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Biomedical subjects

B Tabakoff

Publications and source records attributed to B Tabakoff.

At least 109 records · Page 6Linked to original sources
PubMed1989

Hippocampal and cerebellar beta-adrenergic receptors and adenylate cyclase are differentially altered by chronic ethanol ingestion.

Chronic ethanol ingestion by mice resulted in the loss of high-affinity beta-adrenergic agonist binding sites and a significant decrease in activation of adenylate cyclase by guanine nucleotides and beta-adrenergic agonists in the hippocampus, although no significant change was noted in the total number of beta-adrenergic receptors, as defined by the binding of the antagonist [125]iodocyanopindolol. In cerebellum, chronic ethanol ingestion resulted in a 16% decrease in the total concentration of beta-adrenergic receptors and in a decrease in the affinity for agonist of the high-affinity beta-adrenergic agonist binding sites. However, neither the amount of the high-affinity agonist binding sites nor the activation of adenylate cyclase by agonist was affected. The different responses to ethanol in hippocampus and cerebellum may result from quantitative differences in distribution of beta 1- and beta 2-adrenergic receptors in the tested brain areas and/or differential effects of ethanol on stimulatory guanine nucleotide binding protein in these brain areas.

Adenylyl Cyclases↗
PubMed1989

Methionine lowers circulating levels of acetaldehyde after ethanol ingestion.

Methionine, administered to ethanol treated mice and rats, significantly reduced circulating acetaldehyde levels without altering circulating levels of ethanol. Hepatic levels of acetaldehyde were also lowered by methionine. Methionine was effective when given prior to or after the administration of ethanol, but the time course of the action of methionine suggested the necessity for metabolic transformation of this amino acid in order for the acetaldehyde-lowering effect to be evidenced. Studies with humans, given methionine doses of approximately one-tenth of those used with mice, indicated that methionine can also lower acetaldehyde in humans ingesting ethanol. Given the toxic characteristics of acetaldehyde, methionine may prove effective in reducing the damaging effects of ethanol ingestion.

Acetaldehyde↗
PubMed1989

Chronic tolerance to ethanol in the N:NIH rat.

As the basis for selectively breeding rats from the N:NIH stock on the basis of differential development of tolerance to ethanol, chronic tolerance to the motor-disrupting effects of ethanol was examined. Male (n = 50) and female (n = 46) rats were administered 2.5 g/kg ethanol (i.p.) and the blood-ethanol concentration (BEC) at the time of regain of aerial righting reflex (RARR) was measured. The rats were then placed in inhalation chambers for 8 consecutive days and chronically exposed to ethanol. Thirty-two hours following the cessation of chronic ethanol exposure, the rats were again given a 2.5 g/kg dose of ethanol and the BEC at RARR was again measured. The amount of chronic ethanol tolerance developed, as measured by the difference in BEC at RARR prior to and after chronic ethanol administration, was widely and normally distributed for both male and female rats. Control rats, which did not receive chronic ethanol exposure between the two tests of RARR, did not show tolerance on this measure. A negative correlation (r = -0.46) was found between BEC at RARR prior to chronic ethanol treatment and the amount of chronic tolerance developed using the difference in BEC measure. This correlation suggested that the rats who were initially more sensitive to the effects of ethanol were more likely to display the greatest amount of chronic tolerance. However, using the residuals of the regression analysis of post-chronic ethanol BEC at RARR on prechronic BEC at RARR as an index of tolerance, this negative correlation was not found.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗
PubMed1989

The effect of ethanol on 35S-TBPS binding to mouse brain membranes in the presence of chloride.

The effect of in vitro and in vivo administration of ethanol on the binding of 35S-t-butyl-bicyclophosphorothionate (35S-TBPS) to cortical brain membranes of C57Bl mice was investigated using KCl (100 mM) containing assay media. The in vitro addition of ethanol produced a dose-dependent inhibition of basal 35S-TBPS binding. In the presence of chloride ions, GABA and pentobarbital had a biphasic action (stimulation followed by inhibition) on 35S-TBPS binding, whereas diazepam only stimulated the binding. Ethanol reduced the stimulatory effects of GABA and pentobarbital in a dose-dependent manner, but had no effect on the enhancement of 35S-TBPS binding produced by diazepam. 35S-TBPS binding to cortical brain membranes was inhibited by the putative Cl- channel blocking agent DIDS. This inhibitory action of DIDS was significantly, and dose-dependently reduced by ethanol (greater than or equal to 100 mM ethanol). Chronic ethanol ingestion in vivo, which produced tolerance to and physical dependence on ethanol in the animals, did not alter the stimulatory and inhibitory effects of GABA and pentobarbital on 35S-TBPS binding. The enhancement of 35S-TBPS binding produced by diazepam was slightly, but significantly, enhanced in brain membranes from animals which had undergone 24 hours of ethanol withdrawal. Chronic ethanol treatment did not change the potency of picrotoxin and of the peripheral BDZ-receptor ligand RO 5-4864 to competitively inhibit 35S-TBPS binding. Our results suggest that in vitro addition of ethanol alters the activity of the GABA/benzodiazepine (BDZ) receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

