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Biomedical subjects

R B Roy

Publications and source records attributed to R B Roy.

At least 19 recordsLinked to original sources
PubMed1992

Simulation modelling for HIV infection and AIDS.

In this paper we describe a computer model developed jointly by mathematicians and medical consultants. The aim of the model is to provide practical help to people involved with caring for HIV-infected patients. The program is easy to use and can provide a wide variety of output, ranging from resource requirements and costs to detailed clinical information. The model uses the technique of computer simulation to study the progression of HIV-related diseases in a set of patients. The model can help planners concerned with the broad issues of health care provision, as well as clinical users whose main interest is the management and treatment of individual patients. The model is currently being tested in the Department of Genito-Urinary Medicine in the Royal Victoria Hospital, Bournemouth. The potential capability of the model is illustrated by some results from program runs using data from a set of Bournemouth patients. We argue that the power and flexibility of computer simulation as a technique for dealing with uncertainty and variability is especially appropriate in the case of HIV and AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Platelet activating factor antagonists interact with GABAA receptors.

Platelet activating factor (PAF) is ubiquitous in mammals, and may have multiple functions in the central nervous system. Triazolobenzodiazepine compounds are active both at the GABAA receptor and as PAF antagonists. To investigate whether PAF antagonist activity is involved in the actions of triazolobenzodiazepines, we examined effects of two non-benzodiazepine PAF antagonists on binding and function at the GABAA receptor. The gingkolide terpene, BN 52021 and the dioxolane-based compound BN 52115 had no effect on benzodiazepine binding or chloride channel binding in cortical membrane preparations. However, chloride uptake into cortical synaptoneurosomes was enhanced with 1 microM BN 52021 but not 1 microM BN 52115. The effect of BN 52021 was prevented by 1 microM flumazenil. PAF antagonists appear to augment GABAA receptor function without affecting binding.

Animals↗
PubMed1989

Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration.

The triazolobenzodiazepine compound alprazolam may have unique clinical effects compared to other benzodiazepines, and both behavioral and neurochemical studies have indicated unusual results after acute doses of alprazolam. To determine the effects of chronic dosage in mice, alprazolam (2 mg/kg/day) was administered via osmotic pumps for 1-14 days, and open-field activity, plasma and brain concentrations, benzodiazepine receptor binding in vivo and in vitro, [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding, and muscimol-stimulated chloride uptake were determined. Alprazolam decreased motor activity after 1 and 2 days, but tolerance developed by day 4 and persisted to day 14. Plasma and brain concentrations remained constant during the 2-week period. Benzodiazepine receptor binding in vivo was decreased at day 4 compared to day 1 in cortex (CX) and hypothalamus (HYPO), and remained depressed to day 14 in CX but not HYPO. Benzodiazepine binding in vitro and [35S]TBPS binding were decreased in CX at day 7. Muscimol-stimulated [36Cl-] uptake was decreased at days 4 and 7 compared to day 1, but at day 14 uptake was similar to day 1. These results indicate that behavioral tolerance and receptor downregulation develop rapidly during chronic alprazolam administration. Behavioral and neurochemical changes were similar to those associated with lorazepam administration, but occurred more rapidly and with different regional specificity.

Alprazolam↗
PubMed1989

Persistent alterations in GABAA receptor binding and function after prenatal lorazepam administration in the chick.

Behavioral abnormalities have been reported in young and adult animals exposed to benzodiazepines prenatally. The presence of neurochemical alterations in the GABAergic system after prenatal benzodiazepine exposure was assessed in a chick model which avoids prenatal and postnatal maternal effects. The GABAA receptor complex, the presumed site of benzodiazepine action, was altered in adult chickens previously exposed to lorazepam for 10 days in ovo. Binding was decreased at the putative chloride channel site labeled by [35S]TBPS, coupling was decreased between this site and the GABA binding site, and function of the GABAA receptor in chloride uptake was diminished in animals exposed to prenatal lorazepam. Persistent neurochemical alterations in the GABAergic system accompany prenatal benzodiazepine exposure, and may influence subsequent behavior and development.

