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PubMed2005

Thermodynamically based profiling of drug metabolism and drug-drug metabolic interactions: a case study of acetaminophen and ethanol toxic interaction.

Drug-drug metabolic interactions can result in unwanted side effects, including reduced drug efficacy and formation of toxic metabolic intermediates. In this work, thermodynamic constraints on non-equilibrium metabolite concentrations are used to reveal the biochemical interactions between the metabolic pathways of ethanol and acetaminophen (N-acetyl-p-aminophenol), two drugs known to interact unfavorably. It is known that many reactions of these pathways are coupled to the central energy metabolic reactions through a number of metabolites and the cellular redox potential. Based on these observations, a metabolic network model has been constructed and a database of thermodynamic properties for all participating metabolites and reactions has been compiled. Constraint-based computational analysis of the feasible metabolite concentrations reveals that the non-toxic pathways for APAP metabolism and the pathway for detoxifying N-acetyl-p-benzoquinoneimine (NAPQI) are inhibited by network interactions with ethanol metabolism. These results point to the potential utility of thermodynamically based profiling of metabolic network interactions in screening of drug candidates and analysis of potential toxicity.

Acetaminophen↗
PubMed1992

Fluorescence assay of glucosylceramide glucosidase using NBD-cerebroside.

A sensitive fluorometric assay for glucocerebroside beta-glucosidase [Dinur, T., Grabowski, G.A., Desnick, R.J., and Gatt, S. (1984) Anal. Biochem. 136, 223-234] has been reexamined. It was found that the lipids containing the NBD moiety (12-[N-methyl-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)] used for standardization of the assay are light-sensitive and that the yield of fluorescent light is very sensitive to the composition of the solvent used in the fluorometric measurement. Some protection against fading could be obtained by adding a free-radical trapping agent, SlowFade. The fading of the free NBD-acid, when used for standardization, could be prevented by adding ethanol to the solvent, but this reduced the fluorescence yield. It is recommended that some of the fluorescent substrate be enzymatically hydrolyzed completely to NBD-ceramide, which can be utilized as the standard without the need to add ethanol. A warning about enzyme reaction rate stability with time is given, with a suggestion for ensuring constancy of activity.

4-Chloro-7-nitrobenzofurazan↗
PubMed1986

Characterization of rat testicular alcohol dehydrogenase.

A protein from rat testes that catalyzes the oxidation of ethanol in the presence of NAD+, but not NADP+, has been characterized enzymatically and compared to that of hepatic alcohol dehydrogenase obtained from the same animals. The testicular enzyme, like the hepatic enzyme, has a Km value for ethanol in the 0.5-1.0-mM range and can utilize other alcohols such as n-propanol, n-butanol, and isobutanol, although the Km values for these other alcohols are considerably lower (0.03-0.08 mM) that that for ethanol. The testicular enzyme is more heat-labile than is the hepatic enzyme. Finally, the testicular enzyme catalyzes the oxidation of retinol and its retinol dehydrogenase activity is inhibited by ethanol.

Alcohol Dehydrogenase↗
PubMed2002

Place conditioning: what does it add to our understanding of ethanol reward?

This article describes the proceedings of a symposium at the 2001 RSA annual meeting in Montreal, Quebec, Canada. The cochairs were Fred O. Risinger and Christopher L. Cunningham. Presentations were as follows: (1) Place conditioning: understanding the motivational impact of stimuli, by Rick A. Bevins; (2) Role of historical factors in ethanol place conditioning, by Frank A. Holloway; (3) Ethanol place conditioning in mice: genetic and environmental influences, by Christopher L. Cunningham; and (4) Utilization of place conditioning for understanding the neuropharmacology of the rewarding effects of ethanol, by Fred O. Risinger.

Animals↗
PubMed1987

Gluconeogenesis from serine in rabbit hepatocytes.