Ethanol enhancement of isoproterenol-stimulated melatonin and cyclic AMP release from cultured pineal glands.

Norepinephrine stimulates the synthesis of melatonin in the pineal gland. The action of norepinephrine is believed to be mediated primarily by beta adrenergic receptors, and involves activation of adenylate cyclase. Ethanol, 25 to 50 mM, added to cultured pineal glands in vitro, enhanced isoproterenol-induced stimulation of cyclic AMP and melatonin production. The action of ethanol was observed only at doses of isoproterenol that produced a submaximal effect, and ethanol alone had no effect on cyclic AMP or melatonin release. Butanol, at a concentration of 2 mM, was as effective as 50 mM ethanol in increasing isoproterenol-stimulated cyclic AMP and melatonin release, indicating that the response to alcohols was not due simply to changes in osmolarity, and may reflect a hydrophobic interaction of the alcohols with the cell membrane. The effects of ethanol on pineal cyclic AMP and melatonin release were reversible after a 15-min preincubation, but not after a 2-hr preincubation, suggesting that, over a long incubation period, ethanol may sensitize the pineal beta adrenergic receptor-coupled adenylate cyclase system to isoproterenol. The findings in this study are consistent with earlier work showing that ethanol increases cerebral cortical beta adrenergic receptor-coupled adenylate cyclase activity, and demonstrate that the effect of ethanol on the receptor-effector system can result in an endocrinological response.

1-Butanol↗
PubMed1989

[AIDS and sleep disorders: effect of gp120 on cerebral glucose metabolism].

The neurological complications associated with infection by the AIDS virus, HIV, occurs at an early stage of the disease and often indicate a poor prognosis. A dementia, known as AIDS Dementia Complex, is the most common feature observed, and is found in a majority of patients. The effects of gp120, the external protein envelope of HIV, on cerebral glucose utilization were studied in rats. Intracerebroventricular injection of gp120 significantly reduced glucose utilization in the lateral habenula and the suprachiasmatic nucleus, two regions rich in receptors for Vasoactive Intestinal Peptide (VIP) and the whole brain metabolism showed a significant decrease. The findings suggest that gp120 may alter neuronal function, thereby contributing to sequelae of HIV infection of the brain, and that attachment of HIV particles may involve, for a part, VIP receptors.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Mechanisms of alcohol tolerance.

Functional tolerance to ethanol can be prolonged by administration of the neuropeptide arginine vasopressin (AVP), which acts at specific CNS receptors. AVP receptors in brain (lateral septum) have been shown to be localized, in part, presynaptically, and the mechanism of action of AVP may thus involve modulation of neurotransmitter release. AVP has also been found to increase the levels of mRNA for the cellular proto-oncogene, c-fos, in the septum and hippocampus. This response to AVP, which may be direct or indirect, may underlie the long-term neuroadaptive effects of the peptide. Studies with vasopressin antagonists have indicated a role for endogenous AVP in modulation of ethanol tolerance, and measurement of hypothalamic vasopressin mRNA by Northern blot analysis and in situ hybridization indicates that chronic ethanol ingestion may alter AVP synthesis. Tolerance to the aversive effects of ethanol has been postulated to influence alcohol drinking behavior in some individuals. Elucidation of the mechanism by which AVP affects ethanol tolerance may eventually lead to pharmacological means to modulate tolerance and, consequently, alcohol intake patterns.

Alcohol Drinking↗
PubMed1988

Differences in platelet enzyme activity between alcoholics and nonalcoholics.

