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Biomedical subjects

B Tabakoff

Publications and source records attributed to B Tabakoff.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of moderate alcohol consumption on the central nervous system.

The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as "statistically" normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., approximately 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors--including gestational period, the periodicity of the mother's drinking, genetic factors, etc.--play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system.

Adult↗
PubMed1998

An initial study of the relationship between platelet adenylyl cyclase activity and alcohol use disorder criteria.

Low platelet adenylyl cyclase (AC) activity has been previously proposed to be a trait marker reflecting a genetic predisposition to alcohol dependence. To determine whether low platelet AC activity in alcohol-dependent subjects may be related to specific diagnostic criteria of DSM-IV and ICD-10 alcohol use disorders, we analyzed responses obtained in structured clinical interviews of 36 subjects who were determined to be alcohol-dependent Platelet AC activity when stimulated by guanylyl-imidodiphosphate [Gpp(NH)p] or forskolin was significantly lower in alcohol-dependent subjects as a group, compared with controls. When we analyzed the responses of the alcohol-dependent subjects to questions used to establish the diagnosis of alcohol abuse/dependence and dichotomized the subjects by positive or negative responses, we found that Gpp(NH)p- and forskolin-stimulated platelet AC activities were significantly lower among those alcohol-dependent subjects who had positive responses to questions related to drinking despite negative effects on mood ("Did you ever continue to drink even though you knew it was making you feel depressed, uninterested in things, or suspicious or distrustful of other people?"), drinking despite negative effects on health ("Did you ever continue to drink even though you knew it was causing you a health problem or making a health problem worse?"), or violence when drinking ("Did you get into physical fights while drinking or right after drinking?"). The alcohol-dependent subjects who had negative responses to these questions exhibited Gpp(NH)p- and forskolin-stimulated platelet AC activity that did not differ significantly from values in control subjects. The DSM-IV diagnosis of antisocial personality disorder did not distinguish alcohol-dependent subjects with regard to platelet AC activity. Gpp(NH)p and forskolin-stimulated AC activity may distinguish certain subtypes of alcoholics (i.e., those who develop negative mood in response to drinking, those who continue drinking despite health effects, and those who become violent while drinking).

Adenylyl Cyclases↗
PubMed1998

Effects of abstinence and family history for alcoholism on platelet adenylyl cyclase activity.

Platelet adenylyl cyclase (AC) activity was measured in 32 alcohol-dependent subjects and 27 control subjects who were categorized as either family history-positive (FHP) or family history-negative (FHN) for alcoholism. The interview and blood sample collections were performed shortly after cessation of heavy drinking in the alcoholic group, and repeat blood samples were obtained at the end of the first and second weeks of monitored abstinence. Control subjects received the same interview and provided blood samples at the time of the interview. When subjects were not segregated for FHP or FHN status, there were no statistically significant differences in basal, cesium fluoride (CsF)-, or forskolin-stimulated mean AC activities between the controls and the alcoholics, at study entry or with 1 or 2 weeks of abstinence. On the other hand, over the 2-week course of sobriety from heavy drinking, the CsF-stimulated AC activity of FHP alcohol-dependent subjects decreased significantly (p = 0.03). FHP alcohol-dependent subjects after 2 weeks of sobriety had significantly lower mean CsF-stimulated AC activity than FHN controls (p = 0.04), whereas the FHN alcoholic subjects' CsF-stimulated AC activity did not differ significantly from FHN controls at this point in time. When all subjects were pooled and then categorized as either FHP or FHN, there was a significant difference in mean CsF-stimulated AC activity (p = 0.02) between the FHP and FHN subject groups. Genetic factors and abstinence appear to have roles in determining low platelet AC activity in alcoholic and nonalcoholic subjects. CsF-stimulated platelet AC activity, in particular, appears to act as a trait marker for a genetic vulnerability to developing alcoholism, but recent heavy drinking in male alcoholics is a factor that can mask differences between FHP and FHN subjects.

Adenylyl Cyclases↗
PubMed1997

Forskolin-stimulated platelet adenylyl cyclase activity is lower in persons with major depression.

