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Biomedical subjects

B Tabakoff

Publications and source records attributed to B Tabakoff.

At least 163 records · Page 9Linked to original sources
PubMed1984

Activation of adenylate cyclase by alcohols requires the nucleotide-binding protein.

Ethanol was shown to activate adenylate cyclase in mouse striatal membranes, but significant activation of adenylate cyclase by ethanol concentrations below 500 mM was found only in the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p] or other guanine nucleotides. Ethanol did not alter the amount of guanine nucleotide required for half-maximal activation of adenylate cyclase, but was found to further increase adenylate cyclase activity under conditions wherein the nucleotide binding protein was preloaded with Gpp(NH)p or when hydrolysis of added GTP was blocked using cholera toxin. The stimulation of adenylate cyclase activity by sodium fluoride was also accentuated by ethanol. Ethanol, propanol and butanol all increased adenylate cyclase activity in the presence of Gpp(NH)p, and their effects on adenylate cyclase activity were linearly correlated with their respective carbon chain lengths. Equivalent membrane concentrations of ethanol and chloroform produced similar increases in adenylate cyclase activity under conditions where hydrolysis of added GTP was inhibited. However, chloroform and ethanol had opposite effects on adenylate cyclase activity in assays containing GTP and membranes not treated with cholera toxin. The apparent Km of adenylate cyclase for Mg-ATP and the Arrhenius activation energy for the enzyme in membranes incubated with Gpp(NH)p were similar in the presence and absence of ethanol. Ethanol, in concentrations up to 750 mM, did not alter the pattern of stimulation of adenylate cyclase by calcium and calmodulin. Our results suggest that ethanol modifies the equilibrium for the interaction of the nucleotide-loaded G-protein with the catalytic unit of adenylate cyclase to favor formation of the active nucleotide-G-protein-catalytic unit complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1983

Vasopressin maintenance of ethanol tolerance requires intact brain noradrenergic systems.

We have demonstrated that the mammalian antidiuretic hormone, arginine vasopressin (AVP), will maintain functional tolerance to the hypnotic effect of ethanol in mice, beyond the time in which such tolerance normally dissipates. However, when mice are made tolerant to ethanol and then injected intraventricularly with 6-hydroxydopamine (6-OHDA), AVP is no longer effective in maintaining tolerance. The action of AVP was attenuated by a dose of 6-OHDA which significantly lowered brain norepinephrine, but not dopamine levels, suggesting that the maintenance of ethanol tolerance by AVP may require the presence of intact noradrenergic pathways in brain.

Animals↗
PubMed1983

Alcohol interactions with brain opiate receptors.

Ethanol, added in vitro to mouse caudate membranes, inhibited high-affinity binding of 0.2 nM 3H-dihydromorphine (3H-DHM) over an ethanol concentration range of 250-1,000 mM. At lower, physiologically-attainable ethanol concentrations (e.g.: 50 mM), 3H-DHM binding was significantly increased. Over the concentration range of 50-1,000 mM, ethanol inhibited 0.5 nM 3H-[D-Ala2,D-Leu5]enkephalin (3H-ENK) binding to mouse caudate tissue, and no stimulation of 3H-ENK binding was noted at any of these concentrations of ethanol. Ethanol inhibits opiate binding in a pseudo-competitive manner and, therefore, the concentration of ligand used to assess the effects of ethanol is of major importance. Results obtained with other alcohols which differ in their membrane:water partition coefficients suggest that alcohol effects on opiate binding are not solely dependent on the membrane-disordering properties of the alcohols.

Animals↗
PubMed1983

Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c, C57BL/6, and DBA/2 mice.

The effects of naltrexone on the increase in locomotor activity induced by a low dose (1.35 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (3.5 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice. Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice. Naltrexone, at a dose of 0.1 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice. The duration of loss of righting reflex was, however, differentially affected in all three strains by naltrexone. The BALB mice affected in all three strains by naltrexone. The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone. Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity.

