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Biomedical subjects

H L Williams

Publications and source records attributed to H L Williams.

At least 19 recordsLinked to original sources
PubMed1992

On central muscle relaxants, strychnine-insensitive glycine receptors and two old drugs: zoxazolamine and HA-966.

Zoxazolamine is in the centrally-acting muscle relaxant class of drugs, which reportedly act by decreasing CNS interneuronal activity. These drugs, but not anxiolytics, decrease dopaminergic turnover and induce a pacemaker-like discharge pattern in dopaminergic neurons. A mechanism for these effects was not found in previous reports. We observed that (+)-HA-966, an inhibitor of the glycine modulatory site on the NMDA receptor, has a similar effect on dopaminergic impulse flow, which suggested that this may be the possible site of action of classical muscle relaxants. However, a competitive antagonist of NMDA receptors, NPC-12626, had little effect on impulse flow. Binding of 20 nM [3H]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC50 = 3.16 microM, but only poorly by zoxazolamine, IC50 V 474 microM, and chlorzoxazone, a related drug, caused no displacement. The drugs were then tested for protection from amphetamine neurotoxicity. Neither 50 mg/kg zoxazolamine nor 30 mg/kg (+)-HA-966 prevented (+)-amphetamine (0.1 mmol/kg plus 10 mg/kg iprindole) depletion of striatal dopamine (DA), but 3.0 mg/kg of MK-801, a non-competitive NMDA receptor antagonist, did protect DA content. Since baclofen induces a regular firing rate in DA neurons, zoxazolamine and (+)-HA-966 were tested for displacement of 10 nM [3H]-1-baclofen from cortical synaptosomal GABAb receptors, but were ineffective. Thus, the effects of these muscle relaxants on DA neurons are mediated by a mechanism other than strychnine-insensitive glycine or GABAb receptors.

Amphetamine↗
PubMed1992

Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro.

Compounds that inhibit the P-glycoprotein-related efflux mechanism of multidrug-resistant cells reverse chloroquine resistance in vitro. Hence, the co-administration of chloroquine and an efflux-blocking drug could potentially treat chloroquine-resistant malaria infections. We administered a drug combination (chloroquine and a tiapamil analogue), that has been shown to reverse chloroquine resistance in vitro, to Aotus monkeys but failed to safely clear experimentally-induced chloroquine-resistant Plasmodium falciparum parasitaemias.

Animals↗
PubMed1992

Cannabinoid agonists stimulate both receptor- and non-receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones.

The physiologic activity of (-)-delta 9-tetrahydrocannabinol, the most active component of marijuana, and of many synthetic cannabimimetics may be mediated either through receptor binding and functional coupling to specific signal transduction pathways or through nonspecific interaction with cell membrane components. The cloning of the human and rat cannabinoid receptors has provided the opportunity to investigate the binding properties and signal transduction pathways directly associated with these receptors. Cannabinoid receptor cDNA was transfected into and stably expressed in fibroblast cell lines that do not contain native cannabinoid receptors, thus allowing comparison with untransfected cells. Binding constants measured using [3H]CP55,940 indicated that the rat and human cloned cannabinoid receptors were similar to native cannabinoid receptors measured in brain and neural cell lines. The cloned receptors coupled to the inhibition of cAMP accumulation, as previously demonstrated. CP55,940 binding and inhibition of cAMP accumulation were absent in untransfected cells. Cannabinoid agonist-stimulated release of arachidonic acid and increase in intracellular calcium were observed in both transfected and untransfected cells. Stereoselectivity of cannabinoid agonists was demonstrated for binding and functional inhibition of cAMP accumulation, but not for the release of arachidonic acid and intracellular calcium. Therefore, cannabinoid agonists can stimulate signaling pathways through both receptor- and non-receptor-mediated pathways in the same cell.

Animals↗
PubMed1991

A transduction pathway associated with receptors coupled to the inhibitory guanine nucleotide binding protein Gi that amplifies ATP-mediated arachidonic acid release.

