Effects Of Acute Intoxication Research Articles

Effects of topiramate and other anti-glutamatergic drugs on the acute intoxicating actions of ethanol in mice: modulation by genetic strain and stress.

Compounds with anti-glutamatergic properties currently in clinical use for various indications (e.g., Alzheimer's disease, epilepsy, psychosis, mood disorders) have potential utility as novel treatments for alcoholism. Enhanced sensitivity to certain acute intoxicating effects (ataxia, sedative) of alcohol may be one mechanism by which anti-glutamatergic drugs modulate alcohol use. We examined the effects of six compounds (memantine, dextromethorphan, haloperidol, lamotrigine, oxcarbazepine, topiramate) on sensitivity to acute intoxicating effects of ethanol (ataxia, hypothermia, sedation/hypnosis) in C57BL/6J mice. Analysis of topiramate was extended to determine the influence of genetic background (via comparison of the 129S1, BALB/cJ, C57BL/6J, DBA/2J inbred strains) and prior stress history (via chronic exposure of C57BL/6J to swim stress) on topiramate's effects on ethanol-induced sedation/hypnosis. Results showed that one N-methyl-D-aspartate receptor (NMDAR) antagonist, memantine, but not another, dextromethorphan, potentiated the ataxic but not hypothermic or sedative/hypnotic effects of ethanol. Haloperidol increased ethanol-induced ataxia and sedation/hypnosis to a similar extent as the prototypical NMDAR antagonist MK-801. Of the anticonvulsants tested, lamotrigine accentuated ethanol-induced sedation/hypnosis, while oxcarbazepine was without effect. Topiramate was without effect per se under baseline conditions in C57BL/6J, but had a synergistic effect with MK-801 on ethanol-induced sedation/hypnosis. Comparing inbred strains, topiramate was found to significantly potentiated ethanol's sedative/hypnotic effects in BALB/cJ, but not 129S1, C57BL/6J or DBA/2J strains. Topiramate also increased ethanol-induced sedation/hypnosis in C57BL/6J after exposure to chronic stress exposure. Current data demonstrate that, with the exception of MK-801 and haloperidol, the compounds tested had either no significant or assay-selective effects on sensitivity to acute ethanol under baseline conditions in C57BL/6J. However, significant effects of topiramate were revealed as a function of co-treatment with a NMDAR blocker, genetic background or prior stress history. These findings raise the possibility that topiramate and possibly other anti-glutamatergic drugs could promote the acute intoxicating effects of ethanol in specific subpopulations defined by genetics or life history.

Cholinesterase‐Inhibiting and Genotoxic Effects of Acute Carbofuran Intoxication in Man: A Case Report

Carbofuran belongs to the group of N-methylcarbamate insecticides used for the control of soil-dwelling and foliar-feeding insects in various crops; its consumption totals approximately 20,000 tonnes per year. Although the neurological effects on human beings have been well documented, little is known on its impact on the genome. A 38-year-old, healthy male worker employed in a carbofuran production facility accidentally inhaled the dust of the active ingredient carbofuran. Thirty minutes later, he experienced weakness, fatigue, perspiration, breathing difficulties, cephalalgia, disorientation, abdominal pain and vomiting. Blood samples were taken to measure cholinesterase activity, and to perform the alkaline comet assay and micronucleus assay combined with pancentromeric probes. Analyses were repeated 72 hr after intoxication and compared with the results obtained from regular monitoring conducted 10 days prior to the accident. Cholinesterase activity showed the highest correlation with the number of apoptotic cells, comet assay tail length, and number of long-tailed nuclei, suggesting that these are the genomic end-points primarily affected by carbofuran intake. Only a weak correlation was detected for the total number of micronuclei, centromere-containing micronuclei and nuclear buds. Since those end-points increased significantly 72 hr after the accident, they could be considered as late biomarkers of the effects of carbofuran intoxication. The results of this report suggest that, in the interests of higher standards in risk assessment and health hazard protection, periodical medical examination of carbamate-exposed populations should include genotoxicity testing in addition to the assessment of cholinesterase activity.