L-Serine alone is not gluconeogenic in isolated rabbit hepatocytes, whereas in rat liver this amino acid has been reported to yield as much glucose as does L-lactate itself. The current study has been an investigation into the explanation of the difference between the two species. Hepatocytes were isolated from 48-h-starved, 750- to 1000-g male rabbits, and the viability of each preparation was judged by ATP levels (2.4 +/- 0.2 mumol/g wet wt) at the beginning and end of the incubation as well as gluconeogenesis from 10 mM L-lactate (0.83 +/- 0.08 mumol/min/g wet wt). L-Serine alone produced virtually no glucose or pyruvate accumulation above baseline. Hydroxypyruvate, however, did appear in the incubation mixture. When L-serine and pyruvate were combined to test the functional activity of L-serine:pyruvate aminotransferase (EC 2.6.1.51), however, gluconeogenesis remained at the rate produced by pyruvate alone (0.61 +/- 0.04 mumol/min/g wet wt). On the other hand, the combination of L-serine and L-lactate produced rates of glucose accumulation 35% above that of L-lactate alone. The combination of L-lactate plus hydroxypyruvate produced nearly maximal rates (1.39 +/- 0.08 mumol/min/g wet wt), approaching those achieved by a physiologic ratio (10:1) of L-lactate and pyruvate. Hydroxypyruvate itself was only moderately gluconeogenic (0.44 +/- 0.04 mumol/min/g wet wt). That a reduction of the cytoplasmic free [NAD+]/[NADH] ratio by L-lactate was not its only contribution to L-serine utilization was suggested by the fact that ethanol completely eliminated gluconeogenesis from virtually all precursors (or combinations) tested, with the exception of hydroxypyruvate. It has been concluded from the data that, probably in contrast to the rat, the major pathway for the entrance of L-serine into gluconeogenesis in rabbit hepatocytes is through the pathway initiated by L-serine: pyruvate aminotransferase and that L-lactate is an important participant (i) by generating cytoplasmic reducing equivalents (NADH), (ii) by supplying pyruvate for the transaminating reaction itself, and, perhaps, (iii) by preventing hydroxypyruvate from being reduced by L-lactate dehydrogenase (EC 1.1.1.27) to L-glycerate.

Animals↗
PubMed2026

Comparative profiling of microbial community structure, enzyme potential, metabolic features, and volatile composition in craft and Jiafan Huangjiu processes.

Craft Huangjiu and Jiafan Huangjiu represent two distinct industrial Huangjiu product outcomes with contrasting volatile profiles. This study compared craft Huangjiu (L70) and Jiafan Huangjiu (L79) to characterize their physicochemical, microbial, gene-level functional, metabolic, and volatile features. Because L70 involved mid-fermentation addition of finished Huangjiu, this comparison was not intended to isolate the sole effect of fermentation interruption versus continued fermentation. L79 showed more extensive carbon and nitrogen utilization, with lower residual substrates and higher ethanol and acetic acid contents than L70, whereas L70 retained a less complete fermentation state. At the volatile level, GC-MS and volatile metabolomics consistently showed an ester-enriched profile in L79 and a more alcohol-dominant profile in L70. FlavorDB-based putative annotation and threshold-based OAV analysis further indicated distinct database-assigned descriptor distributions and potential odor-active compounds, with more OAV > 1 ester-related compounds in L79. Metagenomic analysis showed that L70 was dominated by Lactobacillus acetotolerans, whereas L79 contained higher relative abundances of Saccharomyces cerevisiae, Aspergillus oryzae, Aspergillus flavus, and Fructilactobacillus fructivorans. Metagenomic functional annotation showed higher representation of hydrolysis-related CAZy genes and ester-related enzyme annotations in L79. KEGG-based pathway mapping further indicated greater gene-level potential for ethanol-, acetate-, and acetyl-CoA-related metabolism in L79. Accordingly, the L70 profile should be interpreted as the integrated final-product outcome of process intervention, exogenous input, and subsequent fermentation. The findings provide a comparative basis for future flavor regulation and process optimization in Huangjiu and other fermented alcoholic beverages.