Animals↗
PubMed1983

Effect of ethanol on synaptosomal sialic acid metabolism in the developing rat brain.

The total, glycoprotein-bound and glycolipid-bound sialic acid concentration, ad the activities of ecto-sialyltransferase and neuraminidase were determined in synaptosomes from preweanling ethanol-treated and control rats. The period of treatment corresponded to that of maximal synaptogenesis and peak synthesis of sialoglycocompounds (days 27-37 postconception). The average of the peak blood ethanol concentration was 271 mg/100 ml. In the ethanol-treated animals the sialic acid concentration was significantly reduced (approximately 20%) with an equally distributed decrease of glycoprotein- and glycolipid-bound sialic acid. The activity of ecto-sialyltransferase with asialofetuin as exogeneous acceptor was significantly diminished (about 30%) in the ethanol-treated pups. Neuraminidase showed an unchanged activity after correction for the reduction of endogeneous sialic acid substrate concentration. The total protein and lipid concentrations of the synaptosomal preparations did not differ between the groups. These results suggest that ethanol treatment during on of the vulnerable periods of brain development causes an inhibition of the incorporation of sialic acid into synaptosomal membrane-bound sialoglycocompounds. Such an effect of ethanol exposure might disturb intercellular interactions and the functional performance of the membrane during development, and could be of importance in the pathogenesis of the central nervous system manifestations of the fetal alcohol syndrome.

Animals↗
PubMed1983

Acute alcohol intoxication, mood states and alcohol metabolism in women and men.

The course of alcohol absorption and elimination was investigated in seven women and nine men administered a moderate (0.66 ml/kg) dose of 95% ethanol. Women were tested during the postmenstrual phase (Day 6-7), when levels of estrogen and progesterone were estimated to be relatively low. Data reflecting alterations in physical sensations, perceived levels of intoxication, and positive and negative mood states were also collected. Women reached significantly higher peak blood alcohol concentrations (BAC's) than men (p less than 0.01). However, differences in peak BAC's between men and women could be explained by differences in body water content between the sexes. When the raw data on BAC's were corrected for differences in body water content between men and women, no difference in the amount of alcohol metabolized, or in the length of time necessary to metabolize that amount of alcohol, could be found between the sexes. Although women attained higher blood and, presumably, brain levels of ethanol, men did not differ from women in perceived levels of intoxication, physical sensations and mood states. Acute alcohol intoxication appeared to elevate positive mood states during the ascending limb of the BAC curve, but was associated with increased negative affect during the descending limb.

Adult↗
PubMed1983

Ethanol effects on striatal dopamine receptor-coupled adenylate cyclase and on striatal opiate receptors.

The perturbation of neuronal cell membranes by ethanol may result in specific functional changes through modification of the activity of various membrane-bound proteins. In mouse striatum, adenylate cyclase, a membrane-bound enzyme, is coupled to dopamine, as well as to opiate, receptors. Ethanol stimulates striatal adenylate cyclase activity by modifying the regulatory protein ("G-protein")-adenylate cyclase interaction to produce an increased amount of activated enzyme. This action is additive with the effects of dopamine on adenylate cyclase. Ethanol also modifies striatal opiate receptor-effector coupling processes. In the presence of ethanol, opiate receptor affinity is altered, and this alteration is modified by GTP, suggesting that ethanol influences the interaction of the opiate receptor complex with the G-protein. Our results suggest that ethanol can affect receptor-effector coupling, including the binding of opiate agonists to their receptors, through its membrane-disordering capacity, and that particular systems may react in a relatively specific manner with ethanol.

Adenylyl Cyclases↗
PubMed1983

Neurochemical correlates of tolerance and strain differences in the neurochemical effects of ethanol.

