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Biomedical subjects

L G Miller

Publications and source records attributed to L G Miller.

At least 109 records · Page 6Linked to original sources
PubMed1990

Chronic morphine administration augments benzodiazepine binding and GABAA receptor function.

Behavioral and neurochemical evidence indicates links between the opioid and GABA neurotransmitter systems. To assess effects of chronic opiates on the major site of postsynaptic GABAergic activity, the GABAA receptor, we administered chronic morphine and naltrexone to mice and evaluated binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites and GABA-dependent chloride uptake. After morphine (3 days), benzodiazepine receptor binding in vivo but not in vitro was increased in cortex compared to placebo-treated mice. TBPS binding was unchanged in cortex, but muscimol-stimulated chloride uptake was increased at low doses of muscimol. Benzodiazepine and TBPS binding and muscimol-stimulated chloride uptake were unchanged in naltrexone-(8 days) compared to placebo-treated mice. When naltrexone was administered previously to block opiate sites, the increases in benzodiazepine binding and chloride uptake observed with chronic morphine were reversed. These results indicate that chronic morphine but not naltrexone enhances benzodiazepine binding and GABAA receptor function, perhaps by an action at opioid receptors.

Animals↗
PubMed1990

Chronic administration of benzodiazepines--V. Rapid onset of behavioral and neurochemical alterations after discontinuation of alprazolam.

Discontinuation of chronic treatment with alprazolam may cause a characteristic clinical syndrome. To assess the basis of this syndrome, mice were treated with alprazolam, 2 mg/kg, for 7 days, a regimen associated with the development of tolerance and downregulation of receptors. Effects on motor activity and the binding and function of GABA receptors were evaluated 1, 2, 4 and 7 days after discontinuation. Motor activity was similar to controls 1 day after cessation of alprazolam, increased from days 2 to 4 after-alprazolam, and returned to control values by 7 days. The binding of benzodiazepines in vivo and in vitro was increased in the cortex 2 and 4 days after alprazolam and in the hypothalamus at 4 days after alprazolam. Binding returned to control values in all areas by 7 days. Binding at the chloride channel, using [35S]t-butylbicyclophosphorothionate, was not significantly altered after discontinuation. Muscimol-stimulated uptake of [36Cl-] in cortical synaptoneurosomes was increased at 4 days after alprazolam, compared to days 1, 2 and 7. Thus, behavioral and neurochemical alterations was associated with the discontinuation of alprazolam. These alterations were qualitatively similar to those observed following discontinuation of lorazepam but occurred more rapidly and with differing regional specificity.

Alprazolam↗
PubMed1990

Glutamate, kainate and quisqualate enhance GABA-dependent chloride uptake in cortex.

Several lines of evidence indicate a possible interaction between the major inhibitory and excitatory cortical neurotransmitters, GABA and glutamate. To assess the neurochemical basis for such an interaction, we examined the effects of glutamate and several analogs on GABA-dependent chloride uptake in a mouse cortical synaptoneurosome preparation. L-Glutamate and the specific receptor subtype ligands kainate and quisqualate led to a small but significant enhancement in chloride uptake in the presence, but not the absence, of the GABA analog muscimol (5 microM). Enhancement was seen at excitatory amino acid (EAA) concentrations of 2-10 microM, but not at higher concentrations. D-Glutamate, NMDA, the NMDA-related antagonists APV and MK801, and the kainate/quisqualate antagonist CNQX, had no effect on chloride uptake. However, CNQX (50 microM) but not APV (50 microM) blocked the increase in chloride uptake due to kainate or quisqualate (10 microM). In addition, depolarization of synaptoneurosomes using high potassium (40 mM KC1) or ouabain pretreatment (5 microM) blocked the effects of kainate and quisqualate. Glutamate, kainate, and quisqualate had no effect on binding at the benzodiazepine, TBPS, or GABA sites on the GABAA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1990

MIF-1 and Tyr-MIF-1 do not alter GABA binding on the GABAA receptor.