Indirect Effects of Acute Alcohol Intoxication on Sexual Risk-taking: The Roles of Subjective and Physiological Sexual Arousal

Three experiments supported the idea that alcohol fosters sexual risk-taking in men and women, in part, through its effects on sexual arousal. In Experiment 1, increasing alcohol dosage (target blood alcohol levels of .00, .04, .08%) heightened men's and women's risk-taking intentions. Alcohol's effect was indirect via increased subjective sexual arousal; also, men exhibited greater risk-taking than women. In Experiment 2, an extended dosage range (target blood alcohol levels of .00, .06, .08, .10%) heightened men's risk-taking intentions. Alcohol's effect again was indirect via subjective arousal. Physiological sexual arousal, which was unaffected by alcohol, increased risk-taking via increased subjective arousal. In Experiment 3, alcohol increased women's risk-taking indirectly via subjective arousal, but alcohol-attenuated physiological arousal had no effect on risk-taking. Implications for alcohol myopia theory and prevention interventions are discussed.

Effect of acute lead intoxication on behavior in adult and young wistar rats

Effect of acute lead intoxication on behavior in adult and young wistar rats

Acute Alcohol Intoxication Increases REDD1 in Skeletal Muscle

The mechanism by which acute alcohol (EtOH) intoxication decreases basal muscle protein synthesis via inhibition of the Ser/Thr kinase mammalian target of rapamycin (mTOR) is poorly defined. In this regard, mTOR activity is impaired after over expression of the regulatory protein REDD1. Hence, the present study assessed the ability of REDD1 as a potential mediator of the EtOH-induced decrease in muscle protein synthesis. The effect of acute EtOH intoxication on REDD1 mRNA and protein was determined in striated muscle of rats and mouse myocytes using an RNase protection assay and Western blotting, respectively. Other components of the mTOR signaling pathway were also assessed by immunoblotting. For comparison, REDD1 mRNA/protein was also determined in the muscle of rats chronically fed an alcohol-containing diet for 14 weeks. Intraperitoneal (IP) injection of EtOH increased gastrocnemius REDD1 mRNA in a dose- and time-dependent manner, and these changes were associated with reciprocal decreases in the phosphorylation of 4E-BP1, which is a surrogate marker for mTOR activity and protein synthesis. No change in REDD1 mRNA was detected in the slow-twitch soleus muscle or heart. Acute EtOH produced comparable increases in muscle REDD1 protein. The EtOH-induced increase in gastrocnemius REDD1 was independent of the route of EtOH administration (oral vs. IP), the nutritional state (fed vs. fasted), gender, and age of the rat. The nonmetabolizable alcohol tert-butanol increased REDD1 and the EtOH-induced increase in REDD1 was not prevented by pretreatment with the alcohol dehydrogenase inhibitor 4-methylpyrazole. In contrast, REDD1 mRNA and protein were not increased in the isolated hindlimb perfused with EtOH or in C2C12 myocytes incubated with EtOH, under conditions previously reported to decrease protein synthesis. Pretreatment with the glucocorticoid receptor antagonist RU486 failed to prevent the EtOH-induced increase in REDD1. Finally, the EtOH-induced increase in REDD1 was not associated with altered formation of the TSC1*TSC2 complex or the phosphorylation of TSC2 which is down stream in the REDD1 stress response pathway. In contradistinction to the changes observed with acute EtOH intoxication, REDD1 mRNA/protein was not changed in gastrocnemius from chronic alcohol-fed rats despite the reduction in 4E-BP1 phosphorylation. These data indicate that in fast-twitch skeletal muscle (i) REDD1 mRNA/protein is increased in vivo by acute EtOH intoxication but not in response to chronic alcohol feeding, (ii) elevated REDD1 in response to acute EtOH appears due to the production of an unknown secondary mediator which is not corticosterone, and (iii) the EtOH-induced decrease in protein synthesis can be dissociated from a change in REDD1 suggesting that the induction of this protein is not responsible for the rapid decrease in protein synthesis after acute EtOH administration or for the development of alcoholic myopathy in rats fed an alcohol-containing diet.

