 day treated WKY. The results suggest that cocaine administration alters dopamine uptake and characteristics of dopamine uptake sites in the rat brain.

Animals↗
PubMed1990

Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine.

Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate [( 3H]QNB) binding sites in homogenates of striata by approximately 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 +/- 0.3 to 1.0 +/- 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 +/- 10.7 pM; 7-day: 57 +/- 2.8 pM). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 115 +/- 62 microM (55 +/- 3%) and KiH = 1.8 +/- 0.7 microM (45 +/- 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 +/- 8.6%, but affected neither the low- nor the high-affinity Kd (100 +/- 20 and 2 +/- 0.6 microM). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+ the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 +/- 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Ki values of 38 +/- 14 and 201 +/- 78 nM, which represent 74 and 26% of the binding sites, respectively. The high affinity Kd value was unchanged following 7 days of DFP treatment (24 +/- 5 nM). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1 subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.

Acetylcholinesterase↗
PubMed1990

Pentobarbital tolerance and withdrawal: correlation with effects on the GABAA receptor.

A model for the development of pentobarbital tolerance and dependence was characterized and correlated with changes in radioligand binding to the GABAA-benzodiazepine receptor chloride channel complex. While one day of pentobarbital exposure decreased the duration of loss of righting reflex, tolerance to the hypothermic effects of thiopental and barbital took 7 days to develop, indicating that pharmacokinetic and pharmacodynamic tolerance are separable. Increased sensitivity to pentylenetetrazol-induced seizures was first observed after 3 days of pentobarbital exposure, suggesting brain areas involved in seizure control develop tolerance to, and dependence on pentobarbital faster than those involved in temperature regulation. Acute exposure to pentobarbital in vivo did not affect cortical binding of [3H]muscimol in vitro, while tolerance caused a decrease in binding due to an increase in the low-affinity site KD. Pentobarbital tolerance also caused a decrease in the cortical binding of the benzodiazepine, [3H]flunitrazepam. These observations suggest that the acute effects of barbiturates on the GABAA receptor complex are reversible, while tolerance causes receptor modifications which may be related to the development of physical dependence.

Animals↗
PubMed1990

Restraint alters temperature responses to cocaine in spontaneously hypertensive rats.

The body temperature responses to intraperitoneal (IP) or intravenous (IV) cocaine in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were examined under restrained and freely moving conditions. Resting values for rectal temperature (RT), in ambient temperatures of 22-24 degrees C, were significantly (p less than 0.01) higher in SHR than in WKY rats, under both restrained (39.19 +/- 0.07 vs. 38.01 +/- 0.06 degrees C) and freely moving (39.39 +/- 0.08 vs. 38.08 +/- 0.06 degrees C) conditions. Resting RT did not differ between restrained and freely moving conditions within a strain. An heterogeneity of RT response to both IV and IP cocaine was expressed by restraint in SHR. The SHR could be divided into animals which demonstrated hyperthermia to cocaine (SHRH) and those in which RT fell (SHRL) . However, cocaine produced hyperthermia in all freely moving SHR, regardless of the route of administration. The effects of IV cocaine in restrained WKY rats were similar to those in freely moving SHR, whereas IP cocaine decreased RT in all restrained WKY rats. Under conditions of restraint, divergent RT responses to cocaine were demonstrated following IV and IP administration in WKY rats, but not in SHR. These results indicate that restraint stress can significantly modify the body temperature responses to acute cocaine administration in both SHR and WKY rats.

Animals↗
PubMed1990

Effects of cocaine on tyrosine hydroxylase activity in brain areas from SHR and WKY.

Basal tyrosine hydroxylase activity was the same in the nuclei accumbens and hypothalami of WKY and SHR. Basal striatal enzyme activity was lower in SHR than in WKY. Acute and subacute cocaine administration altered enzyme activity only in striata and nuclei accumbens of WKY. The central dopaminergic system of SHR appears to be less active and less sensitive to cocaine than that of WKY.

Animals↗
PubMed1990

Evidence for involvement of cyclic GMP phosphodiesterase in morphine tolerance.

