Search PubMed⌕ Search

Biomedical subjects

P L Hoffman

Publications and source records attributed to P L Hoffman.

At least 19 recordsLinked to original sources

Chronic ethanol exposure results in increased acute functional tolerance in selected lines of HAFT and LAFT mice.

RATIONALE AND OBJECTIVES: Functional (pharmacodynamic) ethanol tolerance can be evidenced within a single session of exposure to ethanol (acute or within-session tolerance), or after repeated ethanol exposures (chronic or between-session tolerance). To investigate whether acute and chronic tolerance to ethanol are inter-related phenomena, the effect of chronic ethanol exposure was evaluated in mice selectively bred for high (HAFT) or low (LAFT) acute functional tolerance to an ataxic effect of ethanol, i.e., loss of balance on a stationary dowel. METHODS: Mice were tested for sensitivity (threshold ethanol concentration for loss of balance on the stationary dowel) and acute functional tolerance to ethanol before and after a regimen of chronic ethanol exposure (twice-daily ethanol injections for 6 days). RESULTS: Chronic ethanol treatment did not alter the threshold for ethanol's ataxic effect (i.e., produced no change in sensitivity). However, this treatment, in a dose-dependent manner, resulted in an increase in the magnitude and rate of development of acute functional tolerance. CONCLUSIONS: This finding supports previous postulates that chronic ethanol tolerance can be characterized by a more rapid acquisition or a greater magnitude of acute (within-session) tolerance. However, the increase in acute tolerance that occurred after chronic ethanol exposure was similar in both selected lines of mice, indicating little or no genetic correlation between acute tolerance and chronic tolerance.

Alcoholic Intoxication↗

Chronic ethanol exposure delays the 'developmental switch' of the NMDA receptor 2A and 2B subunits in cultured cerebellar granule neurons.

Chronic ethanol treatment of cultured neurons from various brain areas has been found to increase NMDA receptor function and to alter the levels of some NMDA receptor subunit proteins. Because the cultured neurons are exposed to ethanol during a period when the NMDA receptor is undergoing developmental changes in subunit expression, we wished to determine whether ethanol treatment alters this developmental pattern. We found that 3 days of treatment of cerebellar granule neurons with ethanol, which was previously reported to increase NMDA receptor function, resulted in a delay in the 'developmental switch' of the NR2A and NR2B subunits, i.e. the developmental decrease in NR2B and increase in NR2A protein expression. As a result, the level of NR2B was higher, and that of NR2A was lower, in the ethanol-treated cells than in control cells. Cross-linking experiments showed that the changes in total receptor subunit proteins levels were reflected in cell-surface expressed proteins, indicating changes in the amount of functional receptors. These results were confirmed by a higher potency of glycine at the NMDA receptor in the ethanol-treated cells, as determined by NMDA/glycine-induced increases in intracellular Ca(2+). The results suggest that the mechanism by which ethanol alters NMDA receptor expression in cultured neurons, where receptors are undergoing development, differs from the mechanism of ethanol's effect on NMDA receptors in adult brain. Changes in the proportion of NR2A and NR2B subunits may contribute to effects of ethanol on neuronal development.

Animals↗

Transgenic and gene "knockout" models in alcohol research.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Paula L. Hoffman and Takeshi Yagi. The presentations were (1) cAMP signaling in ethanol sensitivity and tolerance, by Boris Tabakoff; (2) Synaptic signaling pathways of Fyn-tyrosine kinase, by Takeshi Yagi; (3) Ethanol drinking and sensitization in dopaminergic and serotonergic receptor knockouts, by Tamara J. Phillips; (4) ICAM-1 is involved in early alcohol-induced liver injury in the mouse given enteral alcohol, by Hiroshi Kono; and (5) Strategies for targeted and regulated knockouts, by Robert O. Messing and Doo-Sup Choi.

Adenylyl Cyclases↗

WHP/ISBRA study on state and trait markers in alcoholism.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Boris Tabakoff. The presentations were (1) Overview of the WHO/ISBRA study on state and trait markers in alcoholism, by Boris Tabakoff; (2) Biochemical markers of acute and chronic drinking: Results of the WHO/ISBRA study, by Anders Helander; (3) The impact of country of recruitment and body mass index on biological marker dose-response curves in the WHO/ISBRA Study, by Kate M. Conigrave; (4) Relationship of body water to carbohydrate-deficient transferrin measures, by Larry Martinez; and (5) Platelet adenylyl cyclase activity as a trait marker of alcohol dependence, by Paula L. Hoffman.