We investigated platelet adenylyl cyclase activity in 17 subjects with a history of major depression ("depressed subjects") and 20 controls. Forskolin was used to directly activate adenylyl cyclase, while guanine nucleotides (Gpp(NH)p) and fluoride ions were used to measure adenylyl cyclase activity modulated through the G proteins. Forskolin-stimulated adenylyl cyclase was significantly lower in the depressed subjects (p < 0.0005). There was a statistically significant difference in basal adenylyl cyclase activity between male depressed subjects and male controls. The basal adenylyl cyclase activity was also lower in female depressed subjects, but this difference did not reach statistical significance (p < 0.2). The adenylyl cyclase activity measured after stimulation with a guanine nucleotide or cesium fluoride did not differ between control and depressed male or female subjects. Severity of current depression and the current use of antidepressant medication were not related to the lower forskolin-stimulated enzyme activity in the depressed subjects. The difference in forskolin-stimulated adenylyl cyclase activity appears to reflect a qualitative difference in the adenylyl cyclase enzyme activity in persons with a history of major depression.

Adenylyl Cyclases↗
PubMed1997

Human adenylyl cyclase type 7 contains polymorphic repeats in the 3' untranslated region: investigations of association with alcoholism.

Platelet adenylyl cyclase activity has been proposed as a trait marker for alcoholism [Tabakoff et al. (1988): N Engl J Med 318:134-13;9; Parsian et al. (1996): Alcohol Clin Exp Res 20:745-751]. Human adenylyl cyclase type 7 (ADCY7) is a member of the adenylyl cyclase gene family, and it may be the major form of adenylyl cyclase expressed in human platelets. The published cDNA sequence of ADCY7 indicated the presence of potentially polymorphic regions in the 3' untranslated region of ADCY7. PCR techniques combined with fluorescently labeled primers were used to amplify two separate tetranucleotide repeat regions [(AACA)n] in the 3' untranslated region of ADCY7 from the genomic DNA of 62 unrelated individuals. The upstream (AACA)4-repeat was not polymorphic. Five different genotypes were found in the downstream (AACA)5-7 tetranucleotide repeat region. We also tested the association of the tetranucleotide polymorphism to alcohol dependence. When 30 alcoholic and 17 control individuals were compared, no difference was found in the ADCY7 tetranucleotide polymorphism between alcohol-dependent and control groups. Nevertheless, to our knowledge these are the first polymorphisms reported in an adenylyl cyclase gene. Adenylyl cyclases are important receptor-G protein-coupled effectors and are involved in numerous neuronal functions in the central nervous system. Whether variations in ADCY7 and possible variations in other members of this gene family are underlying other psychiatric disorders remains to be studied.

Adenylyl Cyclases↗
PubMed1997

Pentobarbital decreases the gamma-aminobutyric acidA receptor subunit gamma-2 long/short mRNA ratio by a mechanism distinct from receptor occupation.

Treatment with pentobarbital of primary cultured cerebellar granule cells decreased the gamma-aminobutyric acid, (GABA)A receptor subunit gamma-2 long/short (gamma-2L/S) mRNA ratio. A high dose of pentobarbital (500 microM) decreased the gamma-2L/S ratio by 64%; the decrease was dose and time dependent and reversible. (-)-Hexobarbital (500 microM), the less potent stereoisomer for GABA(A) receptor activation, decreased the ratio slightly (30%) but significantly more than (+)-hexobarbital (20%). Other GABA(A) receptor activators had no (100 mM ethanol) or little (2 microM 5alpha-pregnane-3alpha-ol-20-one) effect on the gamma-2L/S ratio. Furthermore, picrotoxin (10 microM), which blocks the GABA- and pentobarbital-activated GABA(A) receptor channel, neither changed the gamma-2L/S ratio nor blocked the pentobarbital-induced changes. These data suggest that barbiturates alter the gamma-2L/S mRNA ratio by a mechanism that does not require GABA(A) receptor activation. The gamma-2L/S subunit mRNA includes an exon encoding an octapeptide that contains a protein kinase C phosphorylation consensus site. This exon-encoded peptide, occurring in the putative intracellular loop, can be phosphorylated, and in vitro, this phosphorylation has been shown to have functional consequences. This is the first report of a drug-induced alteration in receptor mRNA splicing. Furthermore, the changes in the gamma-2L/S ratio produced by pentobarbital exposure may have significant effects on the function of an important brain protein, the GABA(A) receptor.

