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Biomedical subjects

B Tabakoff

Publications and source records attributed to B Tabakoff.

At least 127 records · Page 7Linked to original sources
PubMed1987

Effects of ethanol on ouabain inhibition of mouse brain (Na+,K+)ATPase activity.

Plots of ouabain inhibition of mouse cerebral cortical (Na+,K+)ATPase activity fitted a two-site model significantly better than a one-site model, consistent with the presence of two forms of the enzyme with different affinities for ouabain. The fraction of enzyme activity with high affinity for ouabain (HAO: Ki = 500 nM), suggested to be localized neuronally, constituted the major portion (60-70%) of activity. Ouabain inhibition of both components of enzyme activity was reduced as KCl concentrations were increased. In vitro, only high concentrations of ethanol affected (Na+,K+)ATPase activity and ouabain inhibition of activity. Ethanol (500 mM) selectively reduced the activity, and increased the sensitivity to ouabain inhibition, of the HAO component, with no significant effect on the low-affinity (LAO) component. On the other hand, following chronic treatment of mice with ethanol in vivo, in a paradigm that produced tolerance and physical dependence, the sensitivity to ouabain of the HAO form of the enzyme was selectively increased. The relative proportions, and the activities of the HAO and LAO components, were not altered. The effects of ethanol, added in vitro, on the HAO component were decreased in ethanol-tolerant animals. The selective effect of chronic ethanol ingestion on (Na+,K+)ATPase activity indicates the specificity of action of ethanol in the CNS.

Animals↗
PubMed1987

Effects of chronic ethanol treatment on the beta-adrenergic receptor-coupled adenylate cyclase system of mouse cerebral cortex.

Chronic ingestion of ethanol, which produced tolerance and physical dependence, resulted in altered function of the cerebral cortical beta-adrenergic receptor-coupled adenylate cyclase system in mice. Although there was no change in basal adenylate cyclase activity, or in the activity of the digitonin-solubilized catalytic unit, stimulation of adenylate cyclase activity by the nonhydrolyzable guanine nucleotide analog guanylylimidodiphosphate [Gpp(NH)p] was reduced in brains of ethanol-fed animals. Ethanol added in vitro increased adenylate cyclase activity, and this enhancement, in the presence of Gpp(NH)p, was also reduced in cortical membranes of ethanol-fed mice. Furthermore, the maximal response to isoproterenol was decreased, and the EC50 for isoproterenol stimulation of adenylate cyclase activity was increased in ethanol-fed animals. The results are consistent with a qualitative or quantitative defect in the function of the stimulatory guanine nucleotide-binding protein (Ns), as well as in the beta-adrenergic receptor, after chronic ethanol exposure. In part, these changes appear to be similar to those that occur during heterologous desensitization of various receptor systems, and may be associated with dependence on or tolerance to ethanol.

Adenylyl Cyclases↗
PubMed1987

Effects of ethanol on the activity of brain enzymes.

Ethanol alters, in a selective manner, the activity of several membrane-bound enzymes in the central nervous system (CNS) which are important for neuronal transmission of information. Ethanol inhibits Na+/K+-transporting ATPase activity, while adenylate cyclase (AC) activity is stimulated by ethanol added in vitro. Ethanol's effects on AC activity are mediated primarily via effects on proteins that regulate AC activity. Ethanol has selective effects on monoamine oxidase activity, in that the B form of the enzyme is more sensitive to inhibition by ethanol added in vitro. The selective effects of ethanol on different membrane-bound CNS enzymes may result from differing membrane lipid microenvironments of the enzymes, or from differences in the enzyme proteins per se.

Adenylyl Cyclases↗
PubMed1987

Differential effects of ethanol on the striatal and cortical adenylate cyclase system.

In the present study, effects of ethanol (EtOH) on C57/BL mouse cortical beta-adrenergic receptor coupled adenylate cyclase (AC) were shown to be different from the effects of EtOH on striatal dopaminergic-stimulated AC activity. The addition of EtOH (500 mM) increased the AC activity by 60% in cortical membrane and by less than 10% in striatal membrane preparations in the absence of guanine nucleotide. The dose-response relationship for EtOH stimulation of cortical AC activity in the presence of guanylylimidodiphosphate (Gpp(NH)p) was biphasic, whereas, in the striatum, a linear dose-response relationship for EtOH was found for stimulation of AC in the presence of Gpp(NH)p. Activation of AC by Gpp(NH)p occurred as an apparent pseudo-first order process. EtOH increased the pseudo-first order rate constant for activation of AC by Gpp(NH)p in the cortex, but not in the striatum. Following 10 min preincubation with Gpp(NH)p, catecholamines and Gpp(NH)p were not able to stimulate further the AC activities in either tissue. Nevertheless, EtOH increased AC activity in both cortex and striatum following the preincubation with Gpp(NH)p. These data suggest that one effect of EtOH in striatal tissue is to promote the interaction of an activated guanine nucleotide-binding regulatory protein (G-protein) with the catalytic unit of AC. In cortical tissue, the effects of EtOH may be attributable to direct actions on the catalytic activity of the enzyme, effects on the rate of activation of the G-protein, and an altered interaction of G-protein with the catalytic unit.