The Effect of Acute Ethanol Intoxication on Salivary Proteins of Innate and Adaptive Immunity

Human salivary proteins: peroxidase, lysozyme, lactoferrin, and IgA, participate in the protection of oral tissues, as well as upper digestive and respiratory tracts, against a number of microbial pathogens. In the current study, we investigated the effect of acute consumption of a large dose of ethanol on representative human salivary proteins of the innate and adaptive immune systems. Eight healthy male volunteers drank an average of 2.0 g (1.4 to 2.5 g/kg) body weight of ethanol, in the form of vodka, in the 6-hour period. Samples of resting whole saliva were collected 12 hours before, then 36 and 108 hours after, the alcohol consumption. The levels of total protein, immunoglobulin A, lysozyme and lactoferrin as well as peroxidase activity were determined in saliva. At 36 hours after alcohol consumption, salivary protein and lysozyme concentrations as well as peroxidase activity were significantly decreased (p = 0.002, p = 0.043, and p = 0.003, respectively), in comparison to the values obtained at 12 hours before drinking. Between 36 and 108 hours after alcohol consumption, the salivary protein and lysozyme concentrations, as well as peroxidase activity showed a tendency to increase, although at 108 hours after the drinking session, the concentration of protein and peroxidase activity were still significantly lower than before drinking. There was no significant change in the level of lactoferrin, after the drinking session. The salivary concentration of IgA tended to increase at 36 hours after alcohol consumption, and at 108 hours it was significantly higher (p = 0.028), when compared to IgA concentration in the saliva collected before drinking (from 8% to 26% and 32% of total protein content, respectively). Our report is the first to show that acute ingestion of relatively large, yet tolerable dose of alcohol, significantly disturbs salivary antimicrobial defense system. Reduced lysozyme level and decreased peroxidase activity may contribute to increased susceptibility to infections, when acute alcohol intake coincides with exposure to pathogens.

Effect of acute lindane and alcohol intoxication on serum concentration of enzymes and fatty acids in rats

This study examines possible synergistic effects of lindane and ethanol on inducing liver injury and serum fatty acid derangement in adult male Wistar rats. When administered together, ethanol and lindane-induced even more pronounced increase of alanine aminotransferase (165±10U/L) and gamma-glutamyltranspeptidase activity (10.3±0.6U/L) than after isolated administration of either substance. In addition, separate administration of lindane and ethanol was followed by a significant decrease of linoleic acid level in the serum (301±38mg/L, 276±35mg/L vs. 416±48mg/L). However, when ethanol administration was followed by lindane injection, serum linoleic acid was at the similar level found in the control group (516±62mg/L). Ethanol-treated rats that received lindane 30min after ethanol administration have shown a marked increase of palmitic (421±27mg/L) and linolic acid level (43±5mg/L) in comparison with rats that have been treated only with ethanol (316±26mg/L for palmitic and 32±2mg/L for linolic acid) or lindane (295±26mg/L for palmitic and 301±38mg/L for linolic acid). Linolic acid level was significantly greater in comparison with control group (29±1mg/L). In conclusion, this study found enough evidence to support the hypothesis that acute ethanol intoxication potentiates lindane-induced liver injury and enhances lipid derangement.