Preliminary evidence had suggested that changes in cyclic GMP (cGMP) hydrolysis via cyclic nucleotide phosphodiesterase(s) occurred during development of tolerance to morphine. To examine this finding further and its possible role in development of tolerance to morphine, rats (150-175 g) were injected with 1 ml of a sustained-release morphine preparation (40 mg/ml). Control rats received 1 ml of the oily vehicle. Antinociception, decreased locomotor activity, respiratory depression and mydriasis were measured at various times from 0.5 through 96 hr of exposure to the drug. Particulate and soluble cGMP hydrolysis were measured for the same time periods from periaqueductal gray (PAG), striatum, medulla and oculomotor nucleus, the brain areas believed to mediate the respective behaviors. Each of the behaviors except mydriasis showed development of complete tolerance (no difference from control behaviors) during the 96 hr of continuous exposure. During development of tolerance, particulate cGMP hydrolysis decreased in PAG and increased in striatum and medulla. Particulate cGMP hydrolysis was not altered in oculomotor nucleus, the brain area mediating mydriasis to which tolerance development was partial or incomplete. Significant changes in soluble cGMP hydrolysis occurred only in PAG before decline in the behavioral effect and did not appear to be involved in tolerance phenomena. Modulation of cyclic nucleotide levels by changes in particulate cGMP hydrolysis may produce or allow for development of complete tolerance to various morphine-induced behaviors.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1989

Butorphanol precipitates abstinence in morphine dependent rats.

Butorphanol precipitated a withdrawal syndrome in rats receiving continuous intracerebroventricular infusions of morphine for three days. However, the potency of butorphanol to induce defecation, urination, teeth chattering and escape behavior was one to two orders of magnitude less on a molar basis than that of naloxone. Wet shake behavior, a prominent feature of naloxone precipitated withdrawal, was absent in morphine dependent animals challenged with butorphanol. These data indicate qualitative as well as quantitative differences in the withdrawal syndromes induced by butorphanol and naloxone.

Animals↗
PubMed1989

Comparative studies of muscarinic and dopamine receptors in three strains of rat.

Cholinesterase activities and characteristics of muscarinic and dopamine receptors from 9 week old male Sprague-Dawley (SD), Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were studied. Plasma cholinesterase activity in WKY was significantly lower (50%) than activity in the other strains. In studies of muscarinic receptors, the number of [3H]QNB binding sites in striata from SD rats was lower (18%) than those from WKY and SHR. However, muscarinic receptor properties (Kd and Bmax) were the same in hypothalami. Studies of dopamine receptors revealed that the densities of both D-1 and D-2 receptors in both striata and hypothalami were significantly higher in SHR than in other strains. However, there were no differences in the affinity constant (Kd). The higher densities in hypothalami from SHR were mainly due to the high population of D-1 and D-2 receptors in the posterior hypothalamus. In the anterior hypothalamus, there was no difference in the population of D-2 receptors. These results provide a substantive basis, i.e. demonstration of alterations in drug metabolizing enzymes and receptor populations, on which to build an understanding of the genetic predisposition to the actions of xenobiotic agents.

Acetylcholinesterase↗
PubMed1989

Differential sensitivity to cocaine in spontaneously hypertensive and Wistar-Kyoto rats.