Adenylyl Cyclases↗

Chronic ethanol exposure attenuates the anti-apoptotic effect of NMDA in cerebellar granule neurons.

Ethanol, added to primary cultures of cerebellar granule neurons simultaneously with NMDA, was previously shown to inhibit the anti-apoptotic effect of NMDA. The in vitro anti-apoptotic effect of NMDA is believed to mimic in vivo protection against apoptosis afforded by innervation of developing cerebellar granule neurons by glutamatergic mossy fibers. Therefore, the results suggested that the presence of ethanol in the brain at a critical period of development would promote apoptosis. In the present studies, we examined the effect of chronic ethanol exposure on the anti-apoptotic action of NMDA in cerebellar granule neurons. The neurons were treated with ethanol in vitro for 1-3 days in the absence of NMDA. Even after ethanol was removed from the culture medium, as ascertained by gas chromatography, the protective effect of added NMDA was significantly attenuated. The decreased anti-apoptotic effect of NMDA was associated with a change in the properties of the NMDA receptor, as indicated by a decrease in ligand binding, decreased expression of NMDA receptor subunit proteins, and decreased functional responses including stimulation of increases in intracellular Ca(2+) and induction of brain-derived neurotrophic factor expression. The latter effect may directly underlie the attenuated protective effect of NMDA in these neurons. The results suggest that ethanol exposure during development can have long-lasting effects on neuronal survival. The change in the NMDA receptor caused by chronic ethanol treatment may contribute to the loss of cerebellar granule neurons that is observed in animals and humans exposed to ethanol during gestation.

Animals↗

Overexpression of type 7 adenylyl cyclase in the mouse brain enhances acute and chronic actions of morphine.

The mechanisms by which morphine-induced analgesia and tolerance and physical dependence on morphine arise have been the subject of intense study, and much work has pointed to the involvement of cAMP-mediated events in the neuroadaptive phenomena leading to morphine tolerance and/or dependence. We overexpressed an opioid receptor-stimulatable form of adenylyl cyclase (type 7) in the central nervous system of mice and demonstrated significant effects of this manipulation on the animals' acute response to morphine, the development of morphine tolerance, and development of sensitization to morphine. Measurements of the acute analgesic response to morphine demonstrated that the ED(50) values for the transgenic mice were significantly lower than the ED(50) values determined for the "wild-type" animals. During chronic treatment with morphine, the transgenic mice developed tolerance more rapidly than the wild-type mice, and transgenic animals of the C57BL/6xSJL background showed a larger sensitization to morphine's effects on locomotor activity than did wild-type mice of the same background. These results indicated that cAMP-generating systems may simultaneously modulate the development of tolerance and sensitization. Interestingly, the signs of physical dependence on morphine in the transgenic mice did not differ from those in their wild-type litter mates, indicating that separate mechanisms may modulate opiate tolerance and opiate dependence.

Adenylyl Cyclases↗

Novel structure having antagonist actions at both the glycine site of the N-methyl-D-aspartate receptor and neuronal voltage-sensitive sodium channels: biochemical, electrophysiological, and behavioral characterization.

A novel series of N-substituted 4-ureido-5,7-dichloro-quinolines were synthesized to contain pharmacophores directed at voltage-sensitive sodium channels (VSNaCs) and N-methyl-D-aspartate (NMDA) receptors. These compounds were shown to act in a use-dependent manner as antagonists of VSNaCs and to act as selective competitive antagonists at the strychnine-insensitive glycine recognition site of NMDA receptors. These agents had little or no effect on alpha-adrenergic receptors, other glutamate receptors, or sites other than the glycine site on the NMDA receptor, and did not block voltage-sensitive calcium channels in vitro. In vivo, the compounds were active in preventing or reducing the signs and symptoms of neurohyperexcitability and had anxiolytic properties. Unlike benzodiazepines, N-substituted 4-ureido-5, 7-dichloro-quinolines showed little interaction with the sedative effects of ethanol, but were effective in controlling ethanol withdrawal seizures. The combined actions of these compounds on VSNaCs and NMDA receptors also impart properties to these compounds that are important for preventing and reducing excitotoxic neurodegeneration, but these compounds lack the undesirable side effects of other agents used for these purposes.