Volatile Organic Compounds↗
PubMed1975

Enzymes regulating glycogen metabolism in swine subcutaneous adipose tissue. II. Glycogen synthase.

Glycogen synthase from swine adipose tissue was purified to apparent homogeneity using ethanol precipitation, DEAE chromatography, and affinity chromatography utilizing glucosamine 6-phosphate as the ligand. The purified enzyme migrated as a single protein component during electrophoresis on polyacrylamide gels at pH 7.3 although some protein failed to enter the running gel. Enzyme incubated with sodium dodecyl sulfate (SDS) migrated as one component (mol wt similar to 90,000) on SDS-polyacrylamide gel electrophoresis. The enzyme was relatively unstable at all stages of the purification procedure, but stability was increased in the presence of glucose 6-phosphate, UDPG, or glycerol. The isoelectric point of the purified enzyme and of enzyme activity in crude homogenates was pH 4.8. The sedimentation coefficient of the enzyme in crude homogenates was 8.5 S. The pH-activity profile showed an optimum at pH 7.8 in the absence of glucose 6-phosphate but no definable optimum between pH 7.0 and 9.2 in its presence. The Km of glycogen synthase I for UDPG was 250 muM in the absence and 37 muM in the presence of glucose 6-phosphate; the K-a for glucose 6-phosphate was 18 mu-M. The K-m of glycogen synthase D for UDPG was 130 mu-M in the presence of glucose 6-phosphate; the Ka for glucose 6-phosphate was 1 mM. The anions sulfate and phosphate activated the enzyme when assays were performed in the absence of glucose 6-phosphate. Fluoride produced activation of enzyme assayed either in the presence or in the absence of glucose 6-phosphate.

Adipose Tissue↗
PubMed1971

Microbial oxidation of amines. Partial purification of a mixed-function secondary-amine oxidase system from Pseudomonas aminovorans that contains an enzymically active cytochrome-P-420-type haemoprotein.

1. Crude extracts of Pseudomonas aminovorans grown on methylamine, di-methylamine, trimethylamine or trimethylamine N-oxide contain an enzyme or enzyme system catalysing the NADH- or NADPH- and oxygen-dependent oxidation of dimethylamine to methylamine and formaldehyde. 2. The enzyme has been partially purified about five-fold. It is unstable, but can be stabilized by addition of 5% (v/v) ethanol. 3. The partially purified enzyme will utilize either NADH (K(m) 6.5mum) or NADPH (K(m) 13.2mum): The following secondary amines have been shown to be substrates: dimethylamine, ethylmethylamine, diethylamine, methyl-n-propylamine, ethyl-n-propylamine, n-butylmethylamine and N-methylethanolamine. The K(m) values and comparative reaction rates for each substrate have been determined. Where the alkyl groups are different, the aldehyde products are derived from both groups. 4. The enzyme system has a pH optimum of 6.8 and is inhibited by mercurials, thiol compounds, cyanide and carbon monoxide. 5. The partially purified preparation had a spectral maximum at 412nm with shoulders at 427 and 550nm. Reduction with dithionite or NAD(P)H bleached the 412nm peak, and the shoulder at 427nm became a peak. Additional peaks appeared at 550 and 580-588nm. Reduction of a preparation bubbled with carbon monoxide enhanced and sharpened the Soret peak and caused it to shift to 422nm. 6. Analysis of the preparation showed the presence of flavin, acid-extractable iron and non-acid-extractable iron in the proportion 1.1:1.9:1. On reduction with dithionite or NADPH the preparation showed an electron-paramagnetic-resonance signal at around g=1.946.

Amines↗
PubMed1996

Desulfovibrio gabonensis sp. nov., a new moderately halophilic sulfate-reducing bacterium isolated from an oil pipeline.