Relation between lipid peroxidation and iron concentration in mouse liver after acute and subacute cadmium intoxication

In this study the effect of acute and subacute cadmium (Cd) intoxication on iron (Fe) concentration and lipid peroxidation (LPO) was investigated in the livers of Swiss mice. Animals were divided into two groups: the Cd group – mice intoxicated with Cd and controls. In acute time-response studies, Fe and malondialdehyde (MDA) levels were determined at 4, 6, 12, 24 and 48 h after a single oral dose of Cd (20 mg Cd/kg b.w.). In the subacute experiment, mice were given 10 mg Cd/kg b.w. orally every day for 14 days; Fe and MDA contents were determined in liver after 1 and 2 weeks. Acute Cd intoxication induced a significantly increased hepatic Fe content after 4 and 6 h, and a statistically significant increase in MDA 6, 12 and 24 h after Cd administration, although a significantly decreased MDA level was observed after 48 h. The results suggest development of early oxidative stress in livers of mice after acute intoxication with Cd. The decreased MDA observed after 48 h occurred presumably due to the adaptive response of the organism. Subacute Cd intoxication induced a significant decrease of hepatic Fe and MDA levels at both investigated time intervals compared with control. These results indicate a positive correlation between hepatic Fe and MDA content and suggest that prolonged Cd intoxication decreases hepatic LPO indirectly, by reducing the Fe content of mouse liver.

Intact Preference Conditioning in Acute Intoxication Despite Deficient Declarative Knowledge and Working Memory

The impact of alcohol on implicit, emotional learning is not well understood, partly because family history, drug use, and task demands influence these processes. The conditioned pattern preference (CPP) task provides a more ecologically valid means to investigate implicit cognition in the lab because it has low demand awareness and relies on learning to associate nonverbal cues with reward. This study examined the effects of acute alcohol intoxication on implicit learning using the CPP task in 83 intoxicated and 69 sober young adults. Information on individual drug use, family history, impulsivity, and alcohol expectancies was also collected. Alcohol intoxication affected explicit, but not implicit learning on the CPP task. In addition, participants who reported a positive family history of addiction (FH+) or individual recreational drug use did not exhibit a preference for cues previously paired with reward. Preference formation on the CPP task recruits motivational neurocircuitry, an effect that is unaltered by alcohol. Group differences in implicit emotional learning on this task may represent neurocognitive differences in individuals at risk for addiction.

Effects of acute alcohol intoxication in the second trimester of pregnancy on development of the murine fetal lung

We hypothesized that administration of alcohol during the second trimester of gestation at the pseudoglandular phase of lung development might lead to aberrant differentiation and growth, similar to that seen in congenital cystic adenomatoid malformation in human. We further hypothesized that these effects would be apparent morphologically and by altered Hoxb5 expression. C57BL/6J mice, exposed to ethanol at embryonic day (E) 11.5 to E13.5, which corresponds to the pseudoglandular stage of lung development, were examined at E18.5. The lungs were analyzed histologically by immunostaining. The average body and lung weight of alcohol-exposed (AE) fetuses were lower than those of control fetuses, the reduction in lung mass being more than the body weight. Histology showed that AE lungs were less developed and exhibited higher expression of Hoxb5 in AE lungs than controls. Alcohol exposure at E13.5 affected fetal lung development, with delayed differentiation and increased Hoxb5.

Acute Alcohol Intoxication Impairs Controlled Search Across the Visual Field

The objective of the two experiments reported was to examine the effects of acute alcohol intoxication and of alcohol expectancies on controlled search across the visual field. After receiving an oral dose of 0.5 g/kg alcohol (Experiment 1), an oral dose of 0.7 g/kg alcohol (Experiment 2), or a placebo, participants searched for a target in large arrays of homogeneous distractors that were either highly similar or less similar to the target. Targets were systematically placed at fixation and at visual angles of 2.5 degrees , 5.0 degrees , 7.5 degrees , and 10.0 degrees . Target detection was less accurate in the placebo condition of both experiments than in the no-beverage control group, suggesting that alcohol expectancies had a negative effect on controlled search. The effects of alcohol at the lower dose and of the placebo on visual search were not different (Experiment 1). At the higher dose, the negative effects of target eccentricity on the accuracy of target detection were larger when targets appeared among highly similar distractors, compared with the placebo condition and with a no-beverage control group. Target eccentricity effects on accuracy or speed were not observed at either dose when targets and distractors were dissimilar. Acute alcohol intoxication at either a low or high dose and placebo-associated intoxication expectancies have a detrimental effect on controlled visual search in large arrays. Acute alcohol intoxication at a high dosage exaggerates the detrimental effects of target eccentricity and of task difficulty on controlled visual search.