Blood platelets are an accessible tissue that reflects the activity of many enzymes found in the brain. To investigate the possible effect on such enzymes of long-term consumption of large quantities of ethanol, we assayed the activities of two enzymes, monoamine oxidase and adenylate cyclase, in platelet membranes of men with alcoholism and controls matched for sex and age. We also compared these two groups in terms of the inhibition of platelet monoamine oxidase activity by ethanol in vitro (400 mM), and in terms of the stimulation of adenylate cyclase activity by various agents. There was no significant difference in monoamine oxidase activity between the alcoholics and the controls. However, the inhibition of monoamine oxidase by ethanol was significantly higher in the platelets of alcoholics. The basal activity of adenylate cyclase was the same in platelets from the alcoholics and the controls, but the platelet adenylate cyclase activity after stimulation with guanine nucleotide, cesium fluoride, or prostaglandin E1 was significantly lower in alcoholics. These differences were not associated with age, race, smoking, or illicit drug use, and there was no significant correlation with the duration of problems with alcohol. The changes were long-lasting; cesium fluoride-stimulated adenylate cyclase activity was lower in alcoholic subjects who had abstained from alcohol for one to four years. Discriminant analysis showed that the use of values for the inhibition of monoamine oxidase activity by ethanol and cesium fluoride-stimulated adenylate cyclase activity correctly classified 75 percent of the alcoholics and 73 percent of the controls. These measures may be of value either as indexes of excessive alcohol consumption or as an indication of a predisposition to alcoholism.

Adenylyl Cyclase Inhibitors↗
PubMed1988

Forskolin promotes the development of ethanol tolerance in 6-hydroxydopamine-treated mice.

Partial depletion of brain norepinephrine by 6-hydroxydopamine prevents the development of functional tolerance to ethanol in mice. This blockade of tolerance development was overcome by daily intracerebroventricular injections of forskolin. These results suggest that interaction of norepinephrine with post-synaptic beta-adrenergic receptors, and activation of adenylate cyclase, is important for the development of ethanol tolerance. Interaction of norepinephrine with alpha 1-adrenergic receptors may be less crucial, since treatment with a phorbol ester activator of protein kinase C did not restore the development of tolerance in mice treated with 6-hydroxydopamine. The importance of the beta-adrenergic receptor-coupled adenylate cyclase system for development of ethanol tolerance, in addition to its previously-reported role in long-term potentiation, suggests that this system may influence neuroadaptive processes in general.

Animals↗
PubMed1988

Effects of chronic ethanol ingestion on mouse brain beta-adrenergic receptors (BAR) and adenylate cyclase.

Previous work showed that chronic ethanol ingestion by C57BL mice resulted in reduced stimulation of cerebral cortical adenylate cyclase (AC) activity by isoproterenol (ISO) and guanine nucleotides (GN). To investigate the mechanism of this change we have assessed the effect of chronic ethanol ingestion on agonist and antagonist binding to BAR in cerebral cortex (mainly beta 1-AR) and cerebellum (mainly beta 2-AR). C57BL mice were fed ethanol in a liquid diet for seven days and were withdrawn for various intervals. Agonist (ISO) binding data were best fit by a two-site model (high and low affinity states) in cortical membranes of control mice. GN induced conversion to a one site model (low affinity state). At the time of withdrawal, ISO binding data in cortical membranes were best fit by a one-site model even in the absence of GN. Antagonist binding was not affected. These results resemble those seen after heterologous desensitization, indicating "uncoupling" of receptor and AC. Control cerebellar ISO binding data were similar to cortical data. Chronic ethanol ingestion, however, did not produce data fit by a one site model in cerebellum. The affinity for ISO of the high affinity state of the BAR was significantly decreased at the time of withdrawal. ISO-stimulated AC-activity in cerebellar membranes was not affected by chronic ethanol ingestion, indicating that, in contrast to cerebral cortex, the cerebellar BAR was not uncoupled from AC.

Adenylyl Cyclases↗
PubMed1988

Cholera toxin-induced ADP-ribosylation of a 46 kDa protein is decreased in brains of ethanol-fed mice.

The acute in vitro effects of ethanol on cerebral cortical adenylate cyclase activity and beta-adrenergic receptor characteristics suggested a site of action of ethanol at Gs, the stimulatory guanine nucleotide binding protein. After chronic ethanol ingestion, the beta-adrenergic receptor appeared to be uncoupled (i.e., the form of the receptor with high affinity for agonist was undetectable), and stimulation of adenylate cyclase activity by isoproterenol or guanine nucleotides was reduced, suggesting an alteration in the properties of Gs. To further characterize this change, cholera and pertussis toxin-mediated 32P-ADP-ribosylation of mouse cortical membranes was assessed in mice that had chronically ingested ethanol in a liquid diet. 32P-labeled proteins were separated by SDS-PAGE and quantitated by autoradiography. There was a selective 30-50% decrease in cholera toxin-induced labeling of 46 kDa protein band in membranes of ethanol-fed mice, with no apparent change in pertussis toxin-induced labeling. The 46 kDa protein has a molecular weight similar to that of the alpha subunit of Gs, suggesting a reduced amount of this protein or a change in its characteristics as a substrate for cholera toxin-induced ADP-ribosylation in cortical membranes of ethanol-fed mice.