Animals↗

Platelet adenylyl cyclase activity as a trait marker of alcohol dependence. WHO/ISBRA Collaborative Study Investigators. International Society for Biomedical Research on Alcoholism.

BACKGROUND: There is compelling evidence that genetic factors play a major role in the development of alcohol dependence. Platelet adenylyl cyclase (AC) activity has been proposed as a biochemical marker for differentiating alcohol-dependent and nondependent subjects, but the sensitivity and specificity of this marker have not been ascertained. The objective of this study was to determine the sensitivity and specificity of platelet AC activity in identifying alcohol-dependent subjects and to ascertain the effect of medical/ psychiatric variables, drinking and smoking history, and age and body weight on AC activity. METHODS: The cross-sectional study was conducted from 1995 to 1998. Participants were 210 Australian White men who were community volunteers and alcohol treatment inpatients in Sydney, Australia. There were 41 nondrinkers, 140 drinkers, and 29 men who were entering alcohol treatment. The main outcome measure was platelet AC activity. Classification variables were plasma ethanol, gamma-glutamyltransferase, aspartate aminotransferase, serum carbohydrate-deficient transferrin (CDT), and urinary 5-hydroxytryptophol/5-hydroxyindoleacetic acid (5-HTOL/5-HIAA) levels, and World Health Organization/International Society for Biomedical Research on Alcoholism Interview Schedule variables, which included alcohol use and dependence criteria. RESULTS: Among subjects who reported abstinence for at least 4 days, both cesium fluoride (CsF)- and forskolin-stimulated platelet AC activities were significantly lower in those with a lifetime history of alcohol dependence compared with those with no such history (p < 0.005 and p < 0.05, respectively). The sensitivity and specificity of CsF-stimulated AC activity to discriminate individuals with a lifetime history of alcohol dependence were 75% and 79%, respectively. Similar values for sensitivity and specificity for CsF-stimulated AC activity were calculated when discriminating current alcohol dependence in the subjects in our sample. Irrespective of the history of alcohol dependence, persons who had consumed alcohol recently (within the last 3-4 days) showed significantly higher mean basal, CsF-stimulated, and forskolin-stimulated AC activity (p < 0.001), as did those who had elevated 5-HTOL/5-HIAA ratios or CDT levels, indicative of recent (heavy) drinking. The "normalization" of platelet AC activity to baseline levels after an individual stops drinking may be related to the generation of new platelets during the abstinence period. Conduct disorder and antisocial personality disorder were not associated with low AC activity, but low forskolin-stimulated AC activity was associated with major depression. CONCLUSIONS: We found that CsF- and forskolin-stimulated platelet AC activity discriminates between subjects with and without alcohol dependence in a population of subjects who had not consumed significant quantities of ethanol recently. Recent alcohol consumption is a confounding variable that can alter the measured levels of AC activity. Forskolin-stimulated platelet AC activity also may be influenced by a history of major depression.

Adenylyl Cyclases↗

Animal models in alcohol research.

Animal models are important tools in the study of alcohol use, abuse, and dependence because they allow researchers to use methods that cannot be used with human subjects. Animal models have been developed to study various aspects of alcohol use and dependence, including alcohol-seeking behavior, alcohol-related organ damage, tolerance to alcohol, and physical dependence on alcohol. Because animal models can be genetically manipulated, they are also valuable for research into the genetic determinants of alcoholism. Issues surrounding the use of animal models in alcohol research include the species of animal used, the method of alcohol administration, and the model's face and predictive validity.

Alcoholism↗

Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: signal transduction cascades and site of ethanol action.