Adenylyl Cyclases↗
PubMed1987

Comparison of the effects of ethanol on beta-adrenergic receptors in heart and brain.

Low, physiologically-attainable concentrations of ethanol affect agonist binding to cerebral cortical and cardiac beta-adrenergic receptors. In cerebral cortex, ethanol decreases the affinity of the high-affinity state of the receptor for isoproterenol. This may reflect a direct action of ethanol on the receptor. Ethanol also potentiates the action of guanine nucleotides on agonist binding, suggesting a second site of action at Ns. In heart, ethanol increases the proportion of low-affinity binding sites, an effect which is similar to that of guanine nucleotides, and may also indicate an action of ethanol at Ns. After chronic ethanol ingestion, the total number of cardiac beta-adrenergic receptors is decreased, but the proportion of high-affinity sites is increased. This change could reflect an increased sensitivity to catecholamines. In cerebral cortex, chronic ethanol results in a single, low-affinity binding site for agonist, compatible with an "uncoupled" receptor. Such a change also occurs during homologous desensitization, and may result from increased norepinephrine turnover during chronic ethanol ingestion. The differential responses to ethanol of similar receptors in heart and brain exemplify the specificity of ethanol's actions on various organ systems.

Animals↗
PubMed1987

Effect of ethanol on mouse cerebral cortical beta-adrenergic receptors.

Low concentrations of ethanol (10-100 mM), added to assays in vitro, altered agonist (isoproterenol) binding to mouse cerebral cortical beta-adrenergic receptors in a reversible manner. Ethanol decreased the affinity of the high affinity form of the receptor for isoproterenol but had no effect on the affinity of the low affinity form of the receptor, the proportion of high and low affinity forms of the receptor, the total number of agonist-binding sites, or antagonist binding. The selective effect of ethanol on the properties of the high affinity agonist-binding site suggested that ethanol alters the characteristics of the complex of the receptor and Gs, the guanine nucleotide-binding protein. In cerebral cortical membranes of mice that had ingested ethanol chronically, isoproterenol binding data were best fit by a one-site model, even in the absence of guanine nucleotides. This change, when considered together with previously reported changes in adenylate cyclase activity, is reminiscent of heterologous desensitization of the beta-adrenergic receptor. Thus, both acute and chronic ethanol administration may produce changes in adrenergic function in brain.

Adrenergic beta-Agonists↗
PubMed1987

Ethanol-induced modulation of 35S-TBPS binding to brain membranes.

The effect of ethanol in vitro on the binding of 35S-t-butylbicyclophosphorothionate to brain membranes was examined. Ethanol inhibited basal binding of 35S-TBPS both in potassium bromide- (KBr)- and potassium chloride (KCl)-containing assay media. Ethanol was, however, considerably weaker in reducing 35S-TBPS binding in buffers with 100 mM KCl. Ethanol had no effect on the inhibition of 35S-TBPS binding produced by GABA and pentobarbital in the presence of KBr or KCl, whereas it clearly altered the enhancement of 35S-TBPS binding produced by these drugs when the assay was carried out in buffers containing KCl.

Animals↗
PubMed1987

Effects of ethanol on adenylate cyclase system in the human platelet.

Effects of ethanol (EtOH) on the alpha 2-receptor-coupled adenylate cyclase (AC) of the human platelet were examined. EtOH increased "basal" AC activity in a linear dose dependent manner. In the presence of Gpp(NH)p (2.5 microM), however, the slope of the dose-response curve for EtOH stimulation of AC activity was biphasic. The increase in activity produced by the addition of EtOH concentration between 0 and 100 mM was much sharper than the increase in activity produced by the concentration in excess of 100 mM. EtOH increased the rate of activation of AC by guanine nucleotides and concomitantly decreased the concentration of magnesium required for half-maximal activation of AC. Prostaglandin-E1 (PGE1) alone stimulated AC activity. Clonidine (3 nM-1 microM) diminished the PGE1 (1 microM)-stimulated AC by a maximum of 30%. EtOH did not alter the concentration of clonidine required for half-maximal inhibition of AC. Our results suggest that the sites of EtOH's action can be assigned to the direct action of the catalytic subunit and to the Ns-protein. Our results also indicate a substantial difference in EtOH's action on catecholamine receptor systems coupled in a stimulatory versus inhibitory manner to AC. Stimulation of AC through Ns-protein is potentiated by EtOH, but inhibition of AC through the Ni-protein is little affected by EtOH.