ATP is copackaged and coreleased with adrenergic, serotonergic, and cholinergic neurotransmitters, suggesting a possible interaction between the signaling pathways for ATP and these coreleased neurotransmitters. Muscarinic m2 and m4, alpha 2-adrenergic, and D2-dopaminergic neurotransmitter receptors, which have in common their ability to inhibit adenylate cyclase through the inhibitory guanine nucleotide binding protein Gi, were transfected and expressed in Chinese hamster ovary (CHO) cells that contain endogenous ATP receptors coupled to the release of arachidonic acid. Normal functional coupling of m2, m4, alpha 2, and D2 receptors was demonstrated by their ability to inhibit forskolin-stimulated cAMP accumulation with dose-response activities consistent with previous reports for these Gi-coupled receptors. Stimulation of m2, m4, alpha 2, and D2 receptors resulted in an augmentation of ATP-stimulated arachidonic acid release. With the exception of the m4 receptor, none of the receptors tested was able to stimulate arachidonic acid release in the absence of ATP. Potentiation of ATP-stimulated arachidonic acid release was independent of changes in cAMP. The augmentation of ATP-stimulated arachidonic acid release and the inhibition of cAMP accumulation were both blocked by pertussis toxin, an inhibitor of Gi, but with different dose-response characteristics. Inhibition of protein kinase C with staurosporine or long-term pretreatment of the cells with the phorbol ester phorbol 12-myristate 13-acetate blocked the augmentation response. This demonstrates that Gi-coupled inhibitory receptors can amplify ATP-receptor-stimulated arachidonic acid release through a pertussis-toxin-sensitive G protein, independent of their ability to inhibit adenylate cyclase activity.

Adenosine Triphosphate↗
PubMed1991

Effects of subchronic amphetamine or amfonelic acid on rat brain dopaminergic and serotonergic function.

Repeated doses of direct or indirect CNS stimulants are known to cause behavioral hypersensitivity. The biochemical basis for hypersensitization remains unclear. Since the dopaminergic system uses a large storage pool that is only slowly mobilized to releasable sites, a change in this relationship may underlie the biochemical changes leading to increased responsiveness to stimulants. To test this hypothesis, rats were first tested with low doses of 2.5 mg/kg amphetamine or 1.0 mg/kg amfonelic acid (AFA) for their locomotor response, then 5.0 mg/kg amphetamine or 2.5 mg/kg AFA were injected daily for 7 days and the rats retested with the lower doses of amphetamine or AFA, respectively. Both drugs produced hypersensitivity, but the cataleptic response to acute dopamine (DA) receptor blockade by haloperidol was unaltered. The ability of haloperidol to increase DA metabolism was unaltered and the ability of acute AFA to synergize with haloperidol was similar in the striatum of stimulant and saline treated rats, but reduced in the medial prefrontal cortex of both AFA and d-amphetamine treated rats. Additional rats had DA2 receptor sensitivity measured in the striatum and frontal cortex, but no significant differences were found. Only amphetamine caused a significant decrease in frontal cortex serotonin type 2 receptors. Since there was no alteration in the ability of AFA to increase neurogenic release of DA in the striatum and a decrease occurred in prefrontal cortex, an increase in the storage to functional pool exchange in the nigrostriatal and mesocortical DA containing neurons seems unlikely. In contrast, both the amphetamine and AFA treatment groups had their brain 5HT and 5HIAA levels reduced by about 50%. This suggests that changes in other transmitter systems may have a permissive effect allowing exaggerated responses to excessive DA release.

Amphetamine↗
PubMed1990

Ipsapirone and 1-(2-pyrimidinyl)-piperazine increase rat locus coeruleus noradrenergic activity.

The effects of systemically administered ipsapirone, an aryl-piperazine compound, and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), on locus coeruleus (LC) noradrenergic activity was investigated. On an equimolar basis both ipsapirone and 1-PP were approximately equipotent in increasing LC neuronal activity. However, pretreatment with 1-PP caused a significantly greater parallel shift to the right of the dose response curve for the inhibitory action of the LC alpha 2-receptor agonist clonidine compared to ipsapirone. Biochemically, pretreatment with SKF 525A, a compound which prevents the formation of 1-PP from ipsapirone, diminished the ipsapirone-induced increase in MOPEG-SO4 levels in the brainstem and cortex. These data, together with the findings that 1-PP is more potent than ipsapirone in displacing 3H-clonidine from cerebral cortical membranes, suggest that the parent drug influences LC neuronal activity via the action of I-PP on LC alpha 2-adrenoceptors.

Action Potentials↗
PubMed1990

Relationships between neuropsychological test performance and event-related potentials in alcoholic and nonalcoholic samples.