Animals↗
PubMed1989

MIF-1 and Tyr-MIF-1 augment muscimol-stimulated chloride uptake in cerebral cortex.

The peptides MIF-1 (Pro-Leu-Gly-NH2) and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) recently have been found to augment the effects of gamma-aminobutyric acid (GABA) on benzodiazepine receptor binding and chloride channel binding (Tyr-MIF-1) at the GABAA receptor complex. To determine whether these peptides affect the function of this complex in chloride transport, we evaluated chloride uptake stimulated by the GABA analog muscimol in synaptoneurosome preparations. In mice treated with either MIF-1 or Tyr-MIF-1 (1 mg/kg IP), maximal chloride uptake in cortex was increased compared with controls. The two peptides had similar effects in cortical preparations, but in cerebellum neither peptide altered chloride uptake. No differences from controls were observed in cortical synaptoneurosomes treated in vitro with either MIF-1 or Tyr-MIF-1. These results suggest that the brain peptides MIF-1 and Tyr-MIF-1 alter function at the GABAA receptor complex, perhaps by binding at a specific peptide receptor.

Animals↗
PubMed1989

Dietary choline intake modulates benzodiazepine receptor binding and gamma-aminobutyric acidA receptor function in mouse brain.

Several lines of evidence suggest that dietary choline intake influences the metabolism of membrane phospholipids with possible effects on GABAergic neurotransmission. Based on these findings, the present experiments determined whether chronic choline supplementation or deficiency alters GABAergic function at the level of the gamma-aminobutyric acid (GABA)/benzodiazepine-chloride channel complex. To accomplish this, mice were fed diets containing 0% (deficient), 0.2% (basal) or 2.0% (supplemented) choline chloride for 28 days, and behavior, ligand binding at several sites in the complex and chloride uptake were determined in various brain regions. For both rotarod ataxia and open-field activity, mice receiving choline supplementation had a decreased response to clonazepam compared to those receiving basal and deficient diets. Choline supplementation significantly increased the in vivo binding of [3H]Ro15-1788 to cortex and cerebellum by 19% and 24%, respectively, and in vitro studies in cortical membranes indicated a significant 36% increase in the maximal number of [3H]flunitrazepam binding sites without a change in affinity, as compared to basal controls. In contrast, [3H]Ro15-1788 binding in vivo in all brain regions from mice fed the deficient diet decreased significantly to 20 to 58% of control values. Dietary choline intake did not alter GABA levels in brain, the binding of [35S]t-butylbicyclophosphorothionate to the chloride channel or the coupling between GABA and either the t-butylbicyclophosphorothionate site or the benzodiazepine site. However, the function of the GABAA receptor, determined by muscimol-stimulated chloride uptake into cortical synaptoneurosomes, was increased significantly in tissue from the supplemented group as compared to both control and deficient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Chronic benzodiazepine administration. III. Upregulation of gamma-aminobutyric acidA receptor binding and function associated with chronic benzodiazepine antagonist administration.

Chronic administration of a benzodiazepine agonist appears to downregulate benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptor function. To examine the effects of chronic treatment with a benzodiazepine antagonist, we administered Ro15-1788, 1, 2 and 5 mg/kg/day to mice via implanted s.c. osmotic pumps for 1 to 14 days. Plasma and cortex (CX) concentrations of Ro15-1788 remained constant between days 1 and 7, indicating no change in pharmacokinetics. Open-field activity studies showed no change in distance traveled or ambulatory time at days 1, 2 and 4, but an increase in both parameters at days 7 and 14 in mice receiving Ro15-1788, 2 mg/kg/day. Benzodiazepine receptor binding was unchanged in CX, cerebellum (CB), hypothalamus, hippocampus and ponsmedulla at 1, 2 and 4 days at a dose of 2 mg/kg/day. Binding was increased in CX, CB and hippocampus at day 7 compared to days 1 and 2, and remained elevated at day 14. Similar results were observed at Ro15-1788 doses of 1 and 5 mg/kg/day. Benzodiazepine binding assessed in vitro in CX and CB also was increased at day 7 compared to day 1, due to an increase in receptor number rather than a change in apparent affinity. Binding of t-[35S]butylbicyclophosphorothionate to the chloride channel site in CX after Ro15-1788, 2 mg/kg/day, was increased at days 7 and 14 compared to days 1, 2 and 4 and controls due to an increase in number of binding sites. t-Butylbicyclophosphorothionate binding in CB was unchanged throughout.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Chronic clonazepam administration decreases gamma-aminobutyric acidA receptor function in cultured cortical neurons.