Animals↗
PubMed1996

The 71 kDa glutamate-binding protein is increased in cerebellar granule cells after chronic ethanol treatment.

Besides the N-methyl-D-aspartate (NMDA) receptor proteins NR1 and NR2, another complex of proteins which has been shown to contain ligand-binding sites characteristic of NMDA receptors is expressed in cerebellar granule cells. One of the proteins in the latter complex is the 71 kDa glutamate-binding protein (GBP). To determine the role of the GBP in the response to NMDA, primary cultures of cerebellar granule cells were treated with an antisense oligonucleotide complementary to mRNA for this protein. This treatment substantially reduced both mRNA and protein levels of the GBP, as well as the response of the cells to NMDA, measured as an increase in intracellular Ca2+ with fura-2 fluorescence. The antisense oligonucleotide treatment did not alter the Ca2+ responses to KC1 or kainate. Chronic ethanol exposure has previously been shown to increase NMDA receptor function and the density of binding sites for the NMDA receptor channel blocker, dizocilpine, in cerebellar granule cells. Chronic exposure of the cells to 100mM ethanol is now shown to result in significant increases in mRNA and protein levels for the GBP (45% and 100%, respectively). Ethanol treatment did not affect mRNA levels for NR1 or NR2A, caused only a small increase (20%) in protein levels for NR1, and resulted in a decrease (30%) in NR2A protein. Although a role of the NMDA receptor NR1/NR2 subunits cannot be ruled out, these results are compatible with the hypothesis of involvement of the GBP in the chronic ethanol-induced increase in NMDA receptor function in cerebellar granule cells.

Animals↗
PubMed1996

Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion.

Chronic ethanol treatment of mice has been shown to result in increased binding of dizocilpine and glutamate to hippocampal NMDA receptors. These changes were suggested to reflect an increase in NMDA receptor number that may underlie certain signs of the ethanol withdrawal syndrome. However, there was no change in binding of a competitive NMDA receptor antagonist, or of ligand binding to the glycine co-agonist site on the receptor after chronic ethanol treatment. Differential changes in the binding of particular ligands at the NMDA receptor suggested the possibility that chronic ethanol ingestion might selectively affect the expression of particular NMDA receptor subunits. Our current work demonstrates that chronic ethanol ingestion by mice, which results in the generation of physical dependence, also produces increases in the NMDA receptor NR1 subunit protein in the hippocampus and cerebellum (approximately 50% and 95%, respectively), and produces increases in the NR2A subunit protein in the hippocampus and cortex (approximately 25% and 40%, respectively). However, the mRNA levels for these subunits were not increased in the respective brain areas by the same ethanol treatment. The changes in NMDA receptor subunit expression in discrete areas of the brain may contribute to the previously observed changes in ligand binding and, possibly, signs of ethanol withdrawal.

Alcoholism↗
PubMed1996

Adenylyl cyclases: mRNA and characteristics of enzyme activity in three areas of brain.

RNase protection assays were used in a comparative analysis of the quantities of mRNA for five "calcium-sensitive" (types I, III, V, VI, and VIII) adenylyl cyclases and one "calcium-insensitive" (type II) adenylyl cyclase in mouse cerebral cortex, cerebellum, and nucleus accumbens. The mRNA levels for type V adenylyl cyclase were dominant in the nucleus accumbens. Type V adenylyl cyclase mRNA was also found in the cerebral cortex and at low levels in the cerebellum. Type I adenylyl cyclase mRNA was the major form in the cerebellum with 15-50-fold higher levels compared with other adenylyl cyclase mRNAs. Type I adenylyl cyclase mRNA was also the most prominent adenylyl cyclase mRNA in the cerebral cortex, although the mRNA levels of other adenylyl cyclase forms were more comparable to those of the type I enzyme in this brain area. The mRNA levels for adenylyl cyclase types II, III, VI, and VIII were intermediate to low depending on the brain area. Cell membranes from the nucleus accumbens demonstrated adenylyl cyclase activity that was synergistically activated by concomitant addition of GTP and forskolin to assay mixtures, reflecting a characteristic of type V adenylyl cyclase protein. Calcium/calmodulin stimulated adenylyl cyclase activity in membranes from all three brain areas. However, synergistic activation of adenylyl cyclase activity by GTP and calcium/calmodulin was noted only with cortical membranes, and this characteristic may reflect the presence of type VIII adenylyl cyclase mRNA in the cortex. Although mRNA for type VIII adenylyl cyclase was almost equivalent in the cortex and cerebellum, the lack of a synergistic effect of GTP plus calcium/calmodulin on the cerebellar enzyme activity may be a result of the significant dominance of type I adenylyl cyclase mRNA (and protein) in the cerebellum. In general, the mRNA levels for the various adenylyl cyclases were predictive of the regulatory characteristics of adenylyl cyclase activity in membranes of the brain areas studied.