Two moderately halophilic sulfate-reducing bacteria were isolated from an African oil pipeline and designated strains SEBR 3640 and SEBR 2840T (T = type strain). Both of these strains possess traits that define the genus Desulfovibrio. The cells of both isolates were motile curved rods that had a single polar flagellum and contained desulfoviridin, and both isolates utilized lactate, pyruvate, malate, fumarate, succinate, and ethanol in the presence of sulfate. Sulfite, thiosulfate, and elemental sulfur were also used as an electron acceptors in the presence of lactate. However, both strains tolerated higher concentrations of NaCl (up to 17%) than all other Desulfovibrio species except Desulfovibrio halophilus, which tolerated a similar level of NaCl. The results of a 16S rRNA gene sequence analysis also placed the designated type strain, strain SEBR 2840, in the genus Desulfovibrio but revealed that this organism was significantly different from D. halophilus and all other validly described Desulfovibrio species. On the basis of our results, we propose that strain SEBR 2840T is a member of a new species of the genus Desulfovibrio, Desulfovibrio gabonensis. The type strain of D. gabonensis is strain SEBR 2840 (= DSM 10636).

Base Sequence↗
PubMed2004

Gastroprotective effect and mechanism of amtolmetin guacyl in mice.

AIM: To investigate the gastroprotective effect and mechanism of amtolmetin guacyl (AMG, MED15) in mice. METHODS: Male and female Kunming strain mice, weighing 18-22 g, were utilized in the experiment. Normal or ethanol-induced gastric mucosal damage models in mice were successfully established to investigate the gastroprotective effect and mechanism of AMG. In the experiment of gastric mucosal damage after repeated treatment with AMG, the mice were randomly divided into 5 groups: normal group, 3 AMG groups receiving (75, 150 and 300 mg/kg), and tolmetin group receiving 90 mg/kg. The mice were randomly divided into 6 groups as follows: normal group, model group, AMG groups with doses of 75, 150 and 300 mg/kg, respectively, and tolmetin group with a dose of 90 mg/kg in ethanol-induced gastric mucosal damage experiment. The severity of gastric mucosal lesions was scored from 0 to 5. Gastric tissue sections were stained with hematoxylin and eosin (HE) and examined under light microscopy. Also gastric tissue sections were stained with uranyl acetate and lead citrate, and examined under electron microscopy. In addition, nitric oxide (NO) and malondialdehyde (MDA) contents, and nitric oxide synthase (NOS) and superoxide dismutase (SOD) activities in the stomach tissue homogenates were measured by biochemical methods. RESULTS: Repeated treatment with AMG (75, 150 and 300 mg/kg) for 7 d did not induce any appreciable mucosal damage, and the average score was not significantly different from that of normal mice. In contrast, tolmetin (90 mg/kg) produced significant gastric mucosal lesions compared with the normal group (P<0.01). AMG (75, 150 and 300 mg/kg) significantly reduced the severity of gastric lesions induced by ethanol in a dose-dependent manner as compared with the model group (P<0.05, AMG 75 and 150 mg/kg vs model; P<0.01, AMG 300 mg/kg vs model). Light and electron microscopy revealed that AMG (150 and 300 mg/kg) induced minimal changes in the surface epithelium layer, without vascular congestion or leucocyte adherence. AMG (75,150 and 300 mg/kg) demonstrated dose-dependent gastroprotective effects on mice in our study. AMG (75, 150 and 300 mg/kg) could significantly increase NO content and NOS level in the stomach homogenates of mice compared with the model group (P<0.05, AMG 75 mg/kg and 150 mg/kg groups vs model group; P<0.01, AMG 300 mg/kg vs model group) respectively. Moreover, AMG (150 and 300 mg/kg) not only significantly increased SOD activities but also obviously decreased the MDA content in the stomach homogenates of mice.

Animals↗
PubMed2003

Bacteria engineered for fuel ethanol production: current status.

