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Biomedical subjects

R W Fuller

Publications and source records attributed to R W Fuller.

At least 271 records · Page 15Linked to original sources
PubMed1986

Immunoglobulin E-dependent stimulation of human alveolar macrophages: significance in type 1 hypersensitivity.

Human alveolar macrophages were obtained during diagnostic bronchoalveolar lavage. Cells were cultured, and morphological examination (including electron microscopy) revealed that not more than 5% of the cultured cells were identifiable as cells other than alveolar macrophages. The cells were sensitized with human myeloma immunoglobulin E. and then challenged with anti-immunoglobulin E anti-sera. The experiments employed a highly specific monoclonal antibody and three affinity purified reagents. The formation of immunoglobulin E/anti-immunoglobulin E complexes facilitated release from alveolar macrophages of leukotriene B4, prostaglandin F2 alpha, thromboxane B2 and the lysosomal hydrolase N-acetyl-beta-D-glucosaminidase. There was no release of active oxygen species, with this stimulus, as measured by lucigenin chemiluminescence. Immunoglobulin E receptors were identified histochemically on the surface of human alveolar macrophages, and were visualized as conjugates with colloidal gold by electron microscopy. These results support the view that human alveolar macrophages may contribute to type 1 hypersensitivity reactions in the lung.

Asthma↗
PubMed1986

Pharmacologic modification of serotonergic function: drugs for the study and treatment of psychiatric and other disorders.

The development of direct serotonin agonists, selective inhibitors of serotonin uptake, serotonin receptor antagonists, and other drugs affecting serotonergic function has aided the study of physiologic functions of brain serotonin neurons in laboratory animals and the recognition and classification of serotonin receptor subtypes. Agents of these types are real or potential drugs for the treatment of psychiatric disorders (e.g., depression) and other disorders such as overeating, alcoholism, myoclonus, and chronic pain. In addition, the agents may permit assessment of the functional state of brain serotonin receptors in humans.

Alcoholism↗
PubMed1986

Persistent depletion of striatal dopamine in mice by m-hydroxy-MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused marked depletion of dopamine and of its two metabolites, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) one week after the last of four daily s.c. injections (20 mg/kg) in mice. Norepinephrine concentration in the frontal cortex was also decreased. m-Hydroxy-MPTP at a higher dose (80 mg/kg s.c.) caused a similar degree of depletion of dopamine and its metabolites in striatum and of norepinephrine in frontal cortex. p-Hydroxy-MPTP and o-hydroxy-MPTP (both at 80 mg/kg s.c.) caused no significant change in striatal dopamine or in cortical norepinephrine concentrations and had little or no effect on the dopamine metabolites. The m-hydroxy analog increases the list of MPTP-like compounds known to cause persistent depletion of striatal dopamine, and the positional isomers of this compound illustrate the strict structural dependency of this effect.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Influence of selective, reversible inhibitors of monoamine oxidase on the prolonged depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) hydrochloride injected s.c. at 20 mg/kg once daily for four days resulted in marked depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in mouse striatum one week after the last dose. Pretreatment with MD 240928, (R)-[4-((3-chlorophenyl)-methoxy)phenyl]-5-[(methylamino)methyl]-2- oxazolidinone methanesulfonate, prevented the depletion of striatal dopamine, DOPAC and HVA, whereas pretreatment with harmaline did not. MD 240928 selectively inhibited type B not type A monoamine oxidase (MAO), whereas harmaline selectively inhibited type A MAO in mouse striatum. Acutely after injection of harmaline, DOPAC and HVA concentrations were decreased in mouse striatum; these changes were not produced by MD 240928. The acute changes in dopamine metabolites reveal that MAO-A not MAO-B is responsible for the oxidation of dopamine in mouse striatum. Protection against the neurotoxic effects of MPTP by MD 240928 but not by harmaline indicates that prevention of dopamine oxidation is not the mechanism of the protective effect; instead the protection probably is due to prevention of MPTP metabolism by MAO-B, this metabolism having been shown to occur by other workers. The results with these reversible, competitive inhibitors of the two types of MAO are in agreement with previously reported results from studies using irreversible inhibitors of MAO.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Central and peripheral catecholamine depletion by 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in rodents.