Adenylyl Cyclases↗
PubMed1996

Alcohol dependence: a commentary on mechanisms.

The alcohol dependence syndrome includes the presence of alcohol tolerance, physical dependence and an inability to control one's alcohol intake. Studies are reviewed that implicate the mesolimbic dopaminergic systems, and the gamma-aminobutyric acid-A (GABAA) and N-methyl-D-aspartate (NMDA) receptors as mediators of various aspects of the alcohol dependence syndrome. It is suggested that alcohol-induced changes in the GABAA receptor may play a role in certain aspects of tolerance to alcohol and in altered abilities of an individual to terminate alcohol intake. Chronic alcohol-induced increases in the activity of NMDA receptors may contribute to the withdrawal signs that are the defining feature of physical dependence on alcohol. It is hypothesized that decreased mesolimbic dopaminergic function, which occurs during alcohol withdrawal, may be involved in the compulsion to initiate and maintain alcohol drinking, another aspect of the alcohol dependence syndrome. Furthermore, evidence is presented that this decreased dopaminergic function could occur secondarily to the increase in NMDA receptor function, such that the alcohol-induced increase in NMDA receptor function could underlie both the overt withdrawal signs and the compulsion to drink alcohol in the alcohol-dependent individual.

Alcohol Withdrawal Delirium↗
PubMed1996

Platelet adenylyl cyclase activity in alcoholics and subtypes of alcoholics. WHO/ISBRA Study Clinical Centers.

Adenylyl cyclase (AC) activity was measured in membrane preparations of platelets from control and alcoholic subjects. The sample consisted of 51 alcoholics who were categorized as type I or type II using the criteria of Gilligan et al. (Genet. Epidemiol. 4:395-414, 1987) and 54 normal controls. Alcoholic males exhibited significantly lower values than controls in basal and fluoride-stimulated platelet AC activity. When male alcoholics were segregated into type I and type II categories, the platelet AC activity did not differ between subtypes, and both subtypes had AC activity that was below control values. Western blot analysis of the quantity of Gs alpha and Gi alpha proteins in a subset of male controls and alcoholic subjects demonstrated no significant relationship between quantity of G proteins and AC activity. The results confirm lower platelet AC activity in male alcoholics, compared with controls. Given the lack of quantitative relations between Gs alpha and Gi alpha proteins and AC activity, the results support the contention that individual differences in platelet AC activity in the alcoholic subjects may reflect quantitative or qualitative differences in the AC catalytic units.

Adenylyl Cyclases↗
PubMed1996

Mechanism of ethanol inhibition of NMDA receptor function in primary cultures of cerebral cortical cells.

Ethanol is a potent inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal preparations. In primary cultures of cerebellar granule cells, ethanol was suggested to interact with the glycine co-agonist site of the receptor by a mechanism involving protein kinase C. In the present study, the interaction of ethanol with various sites on the NMDA receptor was examined in primary cultures of cerebral cortical cells from embryonic rats. NMDA receptor function was determined by measuring increases in intracellular Ca2+ with fura-2 fluorescence. Ethanol inhibited the function of the NMDA receptor in cerebral cortical cells, but in contrast to the results in cerebellar granule cells, phorbol ester treatment did not inhibit the NMDA response, and ethanol did not alter the effect of glycine on NMDA receptor function. Ethanol also did not affect inhibition of the NMDA response by Mg2+ or dizocilpine. The results support the hypothesis that the mechanism of ethanol inhibition of NMDA receptor function can vary in neurons from different brain regions.