The lack of industrially suitable microorganisms for converting biomass into fuel ethanol has traditionally been cited as a major technical roadblock to developing a bioethanol industry. In the last two decades, numerous microorganisms have been engineered to selectively produce ethanol. Lignocellulosic biomass contains complex carbohydrates that necessitate utilizing microorganisms capable of fermenting sugars not fermentable by brewers' yeast. The most significant of these is xylose. The greatest successes have been in the engineering of Gram-negative bacteria: Escherichia coli, Klebsiella oxytoca, and Zymomonas mobilis. E. coli and K. oxytoca are naturally able to use a wide spectrum of sugars, and work has concentrated on engineering these strains to selectively produce ethanol. Z. mobilis produces ethanol at high yields, but ferments only glucose and fructose. Work on this organism has concentrated on introducing pathways for the fermentation of arabinose and xylose. The history of constructing these strains and current progress in refining them are detailed in this review.

Bacteria↗
PubMed2006

Growth inhibition by nitrocompounds of selected uric acid-utilizing microorganisms isolated from poultry manure.

The overall objective of this study was to evaluate the potential ability of nitrocompounds to reduce ammonia volatilization by inhibiting uric acid-utilizing microorganisms. Experiment I was conducted to evaluate the effects of nitrocompounds on the growth of uric acid-utilizing microorganisms isolated from poultry manure during six-hour incubation. There were five treatments: (1) control, (2) 50 mM nitroethane, (3) 50 mM nitroethanol, (4) 50 mM nitropropanol, and (5) 50 mM nitropropionic acid. Optical density values of nitrocompounds were significantly lower than that of control at two, four, and six hours. Plate counts of uric acid-utilizing microorganisms after six-hour incubation exhibited that nitrocompounds greatly reduced the growth of these microorganisms except for the nitroethane (P < 0.05). The nitropropanol and nitropropionic acid treatments showed significantly higher inhibitory effects compared to the nitroethanol. Experiments II and III were conducted to evaluate inhibitory effects of nitrocompounds on growth of uric acid-utilizing microorganisms compared to non-nitrocompounds such as ethanol, propanol, and propionic acid. Experiments II and III consisted of seven treatments: (1) control, (2) nitroethanol, (3) nitropropanol, (4) nitropropionic acid, (5) ethanol, (6) propanol, and (7) propionic acid. The incubation times of Experiments II and III were 6 and 24 h, respectively. The nitrocompounds were significantly more successful in inhibiting growth of uric acid-utilizing microorganisms compared to those non-nitrocompounds. These results suggest that nitrocompounds exhibit potential to reduce ammonia volatilization in poultry manure by inhibiting growth of uric acid-utilizing microorganisms.

Air Pollutants↗
PubMed2000

Application of a physiologically based pharmacokinetic model to estimate the bioavailability of ethanol in male rats: distinction between gastric and hepatic pathways of metabolic clearance.

A portion of ingested ethanol does not reach the systemic circulation in both rats and humans as indicated by higher blood ethanol concentrations following an intravenous administration compared to an equivalent oral administration. The mechanism for this decrease in the oral bioavailability is not yet completely understood. Metabolism by gastric or hepatic alcohol dehydrogenase (ADH), or both, has been implicated. However, the extent to which each pathway of elimination contributes to the first-pass clearance is not known. The purpose of this study was to utilize a physiologically based pharmacokinetic (PBPK) model for ethanol to estimate the relative contributions of hepatic and gastric metabolic clearance to the oral bioavailability of ethanol in male rats. In the current model, calculations of hepatic-first pass metabolic clearance accounted for the competition for metabolism between incoming ethanol from the GI tract and recirculating ethanol. This differs from previous methods that quantified the effect of ethanol entering the liver from the GI tract on the overall rate of metabolism of ethanol by the liver. These models did not specifically describe the effect of recirculating ethanol on the first-pass metabolism of ethanol, and vice versa. The dependence of bioavailability on dose and absorption rate was also investigated. The use of a PBPK model for ethanol in rats allows a more detailed examination of physiological and biochemical factors affecting the bioavailability of ethanol than has previously been possible. The analysis indicates that both gastric and hepatic first-pass metabolism of ethanol contribute to ethanol bioavailability in male rats.