Cerebellar granule neurons cultured in medium containing a physiological concentration of KCl (5 mM) undergo apoptosis. The cells can be rescued by the in vitro addition of NMDA. The protective effect of NMDA is thought to reflect the in vivo innervation of developing cerebellar granule neurons by glutamatergic afferents. In the current work, we investigated the mechanism of the anti-apoptotic (protective) effect of NMDA. NMDA treatment reduced caspase-3-like activity in cerebellar granule neurons, and the time course and concentration dependence of the protective effect of NMDA mirrored the ability of NMDA to induce brain-derived neurotrophic factor (BDNF) expression. Furthermore, a Trk receptor antagonist, K252a, as well as a blocking antibody to BDNF, attenuated the protective effects of both NMDA and BDNF. These results suggest that NMDA-induced BDNF expression mediates the anti-apoptotic effect of NMDA. The protective effects of NMDA and BDNF were reduced by inhibitors of the phosphatidylinositol 3'-OH kinase (PI 3-kinase) signal transduction cascade (wortmannin and LY29004) but not by a MAP kinase kinase (MEK) inhibitor (PD98059) or a protein kinase A inhibitor (Rp-cAMPS). BDNF increased phosphorylation of Akt, a target of PI 3-kinase, and NMDA also induced Akt phosphorylation, but only after an exposure that was long enough to induce BDNF expression. Furthermore, ethanol, which interferes with NMDA receptor function, inhibited the NMDA-induced increase in BDNF levels but did not block the protective effect of BDNF. These findings further support the role of BDNF in the anti-apoptotic effect of NMDA in cerebellar granule neurons and suggest that the NMDA-BDNF interaction may play a key role in in vivo cerebellar granule neuron development, as well as in the deleterious effects of ethanol on the developing cerebellum.

Animals↗

Ethanol sensitivity of NMDA receptor function in developing cerebellar granule neurons.

The mechanism by which ethanol inhibits the function of the NMDA subtype of glutamate receptor has not been elucidated. One possibility that has been suggested is that NMDA receptor subunit composition influences the sensitivity of the receptor to ethanol. We have taken advantage of developmental changes in subunit composition of the NMDA receptor in cultured neurons to examine possible changes in the effect of ethanol. We found an increase in expression of the NR2A subunit, and a decrease in expression of the NR2B subunit of the NMDA receptor in primary cultures of cerebellar granule neurons over time in culture, with no significant change in NR1 expression. This change in NR2 subunit expression was associated with the expected changes in functional properties of the NMDA receptor (measured as the NMDA-induced increase in intracellular Ca2+), i.e., ifenprodil sensitivity and glycine potency were higher when there was a relatively greater proportion of NR2B in the cultured neurons. However, the potency of ethanol to inhibit NMDA receptor function was lower when there was a greater proportion of NR2B subunits. Previous studies showed that ethanol inhibition of NMDA receptor function in cerebellar granule neurons resulted from an ethanol-induced decrease in potency of the co-agonist, glycine, and that this effect of ethanol was blocked by inhibitors of protein kinase C. Our current results suggest that the lower potency of ethanol to inhibit the response of NMDA receptors when cerebellar granule neurons are expressing a greater proportion of NR2B subunits is a result of the higher affinity of the NMDA receptors for endogenous levels of glycine at this point in time.

Animals↗

Role of protein kinase C in ethanol-induced activation of adenylyl cyclase.

Ethanol is known to enhance the activity of adenylyl cyclase (AC) in a number of cells and tissues. Recent work has suggested that the various isoforms of AC show differential sensitivity to ethanol, with Type VII AC being most sensitive. However, the mechanism of action of ethanol is unclear. In the present work, we investigated the effect of ethanol on AC activity in the human erythroleukemia (HEL) cell line, platelets, and AC VII-transfected HEK 293 cells. The HEL cells contain abundant amounts of mRNA for Type VII AC. We found that both ethanol and phorbol dibutyrate (PDBu) treatment enhanced agonist (prostaglandin E1; PGE1)-stimulated AC activity in HEL cells, as well as in platelets and HEK 293 cells transfected with AC VII. Inhibitors of protein kinase C (PKC) blocked the stimulatory effects of both ethanol and PDBu. However, the effects of ethanol and PDBu on AC activity were additive, suggesting that the mechanisms of action of ethanol and PDBu were not identical. Furthermore, a 30-min exposure of HEL cells to ethanol attenuated (desensitized) the ability of ethanol, but not PDBu, to enhance agonist-activated AC activity. On the other hand, a 30-min pretreatment with PDBu attenuated the AC response to the phorbol ester, but not to ethanol; but, after a 20 hr preincubation with phorbol ester, the ability of both PDBu and ethanol to enhance prostaglandin E1-stimulated AC activity was completely eliminated. Finally, pretreatment of HEL cells with pertussis toxin blocked the effect of PDBu, but not ethanol, on AC activity. The results support the involvement of phorbol ester-sensitive PKC(s) in ethanol's enhancement of agonist-activated activity of AC in HEL cells, but suggest that the mechanism of ethanol's action is different from that of PDBu. The findings with pertussis toxin suggest that PDBu activation of PKC(s) may affect AC activity through phosphorylation of a G1 protein, whereas ethanol may act by promoting phosphorylation of a different substrate (e.g., AC VII).

