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Biomedical subjects

J F Tallman

Publications and source records attributed to J F Tallman.

At least 55 records · Page 3Linked to original sources
PubMed1983

Photoaffinity labeling of benzodiazepine receptors causes altered agonist-antagonist interactions.

Previous studies have shown that [3H]flunitrazepam forms irreversible cross-links with brain tissue when exposed to ultraviolet irradiation. Comparison of the amount of [3H]flunitrazepam irreversibly incorporated and the number of benzodiazepine binding sites blocked after photolabeling has indicated that several binding sites are inactivated for each molecule of [3H]flunitrazepam incorporated. To learn the cause of this discrepancy, binding to the benzodiazepine binding sites has been examined using several radiolabeled benzodiazepine antagonists. Binding of a beta-carboline ester, CGS-8216, and Ro 15-1788 was not altered by photolabeling; however, displacement studies revealed that photolabeling converted a homogeneous set of benzodiazepine binding sites into two subsets: one of high affinity (unaltered sites) and one of low affinity. The low affinity sites could be detected by displacement studies of antagonist binding by benzodiazepines, and conversion to a low affinity form accounts for the discrepancy observed after photolabeling using [3H]flunitrazepam as ligand.

Animals↗
PubMed1982

Changes in alpha- and beta-receptor densities in rat brain as a result of treatment with monoamine oxidase inhibiting antidepressants.

The effects of chronic administration of the nonselective monoamine oxidase (MAO) inhibitor, phenelzine, and two selective inhibitors, clorgyline, and pargyline on adrenergic receptor binding and MAO activity were studied in the rat brain. Chronic but not acute administration of both phenelzine and the MAO-A inhibitor, clorgyline, resulted in significant decreases in cortical beta-adrenoreceptor binding ([3H]dihydroalprenolol) of 47 and 24% respectively. In contrast pargyline, which only partially inhibited MAO-A, caused only a nonsignificant (7%) change in rat cortical beta-receptor binding. In a more detailed study, chronic administration of clorgyline also caused changes in alpha-adrenergic receptor binding: by day 3 of treatment, significant changes were already observable in alpha-2-adrenergic receptor binding ([3H]clonidine), although changes in alpha-1 ([3H]WB4101)- and beta ([3H]dihydroalprenolol)-cortical receptor binding were not present until day 10. After 21 days of clorgyline treatment, the Bmax's of alpha-2-, alpha-1- and beta-adrenergic cortical receptors were reduced by 62, 36 and 34% respectively. In brainstem, alpha-2- and beta-receptors were reduced by 60 and 74%. The magnitude of these changes and particularly the rapidity of the alpha-2 changes suggest that clorgyline-induced alpha-2 autoreceptor changes may precede and contribute to the changes in postsynpatic alpha-1- and beta-receptors. These sequential alterations in adrenergic receptors may be pertinent to the efficacy and delay in onset of the clinical changes which follow treatment with these antidepressants.

Adrenergic alpha-Antagonists↗
PubMed1982

Effect of benzodiazepines on cyclic GMP formation in rat cerebellar slices.

Cyclic 3',5' guanosine monophosphate (cGMP) levels, stimulated in brain slices by ouabain, potassium, and sodium azide depolarization, have been found to be inhibited in a dose-dependent fashion by both behaviorally active and inactive benzodiazepines. ED50's for these benzodiazepines bear no relation to potencies established from receptor membrane binding studies; however, these values do correspond to ED50's calculated for several known membrane stabilizing agents tested in this system. The concentration of [3H]flunitrazepam necessary to saturate the benzodiazepine receptor in identical slice preparations is considerably lower than that needed to initiate inhibition of depolarization-induced cGMP stimulation. Some of the reported in vivo actions of benzodiazepines on cGMP formation may be the result of membrane stabilizing actions of the benzodiazepines or mediated indirectly.

Animals↗
PubMed1981

Differences in the beta-adrenergic responsiveness between high and low passage rat glioma C6 cells.

Responsiveness to catecholamines was studied in two different strains of rat glioma C6 cells. The C6 cells of low passage possessed a high capacity to accumulate cyclic AMP in response to (-)-isoproterenol. Cholera toxin was also able to stimulate cyclic AMP accumulation in these cells. High passage C6 cells were unresponsive to (-)-isoproterenol or to cholera toxin except in the presence of a high concentration of phosphodiesterase inhibitor. The affinity of beta-adrenergic receptors on both strains for (-) [3H] dihydroalprenolol was similar; however, C6 low passage possessed several times the number of beta-adrenergic receptors found in C6 high passage. This difference correlated with the difference found in (-)-isoproterenol-stimulated adenylate cyclase between C6 low passage and high passage. The sodium fluoride-stimulated adenylate cyclase was similar in both strains. Cyclic AMP phosphodiesterase activity was 2-3 times higher in homogenates of C6 high passage than in low passage. In intact cells, the rate of breakdown of cyclic AMP was 5-times faster in C6 high passage than in low passage. Thus, differences in beta-adrenergic receptor number and phosphodiesterase activity explain in part the lack of responsiveness of C6 high passage. Our studies indicate that continuous subculturing of rat glioma C6 cells led to complex alterations in the beta-adrenergic receptor-adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1981

Characterization of photoaffinity labeling of benzodiazepine binding sites.