Administration, Oral↗
PubMed2001

Clostridium beijerinckii cells expressing Neocallimastix patriciarum glycoside hydrolases show enhanced lichenan utilization and solvent production.

Growth and the production of acetone, butanol, and ethanol by Clostridium beijerinckii NCIMB 8052 on several polysaccharides and sugars were analyzed. On crystalline cellulose, growth and solvent production were observed only when a mixture of fungal cellulases was added to the medium. On lichenan growth and solvent production occurred, but this polymer was only partially utilized. To increase utilization of these polymers and subsequent solvent production, the genes for two new glycoside hydrolases, celA and celD from the fungus Neocallimastix patriciarum, were cloned separately into C. beijerinckii. To do this, a secretion vector based on the pMTL500E shuttle vector and containing the promoter and signal sequence coding region of the Clostridium saccharobutylicum NCP262 eglA gene was constructed and fused either to the celA gene or the celD gene. Stable C. beijerinckii transformants were obtained with the resulting plasmids, pWUR3 (celA) and pWUR4 (celD). The recombinant strains showed clear halos on agar plates containing carboxymethyl cellulose upon staining with Congo red. In addition, their culture supernatants had significant endoglucanase activities (123 U/mg of protein for transformants harboring celA and 78 U/mg of protein for transformants harboring celD). Although C. beijerinckii harboring either celA or celD was not able to grow, separately or in mixed culture, on carboxymethyl cellulose or microcrystalline cellulose, both transformants showed a significant increase in solvent production during growth on lichenan and more extensive degradation of this polymer than that exhibited by the wild-type strain.

Amino Acid Sequence↗
PubMedDate not supplied

Stereotypic wall climbing in mice during ethanol withdrawal: a new measure of physical dependence.

A new potentially useful measure for assessing physical dependence in mice chronically exposed to ethanol is described. C3H/He mice continuously exposed to ethanol vapor for four (Experiment 1) or three (Experiment 2) days spent more time engaged in stereotypic climbing behavior than controls. This stereotypic climbing behavior correlated well, both temporally as well as in intensity, with other previously described signs of ethanol withdrawal. All measures of withdrawal behavior (including climbing) peaked at eight hours after withdrawal and returned to control levels by 30-33 hours. The utility of this behavioral assay for assessing physical dependence on ethanol is further discussed with reference to possible underlying neurochemical events.

Alcoholism↗
PubMed2004

Ethanol formation in unadulterated postmortem tissues.

During the investigation of aviation accidents, postmortem samples obtained from fatal accident victims are submitted to the FAA's Civil Aerospace Medical Institute (CAMI) for toxicological analysis. During toxicological evaluations, ethanol analysis is performed on all cases. Many species of bacteria, yeast, and fungi have the ability to produce ethanol and other volatile organic compounds in postmortem specimens. The potential for postmortem ethanol formation complicates the interpretation of ethanol-positive results from accident victims. Therefore, the prevention of ethanol formation at all steps following specimen collection is a priority. Sodium fluoride is the most commonly used preservative for postmortem specimens. Several studies have been published detailing the effectiveness of sodium fluoride for the prevention of ethanol formation in blood and urine specimens; however, our laboratory receives blood or urine in approximately 70% of cases. Thus, we frequently rely on tissue specimens for ethanol analysis. The postmortem tissue specimens received by our laboratory have generally been subjected to severe trauma and may have been exposed to numerous microbial species capable of ethanol production. With this in mind, we designed an experiment utilizing unadulterated tissue specimens obtained from aviation accident victims to determine the effectiveness of sodium fluoride at various storage temperatures for the prevention of microbial ethanol formation. We found that without preservative, specimens stored at 4 degrees C for 96 h showed an increase in ethanol concentration ranging from 22 to 75 mg/hg (average 42 +/- 15 mg/hg). At 25 degrees C, these same specimens showed an increase ranging from 19 to 84 mg/hg (average 45 +/- 22 mg/hg). With the addition of 1.00% sodium fluoride, there was no significant increase in ethanol concentration at either temperature.