1-Methyl-4-phenyl-tetrahydropyridine (MPTP) given in single doses to rats depleted norepinephrine concentration in heart and mesenteric artery but had little effect on catecholamine concentration in brain. MPTP did not share with amphetamine the ability to cause persistent depletion of striatal dopamine in iprindole-treated rats. Administration of MPTP via osmotic minipumps implanted s.c. for 24 hrs after a loading dose of MPTP in rats resulted in depletion of striatal dopamine and its metabolites one week later. MPTP in vitro was a reasonably potent, competitive and reversible inhibitor of MAO-A (monoamine oxidase type A). MPTP appeared to inhibit MAO-A in rat brain in vivo as determined by its antagonism of the inactivation of MAO-A by pargyline and by its antagonism of the increase in dopamine metabolites resulting from the administration of Ro 4-1284, a dopamine releaser. The inhibition of MAO-B by MPTP in vitro was noncompetitive, time-dependent, and not fully reversed by dialysis, consistent with the findings of others that MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP given s.c. resulted in marked depletion of dopamine and its metabolites one week later, and the depletion of dopamine was completely prevented by pretreatment with deprenyl, which inhibited MAO-B but not MAO-A. These and other studies in rodents may help in elucidating the mechanisms involved in the destructive effects of MPTP on striatal dopamine neurons that lead to symptoms of Parkinson's disease in humans and in monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Decrease in hypothalamic epinephrine concentration and other neurochemical changes produced by quinpirole, a dopamine agonist, in rats.

Quinpirole, (4 aR-trans)-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-5-propyl-1 H-pyrazolo [3, 4-g]quinoline, is a dopamine agonist selective for the D2 subtype of dopamine receptors. In rats, quinpirole at doses of 0.3 mg/kg i.p. and higher decreased hypothalamic epinephrine concentrations. The doses required for this effect are only slightly higher than the minimum doses that decreased the concentration of dopamine metabolites in cerebral hemispheres. At higher doses of quinpirole (2-3 mg/kg i.p.), dopamine concentration was increased and norepinephrine concentration was decreased in hypothalamus, and MHPG sulfate (the norepinephrine metabolite) concentration was increased in brain stem and in hypothalamus. All of these neurochemical effects of quinpirole were blocked by pretreatment with spiperone, a dopamine antagonist. The effects were not produced by SKF 38393, a selective D1 agonist, or by the dextrorotatory enantiomer of quinpirole, which lacks D2 agonist activity. The data support the interpretation that quinpirole, by activating D2 receptors, results in a decrease in dopamine metabolites, a decrease in hypothalamic epinephrine concentration, and an increased conversion of norepinephrine to MHPG sulfate in rat brain probably through enhanced norepinephrine release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Blockade of a 5-hydroxytryptophan-induced animal model of depression with a potent and selective 5-HT2 receptor antagonist (LY53857).

To test the hypothesis that a new potent and selective 5-HT2 receptor antagonist would be an excellent blocker of D,L-5-hydroxytryptophan (5-HTP)-induced response suppression in an animal model of depression, we administered LY53857 60 min prior to 5-HTP injections into rats working on an operant schedule for milk reinforcement. As predicted, LY53857 pretreatment significantly blocked 5-HTP depression (90%) in doses as low as 0.1 mg/kg ip. When the dose of LY58357 was further reduced to 0.025 mg/kg, blockade of 5-HTP-induced depression was still greater than 30%. In doses as high as 5.0 mg/kg, LY53857 alone had no effect on the baseline performance of rats working a VI 1 schedule. Pretreatment with desipramine (2.5 mg/kg), an antidepressant characterized as having major noradrenergic effects, did not significantly block the 5-HTP-induced depression. These data suggest that the 5-HTP-induced depression is mediated by serotonergic mechanisms involving 5-HT2 receptors, as LY53857 is a selective antagonist of these receptors. These data also support the suggestion, based on other published data from this laboratory, that some antidepressants are antagonizing 5-HT2 receptors in our animal model of depression and may also act in a similar manner in depressed patients. Thus, this new drug could be of interest as a possible antidepressant agent of the general type that was proposed earlier by Aprison and Hingtgen (1981).