Uso de drogas de abuso e evento sentinela: construindo uma proposta para avaliação de políticas públicas

O presente trabalho objetivou operacionalizar o procedimento de vigilância epidemiológica de evento sentinela a partir da internação de jovens com diagnóstico de intoxicação aguda ou efeitos secundários decorrentes do uso de drogas de abuso. O estudo, do tipo retrospectivo, exploratório descritivo, foi desenvolvido no município de Maringá - PR, com jovens internados e cadastrados no Centro de Controle de Intoxicações, nos meses de fevereiro a julho de 2006. As fontes de dados foram a ficha de ocorrência toxicológica, o prontuários hospitalar de pacientes e um roteiro para entrevista domiciliar. A análise foi feita por meio de estudo de casos múltiplos, utilizando o modelo de investigação de eventos sentinela. Foram investigados 10 casos. Fatores de risco em várias áreas e a interface entre políticas de educação, segurança pública, assistência social, economia e saúde, inadequadas e deficientes, parecem determinar a ocorrência do uso de drogas de abuso nos casos investigados.

Acute alcohol intoxication suppresses the pulmonary ELR-negative CXC chemokine response to lipopolysaccharide

Alcohol abuse impairs the pulmonary immune response to infection and increases the morbidity and mortality of bacterial pneumonia. Acute alcohol intoxication suppresses lung expression of CXC chemokines bearing the Glu-Leu-Arg motif (ELR +) following lipopolysaccharide (LPS) challenge, but its effect on the structurally related ELR − CXC chemokines, which attract T cells, is unknown. We therefore investigated the effect of acute alcohol intoxication on the pulmonary response to intratracheal (i.t.) LPS challenge for the ELR − CXC chemokines monokine induced by gamma (MIG or CXCL9), interferon-inducible protein 10 (IP-10 or CXCL10), and interferon-inducible T cell alpha chemoattractant (I-TAC or CXCL11). Male C57BL/6 or C3H/HeN mice were given an intraperitoneal injection of ethanol (3.0 g/kg) or phosphate buffered saline 30 min before i.t. LPS challenge. Chemokine mRNA transcripts were measured at 0, 2, 6, and 16 h. Acute alcohol intoxication inhibited the lung's expression of all three chemokine genes in response to LPS. Lung IFN-γ mRNA was also inhibited by acute intoxication over the same time course. The in vitro effect of ethanol on chemokine secretion was further studied in the MH-S alveolar macrophage cell line. IP-10, MIG, and I-TAC in response to LPS were enhanced by exogenous interferon (IFN)-γ, and these responses were blunted by exposure to ethanol. Alcohol exposure did not affect MH-S cell nuclear factor kappa beta p65 nuclear localization during challenge, despite dose-dependent inhibition of Erk 1/2 phosphorylation. In addition, phospho-signal transduction and activator of transcription 1 was not decreased in the presence of acute ethanol, thereby indicating that acute intoxication does not affect IFN-γ signaling in MH-S cells. Recruitment of CD3+ T cells into the alveolar space 4 days after LPS challenge was moderately impaired by acute ethanol intoxication. These results implicate acute ethanol intoxication as a significant inhibitor of lymphocyte chemoattractant expression during pulmonary inflammation.