Accidents, Aviation↗
PubMed2004

Effect of 5-HT3 receptor over-expression on the discriminative stimulus effects of ethanol.

BACKGROUND: Drug discrimination studies using selective antagonists and agonists have suggested that 5-HT3 receptors may modulate ethanol's discriminative stimulus effects. However, conflicting data between laboratories leaves the issue of 5-HT3 receptor involvement in ethanol's discriminative stimulus effects in question. The present study utilized transgenic mice that over-express 5-HT3 receptors in conjunction with traditional pharmacological techniques to examine the contribution of 5-HT3 receptors to ethanol's discriminative stimulus. METHODS: Ten 5-HT3 over-expressing (5-HT3 OE) and 18 B6SJL wild-type (WT) mice were trained to discriminate 1.5 g/kg ethanol from saline in daily 15 min, milk reinforced operant sessions. After training, ethanol substitution and response-rate suppression dose response curves were determined for ethanol, midazolam, dizocilpine, cocaine, mCPP, MD-354, YC-30 and MDL-72222. Antagonism tests combining ethanol with MDL-72222 and ondansetron were also conducted. RESULTS: The 5-HT3 OE and WT mice learned the ethanol discrimination in a comparable number of training sessions. Similar patterns of substitution were generated in both groups of mice for most test drugs. 5-HT3 OE mice were more sensitive to the rate suppressing effects of dizocilpine and MDL-72222 than were WT mice. Neither of the 5-HT3 antagonist tested significantly attenuated ethanol's discriminative stimulus effects in either 5-HT3 OE or WT mice. CONCLUSIONS: The results of the present study are consistent with a minimal role of 5-HT3 receptors in transducing ethanol's discriminative stimulus effects. Over-expression of 5-HT3 receptors does not alter the relative efficacy of GABAA positive modulators or NMDA antagonists for producing ethanol-like discriminative stimulus effects. However, 5-HT3 receptor over-expression does appear to modulate the response-rate altering effects of the uncompetitive NMDA antagonist, dizocilpine, and the 5-HT3 antagonist, MDL-72222.

Animals↗
PubMed2004

Rapid and chronic: two distinct forms of ethanol tolerance in Drosophila.

BACKGROUND: Ethanol tolerance, defined as a reduction in the intensity of the effects of ethanol upon continuous or repeated exposure, is a hallmark of alcoholism. Tolerance may develop at the cellular or neural systems levels. The molecular changes underlying ethanol tolerance are not well understood. We therefore explored the utility of Drosophila, with its accessibility to genetic, molecular, and behavioral analyses, as a model organism to study tolerance development in response to different ethanol-exposure regimens. METHODS: We describe a new assay that quantifies recovery from ethanol intoxication in Drosophila. Using this recovery assay, we define ethanol pre-exposure paradigms that lead to the development of tolerance. We also use the inebriometer, an assay that measures the onset of intoxication, to study the effects of pharmacological and genetic manipulations on tolerance development. RESULTS: We show that flies develop different forms of ethanol tolerance: rapid tolerance, induced by a single short exposure to a high concentration of ethanol, and chronic tolerance, elicited by prolonged exposure to a low concentration of the drug. Neither rapid nor chronic tolerance involves changes in ethanol pharmacokinetics, implying that they represent functional rather than dispositional tolerance. Chronic and rapid tolerance can be distinguished mechanistically: chronic tolerance is disrupted by treatment with the protein synthesis inhibitor cycloheximide, whereas rapid tolerance is resistant to this treatment. Furthermore, rapid and chronic tolerance rely on distinct genetic pathways: a mutant defective for octopamine biosynthesis shows reduced rapid tolerance but normal chronic tolerance. CONCLUSIONS: Flies, like mammals, develop tolerance in response to different ethanol-exposure regimens, and this tolerance affects both the onset of and the recovery from acute intoxication. Two forms of tolerance, rapid and chronic, are mechanistically distinct, because they can be dissociated genetically and pharmacologically.

Animals↗