Biomedical subjects
Publications and source records attributed to L G Miller.
We have reported what we believe to be the first case of naproxen-associated nightmares. Our brief review of basic sleep physiology and the several questions we have raised might help explain this seemingly unusual adverse effect of naproxen.
The irreversible protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to investigate binding site characteristics on the gamma-aminobutyric acidA (GABAA) receptor complex. In vitro, preincubation with EEDQ led to a concentration-dependent decrease in receptor number for benzodiazepine, t-butylbicyclophosphorothionate (TBPS), and GABA binding sites in cerebral cortex. The effect was maximal at the highest concentration of EEDQ used (10(-4) M) and was greatest for the benzodiazepine site. Pretreatment of membranes with the benzodiazepine antagonist Ro 15-1788, 1 or 10 microM, or the agonist lorazepam, 10 microM, largely prevented the effects of EEDQ. Scatchard analysis indicated no effect of EEDQ, 10(-4) M, on apparent affinity, but a decrease in receptor density for each site. Administration of EEDQ to mice, 12.5 mg/kg i.p., led to a substantial (55-65%) decrease in number of benzodiazepine binding sites in cortex after 4 h. Slightly smaller changes were observed for TBPS and GABA binding. No changes were observed in apparent affinity at any site. Prior administration of Ro 15-1788, 5 mg/kg, prevented the effect of EEDQ on benzodiazepine binding. Density of benzodiazepine binding sites gradually recovered over time, and receptor density returned to control values by 96 h after EEDQ injection. Number of binding sites in cortex for TBPS and GABA also increased over time after EEDQ. Benzodiazepine sites in cerebellum were decreased proportionally to cortex after EEDQ, and increased over a similar time course. Function of the GABAA receptor in chloride uptake in cortex was markedly reduced (65%) by EEDQ.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic benzodiazepine administration has been associated with alterations in binding and function at the GABAA receptor. To evaluate effects of chronic benzodiazepine exposure on messenger RNA (mRNA) concentrations for several GABAA receptor subunits, we treated mice with lorazepam, 2 mg kg-1 daily for 1-28 days and evaluated mRNAs for the alpha 1 and gamma 2 subunits by Northern hybridization. In cerebral cortex, concentrations of mRNA for the alpha 1 and gamma 2 subunits were unchanged from vehicle or control after 1-10 days of lorazepam. However, after 14 days of treatment mRNA concentrations for both subunits decreased to approximately 50% of control values and remained decreased at 28 days. In contrast, no significant alterations were observed for either subunit mRNA in hippocampus or cerebellum over the same time course. Alterations in mRNAs in cortex occur after the development of tolerance and receptor downregulation in this model.
Dissimilatory in situ selenate reduction to elemental selenium in sediments from irrigated agricultural drainage regions of western Nevada was measured at ambient Se oxyanion concentrations. Selenate reduction was rapid, with turnover rate constants ranging from 0.04 to 1.8 h-1 at total Se concentrations in pore water of 13 to 455 nM. Estimates of removal rates of selenium oxyanions were 14.38, and 155 mumol m-2 day-1 for South Lead Lake, Massie Slough, and Hunter Drain, respectively.
Benzodiazepine receptor binding in vivo, as determined by the uptake of the high-affinity specific benzodiazepine receptor ligand [3H]Ro15-1788, was examined following acute and chronic defeat stress in male mice aged 6 weeks, 7 months and 1 year. Specific uptake in 6-week-old mice was increased from control values only in the cerebellum following acute but not chronic stress. Specific uptake in the cortex and hypothalamus was unchanged from control values following both acute and chronic stress. Seven-month-old mice demonstrated an increased specific uptake in the cortex and cerebellum when measured immediately following both acute stress and the final session of chronic stress. This enhanced binding returned to baseline levels by 24 h after stress. One-year-old mice demonstrated no change in specific uptake when measured after acute stress, while binding was enhanced in all brain regions after the final session of chronic stress. This increased binding was still evident at 24 h after the cessation of chronic stress. Changes in benzodiazepine binding differ as a response to acute and chronic stress, and this response varies markedly with age.
Electroconvulsive shock (ECS) has been reported to alter brain second-messengers and neurotransmitter systems, including the gamma-aminobutyric acid (GABAergic) system, and to increase messenger ribonucleic acid (mRNA) for the proto-oncogene c-fos. We evaluated mRNA for the most abundant GABAA receptor subunits, alpha 1 and gamma 2, in brain regions after a single ECS in mice. Alpha 1 and gamma 2 mRNAs were unchanged from controls at 2 hrs after ECS, but both were significantly elevated in cerebellum and hippocampus after 4 hrs. This alteration persisted in cerebellum for alpha 1 mRNA at 8 hrs, but resolved for gamma 2 mRNA in cerebellum and for both subunit mRNAs in hippocampus. No changes in mRNA were observed in cortex for either subunit and no changes in either mRNA were observed in brain regions of sham-treated mice. Thus, ECS appears to be associated with a rapid, reversible increase in GABAA receptor subunit mRNAs in several brain regions.