Are event-related potentials and nonconcurrently measured neuropsychological test performance correlated? Sober male and female middle-aged alcoholics and peer controls were administered an "oddball" event-related potential (ERP) task and several hours later, a battery of neuropsychological (NP) tests. Alcoholics performed significantly poorer than controls on NP tests. Male alcoholics had significantly altered ERP responses (N1, NdA, and P3 amplitudes) but female alcoholics did not differ on any ERP variables from controls. A number of significant correlations between ERP and NP measures were present. The most consistent findings were positive correlations between perceptual-motor (PM) tests and the P3 amplitude at Pz in both male and female alcoholics and in male alcoholics, a negative correlation between PM tests and P3 latency at Pz, findings similar to those seen in Parkinson patients. Significant correlations were most numerous in family history positive alcoholics. The results lead to two conclusions: first, Grant's postulation that sober alcoholics may manifest an intermediate duration organic mental disorder is supported; second, given the lack of ERP differences in the females, ERP measures should not be considered as being causally related to NP performance.

Adult↗
PubMed1990

Studies of cobalamin as a vehicle for the renal excretion of cyanide anion.

To examine the ability of hydroxocobalamin (vitamin B12a, HO-Cbl) to counteract the toxicity of cyanide by promoting the renal excretion of cyanide anion, we studied the pharmacokinetics of HO-Cbl and cyanocobalamin (vitamin B12, CN-Cbl) given in high doses to dogs. After administration of intravenous bolus doses of HO-Cbl and CN-Cbl (5, 10, 25 mg/kg) to female foxhounds, peak plasma concentrations were attained within 1 minute, after which the cobalamins disappeared from plasma in a manner consistent with two-phase distribution and elimination kinetics. While mean t1/2 measurements for the initial distribution phase were similar for HO-Cbl and CN-Cbl, the secondary excretion phase was more prolonged for HO-Cbl than for CN-Cbl (t1/2, 94.75 minutes vs 62.64 minutes, respectively). Pharmacokinetic data permitted the design of a HO-Cbl infusion schedule that resulted in stable plasma concentrations in test animals. When NaCN was then given intravenously to animals preloaded with HO-Cbl (20 micrograms/ml plasma), conversion of HO-Cbl to CN-Cbl in vivo, was documented by both thin-layer and high-performance liquid chromatographic analysis of successive urine samples. Moreover, in dogs preloaded with HO-Cbl (20 micrograms/ml plasma), up to 10% of the cyanide administered as NaCN infusions was recovered in urine as CN-Cbl by 60 minutes, compared with less than 0.3% in dogs not treated with HO-Cbl. In addition, under these conditions of HO-Cbl loading, the minimum doses of NaCN required to produce sublethal signs of cyanide toxicity (hypotension, tachypnea, tachycardia) were found to be increased to levels that in some cases exceeded normally lethal doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of microgravity on brain neurotransmitter receptors.

Neurotransmitter receptor binding and Na+, K+-ATPase activity were examined in the brains of six rats exposed to 7 days of microgravity during the flight of Spacelab 3. The same variables were examined in a group of six ground control rats. 5-HT1 receptor number in the hippocampus was significantly elevated by exposure to the microgravity environment, and cortical sodium-potassium pump activity was significantly depressed. A marginal depression in dopamine D-2 binding in the striatum was noted. Dopamine and 5-HT binding in a wide variety of other central regions, in addition to GABAA, muscarinic acetylcholine, adenosine A1, and opiate receptor binding, and adrenoceptor binding, was unaffected by microgravity exposure.

Animals↗
PubMed1989

Transition from East to West: Vietnamese adolescents and their parents.

A 28-item questionnaire assessing family values was completed by 191 Vietnamese and 639 Caucasian adolescents in Oklahoma City Public Schools and by about half their parents. Vietnamese refugee parents, regardless of time in the United States, strongly endorsed traditional family values. Vietnamese adolescents tended to reject traditional values. This generation gap increased with time in the United States and was greater for girls than for boys. Despite wholehearted endorsement of traditional family values, Vietnamese parents tended to approve certain adolescent privileges. The results suggest that Vietnamese adolescents may receive conflicting messages from their parents. On the one hand, parents endorsed such traditional values as absolute obedience to parental authority but on the other, they registered relative approval of adolescent freedom of choice regarding dating, marriage, and career. Such ambivalence suggests that Vietnamese refugee families may experience considerable strain while adjusting to American values.

Acculturation↗
PubMed1989

The relationship between neuropsychological and late component evoked potential measures in chronic alcoholics.