Adenylate Cyclase Toxin↗

Immunological assessment of the distribution of type VII adenylyl cyclase in brain.

The localization of the nine identified isoforms of adenylyl cyclase in brain has been largely based on determination of patterns of mRNA expression. A polyclonal antibody has now been developed that specifically recognizes Type VII adenylyl cyclase. This antibody was used for immunocytochemical analysis of the distribution of Type VII adenylyl cyclase in rat brain. Labeling of Type VII adenylyl cyclase was observed in several areas, including cerebellum, caudate-putamen, nucleus accumbens, hippocampus and cerebral cortex. In some of these areas, the staining of the adenylyl cyclase protein suggested the possibility of presynaptic localization. For example, in situ hybridization showed Type VII adenylyl cyclase mRNA concentrated in cerebellar granule neurons. The cerebellar granule cell layer, however, showed little immunostaining, while punctate immunostaining was observed in the molecular layer. These results suggested that protein synthesized in the granule neurons may be targeted to the neuron terminals. Punctate staining in the caudate-putamen, globus pallidus and nucleus accumbens also suggested the possibility of axonal and/or dendritic localization of Type VII adenylyl cyclase in these regions. Labeling of the soma of cerebellar Purkinje cells, cortical pyramidal and non-pyramidal cells and interneurons in the cerebellum and hippocampus was also observed. Type VII adenylyl cyclase, like the other adenylyl cyclase isoforms, has distinct regulatory characteristics, including sensitivity to stimulation by Gsalpha and G protein betagamma subunits, modulation by protein kinase C, and high sensitivity to stimulation by ethanol. These characteristics, and the discrete localization of this enzyme, may contribute to its ability to provide signal integration and/or control of neurotransmitter release in particular neurons or brain areas.

Adenylyl Cyclases↗

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↗

Ethanol promotes apoptosis in cerebellar granule cells by inhibiting the trophic effect of NMDA.

When primary cultures of cerebellar granule neurons are grown in a physiological concentration of KCl (5 mM) they undergo apoptosis, which can be prevented by growing the cells in the presence of N-methyl-D-aspartate (NMDA). We now show that ethanol inhibits this trophic effect of NMDA, i.e., promotes apoptosis, and also inhibits the NMDA-induced increase in intracellular Ca2+ concentration in cells grown in 5 mM KCl. Both effects of ethanol show a similar concentration dependence and are reversed by a high concentration of glycine, the co-agonist at the NMDA receptor. The data suggest that the effect of ethanol on apoptosis is mediated, at least in part, by inhibition of NMDA receptor function. This effect of ethanol to increase apoptosis could contribute to the previously described in vivo sensitivity of the developing cerebellum to ethanol-induced damage.

Animals↗

Antisense oligonucleotide to c-fos blocks the ability of arginine vasopressin to maintain ethanol tolerance.

Administration of the neuropeptide, arginine vasopressin, can reduce the rate of dissipation of functional ethanol tolerance in mice that have acquired that tolerance. We previously showed that intracerebroventricular vasopressin administration can also produce an increase in septal c-fos mRNA levels. To evaluate the role of the increased expression of c-fos in the ability of vasopressin to maintain tolerance, ethanol-tolerant mice were given intracerebroventricular injections of vasopressin in the presence or absence of an antisense oligonucleotide to c-fos. The antisense oligonucleotide completely blocked the ability of vasopressin to maintain ethanol tolerance, while a missense oligonucleotide was without effect. The antisense oligonucleotide also attenuated the increase in septal c-fos mRNA levels caused by vasopressin. The results provide evidence for a role of c-fos expression in the maintenance of ethanol tolerance by vasopressin.

Analysis of Variance↗

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↗