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.
Interleukin-1 (IL-1), a cytokine involved in the acute phase reaction to injury and infection, has multiple effects in the central nervous system, including induction of fever and sleep and the release of several neuropeptides. We evaluated effects of IL-1 beta on inhibitory postsynaptic function at the gamma-aminobutyric acidA (GABAA) receptor. IL-1 (100 pg/ml to 10 ng/ml) augmented GABAA receptor function in cortical synaptic preparations. This effect of IL-1 was largely prevented by incubation with a specific IL-1 receptor antagonist. The related cytokines interleukin-6 and tumor necrosis factor did not augment GABA-dependent chloride transport. Similar enhancement of GABAA receptor function was observed in tissue prepared from mice previously injected intraperitoneally with IL-1 (1 microgram). Electrophysiological studies in cultured primary cortical neurons demonstrated that IL-1 enhanced the GABA-mediated increase in chloride permeability, whereas IL-1 alone produced no alterations in resting conductance. Behavioral studies indicated that IL-1 is similarly active in vivo; mice treated with IL-1 showed a decrease in open-field activity and an increase in the threshold for pentylenetetrazol-induced seizures. The interaction of IL-1 with GABAA receptors might account for the somnogenic and motor-depressant effects of this cytokine.
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The effects of glutamate and other more selective excitatory amino acid (EAA) analogs on intracellular free calcium concentration ( [Ca2+]i) were examined in Fura 2-loaded cultured chick embryo cortical cells (90% neuronal). Four EAA receptors were evident in these studies: an N-methyl-D-aspartate (NMDA) receptor, a kainate receptor, and two quisqualate receptors. The [Ca2+]i response to NMDA was blocked or reversed by selective antagonists such as 2-amino-5-phosphonovalerate (APV), MK801 and ketamine, as well as by desmethylimipramine and dextromethorphan. Glycine potentiated the [Ca2+]i response to NMDA, and high concentrations of glycine selectively overcame blockade by kynurenic acid, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and cis-piperidine-2,3-dicarboxylic acid (PDA). The [(Ca2+]i response to kainate was generally larger than the NMDA response, and the kainate response desensitized slightly over the first minute. CNQX was more potent as an antagonist of the kainate response than of the NMDA response, even in the absence of added glycine; kynurenic acid and PDA conversely had little effect on the kainate response in these cells at concentrations which blocked the NMDA response. The desensitization of the [Ca2+]i response to kainate was greatly augmented by quisqualate and by the putative ionotropic quisqualate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). In the absence of kainate, both quisqualate and AMPA increased [Ca2+]i though less so than did NMDA or kainate. Quisqualate (and AMPA and glutamate) were not acting as partial agonists at the kainate receptor, since the potency of these agonists in reversing the kainate [Ca2+]i response was independent of kainate concentration. Quisqualate, but not AMPA, also produced a small increase in [Ca2+]i which preceded the negative effect of this agonist on the kainate response. This increase in [Ca2+]i could also be evoked by quisqualate or glutamate after inhibition of the kainate response by AMPA. Quisqualate and glutamate, but not the other EAA agonists, also increased [Ca2+]i after chelation of extracellular calcium with EGTA. This effect appears to be mediated by the metabotropic quisqualate receptor. These cells should provide a useful system for studying regulation and interactions of EAA receptors, and for screening drugs which might act at these receptors.
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Chronic benzodiazepine agonist administration may lead to decreases in gamma-aminobutyric acidA (GABAA) receptor binding and function, but little information is available concerning chronic GABA-neutral or GABA-negative benzodiazepine exposure. We evaluated effects of chronic exposure to flumazenil (Ro15-1788) and FG 7142 (N-methyl-beta-carboline-3-carboxamide) on GABA-dependent chloride uptake in chick cerebral cortical neurons in primary culture. Acute flumazenil treatment (1 microM) had no effect on chloride uptake, but uptake was increased after 2 days of exposure. Similar increases were observed after 4 and 10 days. Flumazenil, 0.1 microM, had no effect after 10 days, and a 10 microM concentration had a similar effect as the 1 microM concentration. Acute FG 7142 (1 microM) decreased chloride uptake, but uptake was increased markedly after 2, 4, and 10 days of treatment. No effect was observed after treatment for 10 days with 0.1 microM, but a 10 microM concentration showed similar enhancement to the 1 microM concentration. Concurrent treatment with 0.3 microM flumazenil which did not affect chloride uptake and 1 microM FG 7142 for 10 days substantially attenuated the effects of FG 7142, suggesting that FG 7142 effects are mediated at the benzodiazepine site. Benzodiazepine receptor binding was increased in cultures treated for 10 days with 1 microM flumazenil or FG 7142, with an increase in receptor number in both cases but no change in apparent affinity. Neither flumazenil nor FG 7142 (1 microM for 10 days) altered GABA-independent chloride uptake, total cellular protein, protein synthesis or degradation, or neuronal survival. These results indicate that both chronic GABA-neutral and GABA-negative benzodiazepine exposures in cultured cortical neurons lead to increases in GABA-dependent chloride uptake and benzodiazepine binding. Effects of GABA-negative benzodiazepine exposure appear to be greater than those observed with GABA-neutral benzodiazepine exposure.