The endogenous brain peptides MIF-1 and Tyr-MIF-1 have been reported to alter binding at several sites on the GABAA receptor. To determine whether these peptides affect binding at the GABA site, we assessed effects of MIF-1 and Tyr-MIF-1 on [3H]SR 95531 binding in mouse cortical synaptosomal membranes. Neither peptide altered [3H]SR 95531 binding across a wide range of concentrations (10(-12)-10(-6) M). Scatchard analysis indicated no change in either apparent affinity or receptor density at both the high-affinity and low-affinity GABA sites with MIF-1 or Tyr-MIF-1, 10(-9) M. Thus, MIF-1 and Tyr-MIF-1 do not affect binding at the GABA site on the GABAA receptor.

Animals↗
PubMed1990

Neurologic approach to drug-induced movement disorders: a study of 125 patients.

Of 125 patients with neuroleptic (dopamine blocking) drug-induced movement disorders who had been referred to a specialized clinic to differentiate the predominant movement disorder, 63% had tardive dyskinesia, 30% had parkinsonism, 24% had dystonia, 7% had akathisia, and 2% had isolated tremor. Two or more movement disorders coexisted in 31 patients (25%). Functional disability was more severe in patients with akathisia than in other patients. Women outnumbered men at a ratio of 4:1, except for tardive dystonia which affected both sexes equally. The average at onset was 56 years (range, 13 to 87); 69 patients (55%) had onset of movement disorder in the sixth decade. While tardive dystonia was distributed relatively evenly in all age groups, almost a third of patients with parkinsonism had it in the eighth decade. Haloperidol was implicated in 47 patients (37%), followed by amitriptyline/perphenazine in 30%, thioridazine in 27%, and chlorpromazine in 20%. Metoclopramide-induced movement disorders were found in 10 (8%). Most patients (101 or 81%) had history of psychiatric illnesses, but of these only 44 had psychosis. Neuroleptic drugs had been prescribed for 33 patients (26%) who had gastrointestinal problems. It is important to recognize and differentiate various drug-induced movement disorders because such differentiation has pathophysiologic and therapeutic implications. Many patients could have been treated with less potent drugs.

Adolescent↗
PubMed1990

Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA-receptor function.

1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg-1 day-1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg-1 i.p., and GABA-dependent chloride uptake in 3 brain regions at these time points. 3. Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872-resistant (Type 2) sites in both regions. Maximal GABA-dependent chloride uptake was also decreased in the cortex and hippocampus at day 7. 4. Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA-dependent chloride uptake was also decreased only in the cortex. 5. These data suggest that the effects of chronic benzodiazepine administration on the GABAA-receptor may be both region-specific and receptor subtype-specific.

Alprazolam↗
PubMed1990

Chronic benzodiazepine administration: effects in vivo and in vitro.

Chronic benzodiazepine administration is associated with neurochemical alterations in the GABAergic system, as determined in a variety of animal models and tissue culture systems. In animals, effects of chronic benzodiazepine agonists on receptor binding are uncertain, but several studies indicate a decrease in GABA-dependent chloride uptake. In contrast, limited data indicate that chloride uptake is increased after chronic antagonist administration, and results of inverse agonist administration are uncertain. Most animal studies are limited by lack of attention to drug choice and to pharmacokinetic variables, and by failure to determined delivered drug concentrations. More limited data in tissue culture systems are conflicting with regard to effects on benzodiazepine binding, but recent studies indicate that GABA-dependent chloride uptake may be decreased after chronic agonist exposure, and increased after chronic antagonist and inverse agonist administration. Data from these systems may complement results obtained in intact animals, and cultures may allow more detailed examination of the kinetics and specificity of drug effects.

Animals↗
PubMed1990

Kinetic and dynamic components of increased benzodiazepine sensitivity in aging animals.

Male CD-1 mice (age 6 weeks, 6 months, 1 and 2 years) received single 2-mg/kg i.p. doses of clonazepam. Plasma and cortex clonazepam concentrations, rotarod ataxia and in vivo benzodiazepine receptor occupancy were measured at multiple times up to 14 hr after dosage. Elimination of clonazepam from plasma and cortex became slower with age, but cortex concentrations always exceeded those in plasma. The mean ratio was 1.82, and was not influenced by age. Rotarod ataxia was quantitatively greater and of longer duration in aging animals. This was not explained entirely by kinetic changes, as ataxia at any given cortex clonazepam concentration or degree of receptor occupancy was greater in 1-year-old animals than in those age 6 weeks or 6 months. In a second study, 6-week and 1-year-old animals were tested at a fixed time (1 hr) after variable doses of clonazepam (0.01-2.0 mg/kg); findings were consistent with results from the fixed-dose study. In vitro studies evaluated benzodiazepine receptor binding, chloride channel binding and muscimol-stimulated chloride uptake in cortical membrane preparations from animals of the four age groups. Binding affinity and number of binding sites were not influenced by age, or was gamma-aminobutyric acid-dependent muscimol-stimulated chloride uptake (either with or without addition of lorazepam) significantly related to age. Thus, increased overall sensitivity of aging animals to the central depressant effects of clonazepam is evident in the described model.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1990