The behavioral and neurochemical effects of acute and chronic ethanol administration were studied in BALB/c, C57B1/6 and DBA/2 mice. The rates of dopamine synthesis and release in the striatum were estimated by measuring the accumulation of DOPA and DOPAC, respectively, after inhibition of aromatic amino acid decarboxylase with NSD-1024. Biphasic behavioral effects were found in BALB/c and DBA/2 mice, but not in C57B1/6 mice, with low doses of ethanol producing activation and high doses, depression. Biphasic effects were also found in the dopamine response to acute doses of ethanol. The BALB/c and DBA/2 mice showed larger suppressions of DA release in the lower dose ranges of ethanol, and smaller increases at the higher doses than did the C57B1/6 mice. Ethanol stimulated dopamine synthesis in a monophasic, dose-dependent manner, and C57B1/6 mice were less sensitive to this effect of ethanol compared to the other tested strains of mice. Chronic ethanol feeding produced behavioral tolerance to the high-dose depressant effects of ethanol, but not to the low-dose activating effects. Similarly, tolerance developed in the dopaminergic responses to a higher challenge dose of ethanol (3.5 g/kg). These findings demonstrate that genetically determined differences exist in the sensitivity of the dopaminergic systems of mice to ethanol, and suggest that central dopamine neurons may be important in the behavioral effects of ethanol.

Alcoholic Intoxication↗
PubMed1983

Prenatal phenobarbital treatment and temperature-controlling dopamine receptors.

Pregnant mice were fed a phenobarbital-containing diet on days nine through 18 of pregnancy. Following parturition, the offspring of such animals were allowed to reach adulthood and then were tested for their response to an acute injection of apomorphine. Male offspring were less sensitive, while female offspring were more sensitive than matched controls to apomorphine-induced hypothermia. The witnessed differences in apomorphine-induced hypothermia could not be attributed to differences in brain apomorphine levels, alterations in the thermoregulation following non-drug challenges to the mouse's thermoregulatory ability, or changes in alpha-adrenergic receptor function. Our results suggest that prenatal phenobarbital administration produces changes in the function of dopamine receptors which regulate body temperature, and that the prenatally-induced changes last well into adulthood.

Animals↗
PubMed1982

On the mechanism by which dopamine inhibits prolactin release in the anterior pituitary.

An in vitro perfusion system was used to assess the effects of chloride channel blockers, dopamine (DA) receptor agonists and antagonists, and GABA receptor agonists and antagonists on prolactin release from the mouse anterior pituitary. Dopamine and muscimol inhibited prolactin release (IC50 = 6 X 10(-8)M and 10(-5)M respectively). The GABA receptor antagonist bicuculline blocked the inhibition of prolactin release by muscimol but not dopamine. The dopamine receptor antagonist chlorpromazine blocked the dopamine- but not muscimol-induced inhibition of prolactin release. Haloperidol, however, reversed both the muscimol and dopamine induced inhibition of prolactin release. Furthermore, the chloride channel blocker picrotoxinin blocked the inhibition of prolactin release elicited by both dopamine and muscimol. These later results suggest that the anterior pituitary dopamine receptor which mediates the inhibition of prolactin release may be coupled to a picrotoxinin sensitive chloride ionophore and that haloperidol may affect the function of both DA and GABA receptors in the anterior pituitary.

Animals↗
PubMed1982

Effects of ethanol on Arrhenius parameters and activity of mouse striatal adenylate cyclase.