5-Hydroxytryptophan↗
PubMed1985

Differential effects of selected dopaminergic agents on locomotor activity in normotensive and spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) exhibit a significantly higher level of spontaneous locomotor activity than age-matched normotensive controls (WKY). The direct-acting dopamine agonists, apomorphine and pergolide, produced a biphasic effect on locomotor activity levels in normotensive controls. Low doses of these agonists decreased activity levels, while higher doses of these agonists dramatically stimulated activity. In marked contrast to these results was the effect observed in the SHR, in which these agonists at all doses tested decreased activity. Amphetamine, a dopamine releaser, stimulated activity levels in both the WKY and SHR; however, the magnitude of the increase was somewhat attenuated in the SHR.

Amphetamine↗
PubMed1985

Effects of antidepressants on uptake and receptor systems in the brain.

Many antidepressant drugs inhibit the neuronal uptake of norepinephrine, serotonin, epinephrine and/or dopamine. Some newer antidepressant drugs are highly selective in their ability to inhibit the uptake of one or more of these monoamines. This uptake inhibition, which would be expected to increase the synaptic concentrations of the neurotransmitter initially, has traditionally been thought to be the mechanism of antidepressive action of these drugs. Some drugs, which are not uptake inhibitors, may block presynaptic alpha 2 receptors to enhance norepinephrine release, leading by a different mechanism to increased synaptic concentrations of norepinephrine. Adaptive changes in neurotransmitter receptors occur after chronic treatment of laboratory animals with these drugs, and these changes may be important components of the overall mechanism of antidepressant efficacy. Presently, evidence that these adaptive changes occur in humans is limited, and the significance of the changes to the treatment of depression is unknown. Some antidepressant drugs also have high affinity for neurotransmitter receptors, and direct antagonism of these receptors is the basis for some of their side effects, e.g., anticholinergic side effects that are prevalent with the tricyclic drugs.

Animals↗
PubMed1985

Mechanisms of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity to striatal dopamine neurons in mice.

MPTP given to mice in 4 daily doses (20 mg/kg s.c.) resulted in 56-70% depletion of striatal dopamine 1 week after the last dose. Pretreatment with deprenyl or MD 240928, selective inhibitors of monoamine oxidase type B, or with amfonelic acid or nomifensine, selective inhibitors of dopamine uptake, prevented the depletion of striatal dopamine. In contrast, pretreatment with alpha-methyl-tyrosine, Ro 4-1284 or haloperidol did not prevent the depletion of striatal dopamine by MPTP. The results are compatible with the view that dopamine itself is not involved in the neurotoxic effect of MPTP but that MPP+, a metabolite of MPTP formed by MAO-B and accumulated by the dopamine uptake carrier, is responsible for the neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

The effect of intravenous sodium cromoglycate on the bronchoconstriction induced by sulphur dioxide inhalation in man.

Ten healthy subjects received, on separate occasions, intravenous infusions of 0.9% NaCl solution (saline) and of sodium cromoglycate given in a double-blind cross-over fashion. After 20 min of infusion the specific airway conductance (sGaw) of each subject was measured in a body plethysmograph. The subject then breathed first a low (1-20 p.p.m.) and then a higher (4-40 p.p.m.) concentration of sulphur dioxide (SO2) for 2 min while the infusion continued. Measurements of sGaw were repeated after each inhalation of SO2. Sodium cromoglycate infusion did not affect the sGaw measured before challenge with SO2. During the infusion of sodium cromoglycate, the falls in sGaw in response to both concentrations of SO2 were significantly less than those which occurred during saline infusion. Plasma concentrations of sodium cromoglycate were found to be 209 +/- 22 nmol/l at the end of the drug infusion. This is about one-hundredth of lowest dose required to stabilize mast cells in vitro. We conclude that sodium cromoglycate acted by a mechanism which did not involve mast cells. Other possible modes of action are discussed.

Adult↗
PubMed1985

Flumezapine and zotepine: 5-hydroxytryptamine antagonism not involved in the lack of synergism of these antipsychotic drugs with amfonelic acid in rats.

Two antipsychotic drugs, flumezapine and zotepine, resembled clozapine, not spiperone, in not acting synergistically with amfonelic acid to elevate striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in rats. Since flumezapine, zotepine and clozapine antagonize 5-hydroxytryptamine (5-HT) receptors with potency similar to their potency in antagonizing dopamine receptors, the possibility that 5-HT receptor blockade prevented their synergism with amfonelic acid was considered. Methiothepin, a potent 5-HT antagonist and dopamine antagonist, mimicked spiperone in causing a marked increase in striatal DOPAC in amfonelic acid-treated rats, indicating that 5-HT antagonism is not involved in the lack of synergism of flumezapine and zotepine with amfonelic acid.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Pergolide elevation of MHPG sulphate concentration in rat hypothalamus blocked by spiperone and mimicked by other dopamine agonists.