Adenylyl Cyclases↗
PubMed1986

Bicuculline-pentobarbital interactions on [35S]TBPS binding in various brain areas.

The effect of in vitro addition of pentobarbital to brain membrane preparations from cerebellum and cortex of C57B1 mice was examined in the presence and absence of the specific GABAA receptor "antagonist" bicuculline. In the cortex pentobarbital produced a biphasic effect (stimulation followed by inhibition) on [35S]TBPS binding, whereas only inhibition of [35S]TBPS binding was observed in the cerebellum. When bicuculline was added to assay mixtures, the stimulatory action of pentobarbital was markedly enhanced in the cortex. In the cerebellum the presence of bicuculline uncovered a biphasic effect of pentobarbital on [35S]TBPS binding, that is lower doses of pentobarbital increased, while higher doses decreased [35S]TBPS to the membrane receptors from the cerebellum.

Animals↗
PubMed1986

Effects of short-chain alcohols and norepinephrine on brain (Na+,K+)ATPase activity.

(Na+,K+)ATPase activity in synaptic membranes from whole brains of mice was inhibited by a series of short-chain aliphatic alcohols (ethanol through pentanol). The relationship of inhibitory potency to alcohol chain length and to alcohol membrane:water partition coefficient suggested that the inhibitory effect of the alcohols does not depend totally on their interaction with neuronal membrane lipids. Although partitioning into the membranes is important for this inhibitory effect, a direct interaction of alcohol with the enzyme protein may also be involved in the inhibition. Norepinephrine did not significantly potentiate inhibition of (Na+,K+)ATPase activity by low concentrations of ethanol in preparations of either mouse or rat brain. Thus, under our conditions, ethanol, at levels which can be reached in vivo, only slightly inhibited enzyme activity, and the possible importance of this inhibition in mediating the in vivo acute or chronic effects of ethanol on the CNS remains open to question.

Adenosine Triphosphate↗
PubMed1986

Effect of ethanol on the binding of 35S-T-butylbicyclophosphorothionate to mouse brain membranes.

The effect of in vitro addition of ethanol (0.02-1.0 M) on the binding of 35S-TBPS was examined in brain membranes from cerebellum and cortex of naive or chronically ethanol-treated C57B1 mice. In brain membranes of untreated animals, increasing concentrations of ethanol produced a dose-related inhibition of 35S-TBPS binding in the brain areas investigated. Additional studies showed that this effect of ethanol was due to a decreased affinity of 35S-TBPS for its binding sites. Chronic treatment of the animals with ethanol, which produced tolerance to and dependence on ethanol, did not alter ethanol's ability to inhibit the binding of 35S-TBPS. In naive animals, the in vitro addition of GABA or pentobarbital produced a pronounced inhibition of 35S-TBPS, both drugs being more potent in the cerebellum than in the cortex. Picrotoxin also produced a dose-dependent inhibition at 35S-TBPS, but was equally potent in the brain areas investigated. The inhibition by GABA or pentobarbital was not influenced by in vitro addition of a physiologically relevant concentration of ethanol (100 mM), whereas ethanol produced a significant increase in the IC50 values for picrotoxin both in the cortex and in the cerebellum. Furthermore, the inhibitory effects of GABA or pentobarbital on 35S-TBPS binding remained unchanged in animals chronically treated with ethanol for 7 days. Our data indicate that ethanol may affect the GABA receptor system through a rather specific interaction with the 35S-TBPS recognition site, but that this action of ethanol is not altered by the development of tolerance to and dependence on ethanol.

Animals↗
PubMed1986

The effect of 5,7-dihydroxytryptamine treatment on the response to ethanol in mice.

In order to assess the role of the serotonergic system in the development of tolerance to ethanol in the mouse, serotonin neurons in the CNS were lesioned with an intracerebroventricular injection of the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Mice injected with 5,7-DHT responded to an acute dose of ethanol with a longer sleep time and greater fall in body temperature than CSF-treated mice. The increased response to acute administration of ethanol was accompanied by higher circulating levels of ethanol in mice pretreated with 5,7-DHT. When mice were fed an ethanol-containing liquid diet for five days, a higher mortality rate was observed in the 5,7-DHT group compared to the CSF pretreated group of mice. When the groups of mice were tested for tolerance 24 hours after withdrawal, the 5,7-DHT group was less tolerant than the CSF group. Therefore, damage to the serotonin neurons results in altered ethanol disposition, altered initial sensitivity to ethanol, and an inhibition in the development of tolerance in the mouse.