Arrhenius plots of basal and dopamine (DA)-stimulated adenylate cyclase activities exhibited discontinuities at 20 degrees, while the plot of fluoride-stimulated adenylate cyclase activity was linear over the studied temperature range. None of the Arrhenius parameters were altered by in vitro addition of ethanol (75 or 750 mM) to enzyme assay mixtures, and Arrhenius parameters were found to be unchanged when enzyme obtained from animals rendered tolerant to, and physically dependent on, ethanol was assayed. The differences between the response to ethanol of adenylate cyclase and the response of other membrane-bound enzymes [e.g. (Na+-K+)ATPase], as measured by Arrhenius plots, may indicate different sites of action of ethanol. When the specific activity of adenylate cyclase was examined, ethanol was found to stimulate activity at all temperatures tested. The dose-response curve for ethanol activation of basal adenylate cyclase activity was shifted to the right for enzyme obtained from mice chronically treated with ethanol. Analysis of the data indicated that activation of adenylate cyclase by ethanol (as well as by DA) was an entropy-driven process. Since ethanol treatment did not affect the Arrhenius parameters, which appear to be associated with membrane lipids, it is suggested that enzyme activation by ethanol results from direct effects on the enzyme or regulatory protein. Resistance to this effect occurs through changes in protein conformation following chronic ethanol treatment.

Adenylyl Cyclases↗
PubMed1982

Does tolerance develop to the activating, as well as the depressant, effects of ethanol?

Genetically determined differences were demonstrated in the response of mice to low doses of ethanol. Ethanol (1.35 g/kg) produced an increase in locomotion in DBA/2 and BALB/c mice, but did not alter the locomotor activity of C57B1/6 mice. Chronic administration of ethanol produced tolerance to the sedative/hypnotic effects of high doses of ethanol in DBA/2 and BALB/c mice, but the equivalent chronic ethanol administration paradigm produced no tolerance to the activating effects of ethanol in these animals. C57B1/6 mice became tolerant to the hypnotic effects of ethanol, but no change in the behavior of these mice, given a low dose of ethanol, was noted after the mice were withdrawn from chronic feeding with ethanol-containing diets. The results indicate the presence of different mechanisms for tolerance development to the activating and depressant effects of ethanol, and indicate that strain-dependent differences in the activating effects of ethanol are not determined by an animal's greater sensitivity to the sedating effects of this drug.

Animals↗
PubMed1982

Effects of the convulsant methionine sulfoximine on striatal dopamine metabolism.

Experiments were conducted to investigate the effects of the convulsant L-methionine-DL-sulfoximine (MSO) on striatal dopamine (DA) metabolism. Intraventricular injections of MSO produced a transient increase in striatal DA release followed by inhibition of DA release for up to 3 days, which paralleled the inhibition by MSO of the enzyme glutamine synthetase (GS). DA synthesis was decreased for up to 24 h after injection of MSO, but returned to normal within 3 days after MSO administration. Intrastriatal injections of MSO produced a pronounced decrease in striatal DA release and inhibition of striatal GS activity 24 h postinjection but, unlike intraventricular MSO, did not produce behavioral convulsions. Glutamate-DA interactions may be responsible for the observed effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Alterations in opiate receptor function after chronic ethanol exposure.

The dose-response curve for morphine-induced stimulation of striatal dopamine metabolism was shifted to the right in mice which had been withdrawn for 24 hours after chronic consumption of an ethanol-containing liquid diet. The apparent ED50 for morphine was increased by 33% in ethanol-treated mice. Concomitant with the shift in the dose-response curve, the affinity for dihydromorphine of the high-affinity caudate morphine receptor was decreased in ethanol-treated mice. The change in receptor properties after ethanol treatment included a decreased sensitivity of the receptor to the effects of sodium ion on morphine binding. The results suggest: 1) that the effect of morphine on dopamine metabolism in the mouse striatum is, at least in part, mediated by receptors that exhibit a high affinity for dihydromorphine: and 2) that ethanol treatment and withdrawal may induce specific changes in these particular opiate receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

Ethanol alters kinetic characteristics and function of striatal morphine receptors.

Morphine was shown to promote dopamine (DA) synthesis and release in mouse striatum, but mice rendered tolerant and dependent on ethanol were found to be less responsive to morphine's effects on striatal DA metabolism than control animals. Ethanol feeding also produced a change in the affinity of striatal "opiate" receptors for [3H]dihydromorphine, and these ethanol-induced receptor changes may be responsible for the altered biological effect of morphine.

Animals↗