Pergolide increased the concentration of MHPG sulphate (3-methoxy-4-hydroxy-phenylethylene glycol sulphate) in rat hypothalamus, and the increase was prevented by pretreatment with spiperone, a dopamine antagonist. An increase in hypothalamic MHPG sulphate concentration similar to that caused by pergolide was found after injection of quinpirole, a 'partial ergoline' that is a selective D2 agonist not affecting alpha-adrenoceptors, and by (-)-N-propylnorapomorphine, a dopamine agonist not related to the ergolines. Although the increase in MHPG sulphate concentration produced by pergolide had earlier been assumed to result from blockage of alpha-adrenoceptors, the present data indicate that it is an effect produced by dopamine D2 receptor stimulation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Bronchoconstrictor response to inhaled capsaicin in humans.

The effect of inhaled capsaicin, the irritant extract of pepper, on airway tone has been studied in humans. Inhaled capsaicin (2.4 X 10(-10) and 2.4 X 10(-9) mol) caused a dose-dependent fall in specific airways conductance (maximum fall 28 +/- 19 and 38 +/- 19%, respectively; means +/- SD, n = 17). This was maximal within 20 s of exposure and lasted for less than 60 s. There was no difference in the magnitude or duration of bronchoconstriction between normal, smoking, or asthmatic subjects. Capsaicin also caused coughing and retrosternal discomfort. On repeated exposure to capsaicin, there was no evidence for a reduced response (tachyphylaxis). Ipratropium bromide (0.25 mg by inhalation) significantly (P less than 0.05) reduced the bronchoconstriction (maximum falls 34 +/- 14 and 15 +/- 9% after saline and ipratropium bromide, respectively; means +/- SD n = 6), indicating that it was dependent on a cholinergic vagal reflex rather than on local release of substance P from nerves in the airway. Inhaled sodium cromoglycate (10 mg by nebulizer or 40 mg as a dry powder), however, had no significant effect on the bronchoconstrictor response. Capsaicin may be a useful tool for investigating nonmyelinated nerve reflexes in human airways.

Adult↗
PubMed1985

Comparison of 1-methyl-4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and p-chloroamphetamine as monoamine depletors.

1-Methyl-4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine (PC-MPTP) failed to mimic the effects of MPTP in producing persistent depletion of striatal dopamine and its metabolites in mice one week after the last of four daily doses. MPTP was given at 20 mg/kg, whereas PC-MPTP was given at doses up to 80 mg/kg. In rats, p-chloroamphetamine (PCA) given in a single dose of 0.1 mmole/kg (20.6 mg/kg) i.p. caused marked depletion of hypothalamic serotonin and 5-hydroxyindoleacetic acid (5HIAA) concentration at 6 hrs, and the depletion persisted at 1 day and at 1 week. In contrast, PC-MPTP given at an equimolar dose failed to affect either serotonin or 5HIAA concentration at these times. Apparently the addition of a p-chloro substituent to MPTP eliminates its neurotoxicity to striatal dopamine neurons, and replacement of the aminoisopropyl side chain of PCA with a 1-methyl-1,2,3,6-tetrahydropyridin-4-yl group eliminates its neurotoxicity to brain serotonin neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

The pharmacologic profile of fluoxetine.

Fluoxetine is a selective inhibitor of serotonin uptake in vitro. Unlike many antidepressant drugs, fluoxetine has little affinity for muscarinic, histaminic H1, serotonergic 5-HT1 or 5-HT2, or noradrenergic alpha 1 or alpha 2 receptors on rat brain membranes in vitro. Fluoxetine inhibits serotonin uptake in vivo without affecting norepinephrine uptake. Neuroendocrine and behavioral consequences of enhanced serotonergic function resulting from fluoxetine's inhibition of serotonin uptake in vivo are described. Fluoxetine is relatively nontoxic in several animal species. The specificity of action of fluoxetine makes it a good candidate as an antidepressant drug.

Aggression↗