Chronic benzodiazepine administration. VI. A partial agonist produces behavioral effects without tolerance or receptor alterations.

Chronic benzodiazepine administration has been reported to lead to behavioral tolerance and, in some cases, downregulation of gamma-aminobutyric acid A (GABAA)-receptor binding and function. So-called "partial agonist" benzodiazepines appear to cause limited benzodiazepine effects and little or no behavioral tolerance. To evaluate behavioral and neurochemical effects of a partial agonist during chronic administration, we treated mice with Ro16-6028, 0.25, 1 and 4 mg/kg/day by implanted osmotic pumps, evaluating open-field activity and binding and function at the GABAA receptor. All three doses of Ro16-6028 caused dose-dependent decreases in vertical movements (rearing), and no tolerance was observed up to 14 days at any dose. In contrast, tolerance occurred to the effects of clonazepam at 7 days. Benzodiazepine receptor occupancy was essentially complete in all brain regions evaluated at doses of 1 and 4 mg/kg/day. Benzodiazepine binding in vivo at 0.25 mg/kg/day was transiently decreased in cortex at 7 days but was unchanged in any other brain region. Benzodiazepine binding in cortex in vitro was unchanged over time at any of the three doses, as were t-butylbicyclophosphorothionate binding and binding at the low- and high-affinity GABA sites measured by [3H]SR-95531. GABAA receptor function as determined by muscimol-stimulated chloride uptake was unchanged over 14 days of administration at Ro16-6028 doses of 0.25 and 4 mg/kg/day. Concentrations of Ro16-6028 were constant during administration at 1 and 4 mg/kg/day. These data indicate that chronic Ro16-6028 causes dose-dependent behavioral effects without the development of tolerance and that, despite substantial or complete benzodiazepine receptor occupancy, few effects occur at the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cocaine augments peripheral benzodiazepine binding in humans.

Acute cocaine administration has been reported to alter central benzodiazepine binding in animals. The authors examined the effects of chronic cocaine use on binding at the peripheral benzodiazepine site on platelets in cocaine users (N = 8), heavy ethanol users (N = 4), and controls (N = 7). The groups were matched for age and sex. None of the subjects reported recent benzodiazepine use, but neither serum nor urine testing was performed. Apparent affinity at the peripheral benzodiazepine site was similar in the three groups. However, the number of binding sites was significantly greater in cocaine users. These results indicate that cocaine use affects peripheral benzodiazepine binding in humans and might also alter central benzodiazepine effects.

Adult↗
PubMed1990

Current issues in NSAID therapy.

More than a dozen NSAIDs are commercially available in the United States. Diclofenac may not be as effective for dysmenorrhea. Although most are equally efficacious, indomethacin is the preferred agent for hemicrania continua and chronic paroxysmal hemicrania. Although all NSAIDs should theoretically be beneficial in gout, the greatest experience is with indomethacin. Sulindac may be the preferred agent for diabetic neuropathy. Fenoprofen appears to be the most offensive NSAID in terms of nephrotoxicity. NSAIDs may antagonize antihypertensive therapy, although this effect may not persist beyond 1 month. Generally, use of NSAIDs in pediatric patients is limited to naproxen and tolmetin. Concomitant therapy with methotrexate, lithium, and AZT should be approached with caution. NSAIDs have similar propensities to cause gastrointestinal side effects. Sucralfate has consistently proved beneficial as cytoprotective therapy for use with NSAIDs without impairing absorption of the NSAID, NSAIDs generally should be avoided prior to surgery, although sulindac or nonacetylated salicylates have a negligible effect on platelet function and may be used if continued NSAID therapy is required. Hepatotoxicity, although rare with NSAIDs, is most common with phenylbutazone and least common with the fenamates.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Cigarettes and drug therapy: pharmacokinetic and pharmacodynamic considerations.