The specific photoaffinity labeling of membrane-bound and detergent-solubilized benzodiazepine binding sites has been investigated using UV irradiated [3H] flunitrazepam as a photochemical probe. The time course and the regional and pharmacological specificity of the photolabeling reaction has been determined for "brain-specific" benzodiazepine binding sites; "peripheral-type" binding sites treated in an identical manner were not specifically labeled. Comparison of the number of sites labeled and blocked by [3H]flunitrazepam photolabeling of detergent-solubilized preparations indicated that about one site was blocked and unavailable for reversible binding for each site photolabeled. In contrast, when membrane-bound sites were photolabeled, about four sites were inactivated for each site photolabeled. Examination of photolabeled binding sites from various brain regions including cortex, striatum, and hippocampus using sodium dodecyl sulfate-polyacrylamide gel electrophoresis gave only a single labeled band of apparent Mr = 48,000.

Affinity Labels↗
PubMed1981

Phospholipid methylation: a possible mechanism of signal transduction across biomembranes.

The conversion of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) is catalyzed by two methyltransferases with S-adenosylmethionine as the methyl donor. PC formed by transmethylation is further metabolized by phospholipase A2. The synthesis and degradation of methylated phospholipids are involved in regulating the number of the beta-adrenergic receptors and their coupling to adenylate cyclase in rat reticulocytes, HeLa cells, and rat astrocytoma cells. Methylation of the phospholipids in these cells is stimulated by binding of agonists to the beta-adrenergic receptors. Accumulation of phosphatidyl-N-monomethylethanolamine causes an increase in membrane fluidity and enhances the coupling of the receptors to adenylate cyclase. Agents that inhibit phospholipid methylation decrease the number of receptors in intact HeLa cells, while increased phospholipid methylation unmasks cryptic receptors. Conversely, the degradation of methylated phospholipids appears to be closely associated with the desensitization of the beta-adrenergic receptors following prolonged stimulation with isoproterenol. Inhibition and stimulation of phospholipase A2 causes inhibition and stimulation of this desensitization process.

Adenylyl Cyclases↗
PubMed1980

Interaction of diphenylhydantoin and benzodiazepines in the CNS.

Using extracellular unit recording and microiontophoretic techniques, the anticonvulsant diphenylhydantoin (DPH) was found to increase the physiological efficacy of the benzodiazepines. This increased biological effect could be correlated with an enhanced specific binding of benzodiazepines measured in vivo following pretreatment of rats with DPH. The increased binding of benzodiazepines is due to an increase in the total number of benzodiazepine binding sites without an alteration in the affinity of these sites for [3H]diazepam. The data show that the effects of DPH on benzodiazepine binding are qualitatively different and independent from the effects of gamma-amino-butyric acid. Based on the dose-responsive relationship between benzodiazepine binding effects and the anticonvulsant activity of DPH and reports of other convulsant, anticonvulsant compounds which alter benzodiazepine binding, it is suggested that the benzodiazepine binding site may be relevant to convulsant-anticonvulsant activity.

Animals↗
PubMed1980

Receptors for the age of anxiety: pharmacology of the benzodiazepines.

Investigation of the actions of the benzodiazepines has provided insights into the neurochemical mechanisms underlying anxiety, seizures, muscle relaxation, and sedation. Behavioral, electrophysical, pharmacological, and biochemical evidence indicates that the benzodiazepines exert their therapeutic effects by interacting with a high-affinity binding site (receptor) in the brain. The benzodiazepine receptor interacts with a receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter, and enhances its inhibitory effects. The benzodiazepine receptor may also interact with endogenous substances and several naturally occurring compounds, including the purines and nicotinamide, are candidates for this role. Both the purines and nicotinamide possess some benzodiazepine-like properties in vivo, although further work will be required to confirm their possible roles as endogenous benzodiazepines.

Animals↗
PubMed1980

New biological research relevant to anxiety.

It is reasonable to suggest that further understanding of the physiology and the mode of action of the drugs that are most effective in decreasing human anxiety, the BDZ, may provide important clues to the understanding of anxiety. BDZ receptors have recently been discovered in human brain where they have a differential distribution. Good correlations have been obtained between the clinical potency of a series of BDZ and the tightness with which they bind to brain membranes. It has been discovered that BDZ may exert part of their therapeutic action by enhancing the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Thus it appears that some of the actions of diazepam may be a result of increasing the ability of GABA to quiet brain cell activity. A number of endogenous compounds have been discovered that are produced in brain and that may act like BDZ, but at the present time no single candidate has convincingly emerged as the endogenous BDZ. A world-wide search for the endogenous BDZ continues. Finally, a brain structure, the nucleus locus coeruleus, has been proposed as possibly relevant to anxiety-like behavior. Electrical stimulation of this area can produce anxiety-like behavior in monkeys that can be blocked by diazepam. Thus, for the first time in many years, the above-mentioned discoveries have increased hope that significant progress will be made in our understanding of the severe and at times incapacitating mental problem of severe anxiety.

Animals↗