5,7-Dihydroxytryptamine↗
PubMed1986

Effects of prenatal phenobarbital on benzodiazepine receptor development.

Phenobarbital (PB) was administered to pregnant mice during days 9-21 of gestation. Forebrain and cerebellar [3H]flunitrazepam ([3H]FLU) binding was assayed in the offspring at birth and at 21 days of age. Prenatal treatment produced a decrease in the number (Bmax) of [3H]FLU receptors in both the forebrain and cerebellum at birth. A small decrease in the [3H]FLU dissociation constant (KD) values in the forebrain was also detected at birth, but no changes were seen in the [3H]FLU KD values in the cerebellum. No changes were observed in forebrain and cerebellar [3H]FLU Bmax or KD values at 21 days of age, indicating that the effects of prenatal exposure to PB on [3H]FLU binding are eliminated during the postnatal development of the forebrain and cerebellum. The receptor affinity for the triazolopyridazine CL 218,872, which distinguishes the type I and type II benzodiazepine (BDZ) receptors, was not altered by prenatal PB treatment. The coupling of the BDZ receptor to the gamma-aminobutyric acid and pentobarbital binding sites was unaffected by exposure to PB in utero.

Animals↗
PubMed1986

Regulation of neurotransmitter aspartate metabolism by glial glutamine synthetase.

Aspartate levels and release from rat striatal slices following the inhibition of glutamine synthetase (GS) by methionine sulfoximine (MSO) were studied. Striatal levels of aspartate and glutamine were decreased over time in a manner that correlated with GS inhibition. Ca2+-dependent, K+-stimulated aspartate release was diminished in striatal tissue slices from animals pretreated with MSO. The decreased release of aspartate correlated over time with the inhibition of GS. The addition of glutamine to the perfusion medium completely reversed the effects of MSO on calcium-dependent aspartate release. It is suggested that glutamine is a major precursor for transmitter aspartate.

Analysis of Variance↗
PubMed1986

Ethanol does not modify opiate-mediated inhibition of striatal adenylate cyclase.

Ethanol increases the activity of "basal," guanine nucleotide- and dopamine-stimulated adenylate cyclase in mouse striatum. In contrast, ethanol, in vitro, did not modify the inhibition of striatal adenylate cyclase activity by opiates (morphine or [D-Ala2,D-Leu5] enkephalin). Following chronic in vivo ethanol treatment of mice, there was also no change in the character of opiate inhibition of striatal adenylate cyclase activity. Since ethanol, in vitro, does decrease striatal opiate receptor binding, the results suggest that the changes in affinity detected by ligand binding studies are not relevant for receptor-coupled adenylate cyclase activity, or that opiate receptor binding and opiate regulation of adenylate cyclase can be modulated independently. The selective effects of ethanol on systems that modulate adenylate cyclase activity may produce imbalances in neuronal function during in vivo ethanol exposure.

Adenylyl Cyclase Inhibitors↗
PubMed1986

Acute and chronic effects of ethanol on receptor-mediated phosphatidylinositol 4,5-bisphosphate breakdown in mouse brain.

Phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown was stimulated by agonists acting at muscarinic cholinergic and alpha 1-adrenergic receptors in mouse brain. Ethanol, in vitro, inhibited basal cerebral cortical PIP2 breakdown with a threshold concentration of 75-100 mM. Basal PIP2 breakdown in hippocampus and striatum was less sensitive to ethanol. A high concentration of ethanol (500 mM) increased the EC50 for carbachol stimulation of PIP2 breakdown in all three brain areas, but had no effect on the EC50 for norepinephrine. Following chronic ingestion of ethanol by mice, the EC50 for carbachol stimulation of PIP2 breakdown in cortex was decreased, and there was no change in striatum. These effects were consistent with previously observed increases in quinuclidinylbenzilate (QNB) binding in cortex, but not striatum, of mice fed ethanol chronically. However, in hippocampus, where chronic ethanol ingestion had also induced an increase in QNB binding, the EC50 for carbachol stimulation of PIP2 breakdown was increased. Binding studies using the specific M1 muscarinic cholinergic receptor antagonist, pirenzepine, revealed that the number of pirenzepine-binding sites was increased in cortex, but not hippocampus (or striatum) of ethanol-fed mice. These results support the hypothesis that high affinity pirenzepine-binding sites are coupled to PIP2 breakdown in mouse cortex. The changes in cerebral cortex represent one of the first demonstrations of a functional correlate of a change in receptor density in ethanol-treated animals. Increased sensitivity to cholinergic agonists in cortex may contribute to particular signs of ethanol withdrawal.

Animals↗