Physiological, pharmacological and toxicological responses to two regimens of cocaine administration were compared between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. An initial experiment examined renal excretory and hemodynamic function in response to an acute volume load in anesthetized SHR and WKY following subacute cocaine treatment (20 mg/kg, s.c., twice a day for 9 days). Anticipated renal responses to volume loading were obtained but the responses of cocaine-treated SHR and WKY did not differ from vehicle-treated rats. A second group of experiments compared responses to continuous i.v. infusions of cocaine (1.25 mg/kg.min). In freely moving animals, no differences were noted between SHR and WKY in the increases in mean blood pressure (MBP) and heart rate (HR) produced during cocaine infusion. The elapsed time-to-onset of convulsions (Tc) elicited by cocaine was similar in both strains. However, when rats were subjected to restraint during the infusion period, pressor and tachycardic responses were observed to be significantly less in WKY than in SHR or in freely moving rats of either strain. Restraint also differentially affected rectal temperature (RT) responses to cocaine. Hypothermic responses to cocaine were observed in all WKY. Both hypothermic and hyperthermic responses were observed in SHR. A significant correlation was demonstrated between the Tc and the maximal change in RT produced during cocaine infusion. Division of SHR into two arbitrary groups was made, based on the direction of cocaine-induced change in RT. A significant (p less than 0.01) shortening of the Tc was obvious in SHR (8 of 15) in whom cocaine produced a hyperthermia. These animals were designated SHRH. The mean value for Tc in those SHR which demonstrated a lowering in RT (SHRL; 7 of 15) in response to cocaine was similar to that for WKY. Moreover, the SHRH evidenced significantly greater increases in HR, but not MBP, to cocaine infusion than did SHRL. The results indicate that restraint stress causes expression of a significant heterogeneity in the RT response of SHR to cocaine. The magnitude and direction of the RT responses are negatively correlated with sensitivity to the convulsive effects of cocaine in SHR. Stress may modify toxic responses to cocaine by interactions with body temperature homeostasis.

Animals↗
PubMed1989

Comparative pharmacological and biochemical studies between butorphanol and morphine.

A number of in vivo and in vitro studies were undertaken to compare the pharmacological and biochemical effects of the partial agonist, butorphanol, with that of morphine. Both compounds were equipotent antinociceptive agents in the rat tail withdrawal test. In the acetic acid writhing test butorphanol had approximately 3.5 times the antiwrithing activity on a molar basis than morphine. In a study of the effects of these compounds on body temperature, butorphanol as well as morphine produced hyperthermia after acute dosing. Additionally, butorphanol produced a profound diuresis and decrease in urine osmolality after acute administration. In contrast, morphine produced an antidiuresis throughout most of the study period with no significant changes in urine osmolality from control. Butorphanol administration had no effect on respiratory rate, while morphine markedly decreased respiratory rate. In in vitro radioligand displacement studies, butorphanol was a potent competitor against 3H-DAGO, 3H-DPDPE, and 3H(-)-EKC binding, exhibiting 3, 10, and 30 times more activity, respectively, than morphine. Both compounds were weak inhibitors of 3H-(+)-SKF 10047 binding, yielding IC50 values of in excess of 1 microM. The results indicate that butorphanol has multiple actions on the opioid receptor system, and shares similarities as well as differences in its mechanism(s) of actions with morphine.

Analgesia↗
PubMed1989

Effects of picrotoxin treatment on GABAA receptor supramolecular complexes in rat brain.

The effects of acute and chronic administration of a subconvulsive dose of picrotoxin on t-[35S]butylbicyclophosphorothionate ([3S]TBPS), [3H]muscimol, and [3H]flunitrazepam binding characteristics in various regions and on the convulsant potency of picrotoxin in Sprague-Dawley rats were examined. Acute administration of a subconvulsive dose of picrotoxin (3 mg/kg, i.p.) significantly increased [35S]TBPS and [3H]muscimol binding in cerebellum (CB) with no change in frontal cortex (FC). In rats treated chronically with picrotoxin (3 mg/kg, i.p., daily for 10 days), the Bmax of [35S]TBPS binding site was significantly decreased in the FC, striatum (ST), and CB with no change in KD values. Neither [3H]muscimol binding in the FC and CB nor [3H]flunitrazepam binding in the FC was affected in these rats. In addition, the potency of pentobarbital to inhibit [35S]TBPS binding in vitro was not altered following acute or chronic treatment of picrotoxin. Chronic administration of picrotoxin did not affect convulsive ED50 or LD50 of picrotoxin; however, it delayed the onset of convulsions and increased the time to death. These results suggest that treatment with picrotoxin at a subconvulsive dose for 10 days causes down-regulation of [35S]TBPS binding sites and that this down-regulation might be related, at least in part, to the decreased extent of convulsant potency of picrotoxin. In addition, the results indicate possible interaction between convulsant binding sites and GABAA receptor sites in the CB following picrotoxin treatment.

Animals↗