Chronic benzodiazepine administration has been reported to decrease gamma-aminobutyric acidA (GABAA) receptor function in animals and may alter benzodiazepine binding in neuronal cultures. To assess GABAA receptor function in neuronal cultures exposed to chronic clonazepam, we measured muscimol-stimulated chloride uptake in chick cerebral cortical cultures treated acutely and for 2, 4, and 10 days. Acute clonazepam administration (1 microM) led to an increase in GABA-related chloride uptake at lower doses of muscimol. After chronic clonazepam (1 microM), maximal uptake was markedly decreased at day 10, but maximal uptake was unchanged after 2- and 4-day treatments. Benzodiazepine receptor binding was decreased by approximately 60% after 10 days due to a decrease in receptor number. Decreases in chloride uptake were also observed after 10 days of treatment with 0.1 and 10 microM clonazepam. Concomitant treatment with 0.1 microM Ro15-1788 abrogated the effect of 0.1 microM clonazepam on chloride uptake. Chronic clonazepam treatment (1 microM) did not alter total cellular protein, cellular protein synthesis or degradation or percentage of neuronal cells, as determined morphologically and by [3H]ouabain binding.

Animals↗
PubMed1989

Prenatal lorazepam administration is associated with GABAA receptor alterations in late embryonic and mature chicks.

Prenatal benzodiazepine administration has been associated with alterations in behavior in young and mature animals. Prior studies of neurochemical changes in animals treated in utero have produced conflicting results. We used a chick embryo system to assess the effects of chronic lorazepam administration on binding and function at the GABAA receptor in late embryos and in mature animals. Administration of lorazepam for 10 days of embryonic development (E8-E18) led to decreases in binding of the chloride channel ligand TBPS and in muscimol-stimulated chloride uptake in late embryos (E18). Similar alterations were observed in mature animals after the same regimen of prenatal lorazepam. Persistent alterations in GABAA receptor binding and function after prenatal lorazepam may be due to effects of neuronal differentiation or on receptor regulation. These neurochemical effects may underlie the behavioral abnormalities associated with prenatal benzodiazepine administration.

Animals↗
PubMed1988

Lorazepam administration during embryonic development alters GABAA receptor binding and function.

Prenatal exposure to diazepam has been reported to lead to behavioral alterations in young and mature animals, but the neurochemical basis of this effect is uncertain. To examine effects of embryonic benzodiazepine exposure on the gamma-aminobutyric acidergic (GABA)ergic) system, we assessed binding and function at the GABAA receptor complex in chick embryos treated with lorazepam, 2 mg/kg, for 2-10 days. There was no change in benzodiazepine receptor binding in cortex after lorazepam administration, but a decrease in the number of chloride channel sites was observed. Overall function at the GABAA receptor complex as assessed by chloride uptake into cortical synaptoneurosomes was decreased after 10 days of lorazepam, and possibly increased after 4 days of lorazepam. Similar results were obtained when embryos were treated for 2- and 4-day periods beginning on day 8. These results indicate that chronic lorazepam administration to embryos alters binding and function in the GABA system measured soon before hatching. These alterations, if persistent, may contribute to the behavioral changes seen in animals exposed prenatally.

Animals↗