Adenosine Diphosphate↗
PubMed1988

Regulation of vasopressin and oxytocin synthesis in anterior pituitary and peripheral tissues.

Recent studies have demonstrated the presence of immunoreactive oxytocin (OT) and vasopressin (VP), OT and VP receptors and physiological functions for these two hormones in a variety of peripheral tissues, including anterior pituitary gland. The objectives of this study were to determine if (i) OT and VP genes are expressed in rat testis and anterior pituitary gland and (ii) if osmotic stimulation known to modify the regulation of OT and VP genes in hypothalamus, would modify the expression of these genes in rat testis and anterior pituitary gland. Using oligonucleotide probes (courtesy of Drs. M. Brownstein and W. Scott Young, NIMH) corresponding to the VP gene or OT gene and specific fractions of human OT and VP genes (courtesy of Dr. J. Battey, NCI) subcloned in the pGEM-3 riboprobe system, and Northern blot and slot blot techniques, OT and VP mRNAs were found in rat testis and anterior pituitary gland. When adult male rats (SD) were either deprived of drinking water or offered 2% salt solution as a sole source of drinking fluid for 72 hrs, both OT and VP mRNA levels were increased in hypothalamus, anterior pituitary gland and testis. Our data suggest that testis and anterior pituitary gland could also be sites of synthesis of OT and VP and that the same stimulus may regulate these genes in various tissues.

Animals↗
PubMed1988

Receptors with V1 characteristics mediate the maintenance of ethanol tolerance by vasopressin.

The neurohypophyseal hormone arginine vasopressin (AVP) acts in the central nervous system (CNS) to maintain functional tolerance to several effects of ethanol. The ability of exogenous vasopressin (administered i.c.v.) to maintain tolerance to the hypnotic effect of ethanol was blocked more effectively by antagonists acting at V1 receptors than by a V2-selective antagonist. Similarly, a V1-selective agonist was more potent than AVP in maintaining tolerance, whereas V2-selective agonists were inactive. These results indicate that vasopressin maintains ethanol tolerance via an action at CNS receptors that have the characteristics of V1 vasopressin receptors. Furthermore, a V1-selective antagonist, given alone, enhanced the rate of loss of tolerance, whereas a V2-selective antagonist did not, supporting a role for endogenous AVP, also acting at V1 vasopressin receptors, in the maintenance of ethanol tolerance. Characterization of the CNS receptors that mediate the modulation of ethanol tolerance by vasopressin suggests a mechanism of action of the peptide hormone in the CNS, and may contribute to the eventual development of therapies to modify functional ethanol tolerance.

Animals↗
PubMed1987

Effect of ethanol on cardiac beta-adrenoceptors.

Liquid diets are commonly used as vehicles for chronic administration of ethanol to rodents. After mice had consumed an ethanol-free liquid diet for either seven or eight days, the number of cardiac beta-adrenoceptors and the maximum response of adenylate cyclase to isoproterenol were decreased. This change was associated with a decrease in the number of high-affinity agonist binding sites. When mice were fed ethanol in the liquid diet, there was a further decrease in the number of cardiac low-affinity agonist (isoproterenol) binding sites, but no further change in the biochemical response to isoproterenol. The data suggest that stress and/or nutritional factors can alter the number, the coupling and the function of cardiac beta-adrenoceptors and that chronic ethanol ingestion enhances certain aspects of these changes.

Adenylyl Cyclases↗
PubMed1987

Effect of an imidazobenzodiazepine, Ro15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital.

The imidazobenzodiazepine, Ro15-4513, which is a partial inverse agonist at brain benzodiazepine receptors, reversed the incoordinating effect of ethanol in mice, as measured on an accelerating Rotarod. This effect was blocked by benzodiazepine receptor antagonists. In contrast, Ro15-4513 had no effect on ethanol-induced hypothermia in mice. However, Ro15-4513 reversed the hypothermic effect of pentobarbital, and, at a higher dose, also reversed the incoordinating effect of pentobarbital in mice. The data support the hypothesis that certain of the pharmacological effects of ethanol are mediated by actions at the GABA-benzodiazepine receptor-coupled chloride channel.

Animals↗