Cigarette smoking-induced alterations in drug absorption, distribution, metabolism, excretion, and effectiveness are reviewed. Drug therapy can be affected pharmacokinetically by polyaromatic hydrocarbons and pharmacodynamically by nicotine. Pentazocine and phenylbutazone show increased metabolism in smokers and may have to be given in higher dosages. Smokers experience less pain relief with propoxyphene than do nonsmokers. Codeine, meperidine, and morphine are unaffected pharmacokinetically, and the effect on acetaminophen is probably not clinically important. Carbamazepine, phenytoin, and phenobarbital are not influenced. Heparin metabolism is elevated in smokers; this effect may necessitate modest increases in dosage. Warfarin clearance is increased, but this is not associated with a change in prothrombin time. Pindolol and propranolol are unaffected pharmacokinetically, but direct effects of nicotine may interfere with blood pressure control. Smoking transiently diminishes the diuretic effect of furosemide, inconsistently affects protein binding of lidocaine, and has no effect on prednisone, prednisolone, or dexamethasone. The metabolism of estrogens to less active metabolites is increased. Smoking is associated with decreased subcutaneous absorption of insulin and increased dosage requirements. Healing of GI ulcers with histamine H2-receptor antagonists may be compromised in smokers; sucralfate is probably more useful. Imipramine, benzodiazepines, chlorpromazine, and glutethimide may be influenced, and theophylline metabolism is accelerated. Cigarette smoking can affect the pharmacokinetic and pharmacodynamic properties of many drugs.

Animals↗
PubMed1989

Interaction of caffeine with the GABAA receptor complex: alterations in receptor function but not ligand binding.

Behavioral and neurochemical evidence indicates interactions between caffeine and other adenosine receptor ligands and the gamma-aminobutyric acid (GABA)-benzodiazepine system. To assess the effects of caffeine on binding and function at the GABAA receptor, we studied the effects of behaviorally-active doses of caffeine on benzodiazepine and Cl- channel binding and on overall function of the GABAA receptor as measured by Cl- uptake. There was no effect of caffeine on benzodiazepine receptor binding in cortical synaptosomal membranes at concentrations of 1-100 microM. No effects on benzodiazepine binding were found ex vivo in mice treated with caffeine, 20 and 40 mg/kg. At the putative Cl- channel site labeled by t-butylbicyclophosphorothionate (TBPS), binding was unchanged in vitro after caffeine treatment (1 and 10 microM) in washed and unwashed membranes. However, in ex vivo studies caffeine (20 and 40 mg/kg) increased numbers of TBPS sites in unwashed but not washed membranes. Muscimol-stimulated Cl- uptake into cortical synaptoneurosomes was decreased in mice treated with caffeine, 20 and 40 mg/kg. Similar results were observed in in vitro preparations treated with 50 microM but not 100 microM caffeine. These results indicate that caffeine administration significantly alters the Cl- transport function of the GABAA receptor complex.

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

Metoclopramide-induced movement disorders. Clinical findings with a review of the literature.

Metoclopramide, a dopamine-2 receptor antagonist used for various gastrointestinal disorders, may cause or exacerbate a variety of extrapyramidal movement disorders. To draw attention to the frequent occurrence of metoclopramide-induced movement disorders, we identified and studied 16 patients who had been exposed to this neuroleptic. The average age at onset was 63 years (range, 24 to 85 years), and women outnumbered men 3 to 1. Tardive dyskinesia was the most common movement disorder (n = 10 [63%]). Five patients had metoclopramide-induced parkinsonism, 1 patient had tardive dystonia, and 1 patient had akathisia. The average duration of exposure prior to onset of movement disorders was 12 months (range, 1 day to 4 years). Therapy was continued for an average of 6 months (range, 1 day to 2 years) after the onset of symptoms, reflecting clinical nonrecognition of the movement disorder and its relationship to metoclopramide. To prevent persistent and disabling movement disorders, long-term use of metoclopramide should be avoided, and patients should be carefully observed for potential neurologic reactions.

Adult↗