Benzodiazepine derivatives are presumed to exert their pharmacologic activity via interaction with specific molecular recognition sites, termed benzodiazepine receptors, within the brain. The various benzodiazepines used in clinical practice differ considerably in their intrinsic receptor affinity, but the qualitative character of the drug-receptor interaction is similar or identical among this class of drugs. All benzodiazepines are lipophilic (lipid-soluble) substances that relatively rapidly cross the blood-brain barrier and equilibrate with brain tissue. After equilibrium is attained, a constant brain:plasma ratio is maintained, such that plasma concentrations proportionately reflect concentrations of drug in brain. Brain concentrations are proportional to the extent of receptor occupancy, which in turn determines the acute behavioral effect. Clinical differences among benzodiazepines largely reflect differences in pharmacokinetic properties. The onset of action after single oral doses reflects the rate of absorption from the gastrointestinal tract, whereas the duration of action is determined by the rate and extent of drug distribution to peripheral tissues, as well as by the rate of elimination and clearance. During multiple dosage, long half-life drugs accumulate, with the concurrent possibility of daytime sedation. However, a benefit of long half-life drugs is that rebound insomnia on abrupt termination is unlikely. Short half-life drugs accumulate minimally and have a lower likelihood of producing daytime sedation. However, they may be more likely to produce rebound insomnia on abrupt discontinuation.
To determine the influence of sucralfate on the absorption of erythromycin, prior to evaluating its efficacy in decreasing erythromycin-associated gastrointestinal (GI) intolerance, we assessed pharmacokinetic parameters in six healthy adult volunteers. Erythromycin ethylsuccinate administered alone or with sucralfate as a single dose was compared. Sucralfate did not significantly alter the elimination rate constant, half-life, or area under the curve for erythromycin ethylsuccinate. It is therefore unlikely that efficacy of erythromycin ethylsuccinate will be altered when sucralfate is coadministered.
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Sulpiride is a selective D2-receptor antagonist with antipsychotic and antidepressant properties. Although initially thought to be free of extrapyramidal side effects, sulpiride-induced tardive dyskinesia and parkinsonism have been reported occasionally. We studied a 37-year-old man who developed persistent segmental dystonia within 2 months after starting sulpiride therapy. We could not find any previous reports of sulpiride-induced tardive dystonia.
Neutron spectrum measurements were performed on the aluminum oxide filter installed in the Brookhaven Medical Research Reactor (BMRR). For these measurements, activation foils were irradiated at the exit port of the beam facility. A technique based on dominant resonances in selected activation reactions was used to measure the epithermal neutron spectrum. The fast and intermediate-energy ranges of the neutron spectrum were measured by threshold reactions and 10B-shielded 235U fission reactions. Neutron spectral data were derived from the activation data by two approaches: (1) a short analysis which yields neutron flux values at the energies of the dominant or primary resonances in the epithermal activation reactions and integral flux data for neutrons above corresponding threshold or pseudo-threshold energies, and (2) the longer analysis which utilized all the activation data in a full-spectrum, unfolding process using the FERRET spectrum adjustment code. This paper gives a brief description of the measurement techniques, analysis methods, and the results obtained.
A collaborative effort by researchers at the Idaho National Engineering Laboratory and the Brookhaven National Laboratory has resulted in the design and implementation of an epithermal-neutron source at the Brookhaven Medical Research Reactor (BMRR). Large aluminum containers, filled with aluminum oxide tiles and aluminum spacers, were tailored to pre-existing compartments on the animal side of the reactor facility. A layer of cadmium was used to minimize the thermal-neutron component. Additional bismuth was added to the pre-existing bismuth shield to minimize the gamma component of the beam. Lead was also added to reduce gamma streaming around the bismuth. The physics design methods are outlined in this paper. Information available to date shows close agreement between calculated and measured beam parameters. The neutron spectrum is predominantly in the intermediate energy range (0.5 eV - 10 keV). The peak flux intensity is 6.4E + 12 n/(m2.s.MW) at the center of the beam on the outer surface of the final gamma shield. The corresponding neutron current is 3.8E + 12 n/(m2.s.MW). Presently, the core operates at a maximum of 3 MW. The fast-neutron KERMA is 3.6E-15 cGy/(n/m2) and the gamma KERMA is 5.0E-16 cGY/(n/m2) for the unperturbed beam. The neutron intensity falls off rapidly with distance from the outer shield and the thermal flux realized in phantom or tissue is strongly dependent on the beam-delimiter and target geometry.