The relationships between event-related potential (ERP) measures and neuropsychological measures were investigated in a group of 39 male alcoholics and 22 age-matched male controls. Late component ERP measures such as N1, Nd, and P3 components and neuropsychological measures of perceptual-motor function, semantic and figural memory and verbal abstracting functions were included in a correlational analysis. No significant correlations between N1 amplitude or latency and neuropsychological tests were obtained. However, visual Nd amplitude correlated significantly with perceptual-motor tests and figural memory scores in the alcoholics. Significant correlations were found in alcoholics for visual P3 amplitude at PZ and delayed figural memory scores and two of the perceptual-motor tests. No significant correlations were obtained among the controls. These data indicate that significant relationships exist between some neuropsychological and ERP measures but that these relationships are restricted to measures of perceptual-motor functioning and to delayed figural memory.

Adult↗
PubMed1988

Dose effects of methaqualone on stimulus encoding in a memory scanning task.

Three task variables, stimulus quality, memory set size and response type, were used in a Sternberg binary classification task to define stimulus encoding, short-term memory scanning, and response selection stages within a serial stage reaction process. Mean reaction times, and the slopes and intercepts of the function relating reaction time to memory set size, were used to test the hypothesis that performance deficits seen at two doses of methaqualone (2.9 mg/kg and 5.9 mg/kg), in the range formerly in common clinical use, were specific to the stimulus encoding stage of the reaction process. Mean reaction times were increased significantly by the methaqualone at both doses, but the effects of the two doses did not differ from one another. The intercept of reaction time as a function of set size showed significant main effects of methaqualone, stimulus quality, and response type, and a significant hyper-additive interaction of methaqualone with stimulus quality. At 2.9 mg/kg, the intercept was increased by methaqualone but only with degraded stimuli. At 5.9 mg/kg, the intercept was increased by methaqualone for both high and low quality stimuli. These results suggested a dose-dependent selective effect of methaqualone on the stimulus encoding stage of the reaction process.

Adult↗
PubMed1987

Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission.

Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED50 = 4.5 mg/kg i.p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3-10 mg/kg i.v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [3H]-5HT from the 5HT1a binding site in the hippocampus with IC50 values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [3H]-5HT from both 5HT1a and 5HT1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.

Aggression↗
PubMed1987

Effects of sodium intake during two parities on Na status in blackface sheep.

A low-sodium diet was given to Blackface ewes over two reproductive seasons. This diet provided a total of 3-7 mmol/d except during lactation when the intake was about 11 mmol/d. Control ewes were given the same diet supplemented with sodium chloride to provide recommended levels which were about tenfold that of the experimental diet. The output of Na in urine and faeces from ewes given the low-Na diet was very low, about 3 mmol/d, from early in the experiment and continued at about this level throughout. Lambs born to low-Na ewes and given a low-Na diet similar to that of their dams during lactation, grew, after weaning, more slowly than corresponding lambs from control ewes, but at 6 months of age when six from each group were killed, tissue Na contents were only slightly lower in experimental than control lambs. Fluids and tissues obtained at the end of the second lactation from four ewes of each group that had suckled twin lambs, were analysed for Na and potassium. The Na concentration in saliva and rumen fluid of low-Na ewes was about half that of control ewes and there were corresponding increases in K: the differences were significant. Although Na concentrations for experimental ewes were generally lower than those for control ewes in the tissues analysed (liver, kidney, heart, brain and bone), the difference was significant only for the heart (P less than 0.05). Haemoglobin and packed cell volume were significantly elevated in low-Na ewes (P less than 0.01), indicating decreased body fluid volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of sodium intake on lactation and Na levels in body fluids of Blackface ewes.

1. A low-sodium diet was given to Blackface ewes over two reproductive seasons; the diet provided 3-7 mmol Na daily, except for the period of lactation, when Na intake was increased to around 11 mmol/d. The diet of the control ewes was supplemented with sodium chloride to provide the recommended allowance of about ten times the level in the experimental low-Na diet. 2. Milk production was assessed during the first 2 months of lactation from incremental changes in the live weight of lambs during controlled sucking periods. Na and potassium were determined in milk and also in plasma, saliva and urine. 3. Neither yield nor concentration of Na and K in milk was affected by the level of Na in the diet. These results were supported by the similarity in live-weight gain of lambs in both years regardless of diet. 4. Plasma Na and K concentrations were not affected by the level of dietary Na. Na concentration in saliva and urine was significantly lower in the treated than in the control ewes, and K concentration in saliva was significantly higher.

Animals↗