Animals↗
PubMed1996

mu-Opioid receptors inhibit dopamine-stimulated activity of type V adenylyl cyclase but enhance dopamine-stimulated activity of type VII adenylyl cyclase.

The introduction of D1A dopamine receptors and mu-opioid receptors into HEK 293 cells that were also transiently transfected with adenylyl cyclase cDNA imparted to dopamine and to mu-opioid receptor agonists the ability to modulate the activity of the expressed adenylyl cyclase. Dopamine added to cells expressing D1A receptors and type V adenylyl cyclase significantly stimulated type V enzyme activity. The concomitant addition of morphine produced a dose-dependent inhibition of dopamine-stimulated type V adenylyl cyclase activity. On the other hand, if the HEK 293 cells were transfected with cDNA for type VII adenylyl cyclase instead of the type V isoform, morphine stimulated this adenylyl cyclase activity beyond the stimulation produced by dopamine. Both the inhibitory and stimulatory effects of morphine were blocked by naloxone or pretreatment of the transfected HEK 293 cells with pertussis toxin. When expressed in the HEK 293 cells, the alpha subunit of transducin, which is considered to be the putative scavenger of the beta gamma subunits of G proteins, suppressed the stimulatory effect of morphine on type VII adenylyl cyclase. We also expressed the adenylyl cyclases in cells that were transfected with D1A receptor and G beta 1 and G gamma 2 cDNAs. Dopamine was more efficacious in stimulating type VII adenylyl cyclase activity in cells concomitantly transfected with the beta gamma subunit cDNAs than in cells not transfected with these G protein subunits. Transfection with beta gamma subunit cDNAs did not affect dopamine stimulation of type V adenylyl cyclase activity, and morphine-induced inhibition of type V adenylyl cyclase activity was still evident in cells cotransfected with the alpha subunit of transducin. These data support the contention that the effects on type VII adenylyl cyclase activity mediated through the G1/G(o) proteins may depend on the actions of the beta gamma subunits. The same is not the case for type V adenylyl cyclase. Our data demonstrate that both qualitative and quantitative responses to mu-opioid receptor stimulation depend on the isoform of adenylyl cyclase expressed in neurons or other cells of the body.

Adenylate Cyclase Toxin↗
PubMed1996

Gangliosides reduce the development of ethanol dependence without affecting ethanol tolerance.

Mice given an ethanol-containing liquid diet, as their sole source of nutrients and fluid, rapidly developed functional tolerance to and physical dependence on ethanol. The presence of physical dependence was demonstrated by measured signs of central nervous system hyperexcitability upon withdrawal of ethanol. The withdrawal hyperexcitability, which included tremors, handling-induced seizures and spontaneous clonic/tonic seizures, was more pronounced when mice consumed the ethanol-containing diet for 7 days, compared with 5 days. Daily treatment of the animals with either a ganglioside mixture (extracted bovine brain gangliosides, 250 or 500 mg/kg i.p.) or ganglioside GM1 (100 mg/kg i.p.) for the terminal two-thirds of the ethanol administration period resulted in a significant reduction in the ethanol withdrawal signs. On the other hand, tolerance to the hypnotic action of ethanol, tested 30 hr after withdrawal of ethanol, was unaffected by ganglioside treatment. Ganglioside GM1 given i.c.v. at a daily dose of 10 micrograms during the ethanol ingestion period was as effective as 100 mg/kg GM1 given i.p. in reducing signs of ethanol withdrawal. The daily administration of gangliosides during the feeding of the ethanol diet did not alter the animals' ethanol consumption, intoxication or blood ethanol levels at the time of ethanol withdrawal. A single dose of GM1 given either i.p. or i.c.v. 16 hr before withdrawal produced no effect on the measured ethanol withdrawal signs. Our prior work and the work of others has demonstrated a relationship between up-regulation of N-methyl-D-aspartate receptor numbers in brain and the manifestation of ethanol withdrawal signs. Daily administration of GM1, during the last 5 days of a 7-day period of ethanol ingestion, prevented the up-regulation of N-methyl-D-aspartate receptors in the hippocampus and reduced the ethanol withdrawal signs. Our data demonstrate that the daily administration of gangliosides during the period of ethanol consumption may prevent the development of ethanol physical dependence, while leaving ethanol tolerance intact.

Animals↗