Magnetic resonance analysis of the effects of acute ammonia intoxication on rat brain. Role of NMDA receptors

Acute ammonia intoxication leads to rapid death, which is prevented by blocking N-methyl-d-aspartate (NMDA) receptors. The subsequent mechanisms leading to death remain unclear. Brain edema seems an important step. The aim of this work was to study the effects of acute ammonia intoxication on different cerebral parameters in vivo using magnetic resonance and to assess which effects are mediated by NMDA receptors activation. To assess edema induction, we injected rats with ammonium acetate and measured apparent diffusion coefficient (ADC) in 16 brain areas. We also analyzed the effects on T1, T2, and T2* maps and whether these effects are prevented by blocking NMDA receptors. The effects of acute ammonia intoxication are different in different brain areas. T1 relaxation time is reduced in eight areas. T2 relaxation time is reduced only in ventral thalamus and globus pallidus. ADC values increased in hippocampus, caudate-putamen, substantia nigra and cerebellar cortex, reflecting vasogenic edema. ADC decreased in hypothalamus, reflecting cytotoxic edema. Myo-inositol increased in cerebellum and substantia nigra, reflecting vasogenic edema. N-acetyl-aspartate decreased in cerebellum, reflecting neuronal damage. Changes in N-acetyl-aspartate, T1 and T2 are prevented by blocking NMDA receptors with MK-801 while changes in ADC or myo-inositol (induction of edema) are not.

Effects of acute alcohol intoxication on visuospatial attention

The aim of the present study was to examine the effects of acute alcohol intoxication on the spatial distribution of visual attention measured with simple reaction times (RTs) to targets presented over an extended region of the visual field. Control (n=10) and alcohol groups (n=14) were tested with the same protocol. Participants were tested in two different conditions; in Experiment I, participants were instructed to direct their visual attention to the centre, while in Experiment II they were asked to orient their attention covertly to both right and left, but not to the centre. Throughout participants were required to fixate a small cross in the centre of the computer screen. In the alcohol group, participants received an alcohol dose of 0.4 g/kg so as to produce a blood alcohol concentration (BAC) in the range of 0.08% during the experiments. The spatial distribution of RTs was analysed graphically with geostatistical methods and statistically through analysis of variance of particular regions of the visual field. Results showed that controls were able to direct their attention tightly towards the centre (Expt I) and also to divide attention (Expt II) to the right and left. Participants in the alcohol group fixed their attention more diffusely in the centre (Expt I) and were unable to disengage attention from the centre in Experiment II. We conclude that acute alcohol intoxication impairs the ability to dissociate attention from gaze.

Ethanol Inhibits the Sensory Responses of Cerebellar Granule Cells in Anesthetized Cats

Granule cells occupy a strategic position in the transmission of afferent information to the cerebellar cortex. They are also the most abundant type of neurons in the cerebellum. The functions of the cerebellum are thought to be sensitive to acute alcohol intoxication. The effects of acute alcohol intoxication on the in vivo physiology of cerebellar granule cells are, however, not completely known. We studied chloralose-anesthetized cats at ethanol doses relevant to human drinking (0.3-1.2 g/kg). We recorded the electrophysiological responses of granule cell clusters to auditory and visual stimulation, and simultaneously monitored the concentration of ethanol in the cerebrospinal fluid (CSF). At an intravenous ethanol dose of 0.3 g/kg, CSF ethanol concentration peaked in 10 minutes at 17 mM, equivalent to a blood alcohol concentration (BAC) of about 0.08 g/dL. Ethanol quickly and almost completely abolished both auditory and visual responses from granule cells. Complete or near-complete inhibition lasted 15 to 20 minutes; approximately 50% recovery required an additional 15 minutes, and a full recovery yet another 15 minutes. A higher ethanol dose at 1.2 g/kg resulted in a more severe inhibition and required longer time for recovery. The relationship between ethanol dose, CSF ethanol concentration, and granule cell responses was dynamic and nonlinear, critically depending upon the elapsed time. Cerebellar granule cell sensory responses are highly sensitive to ethanol inhibition. A rapid development of acute tolerance appears to be a major factor contributing to the dynamic and nonlinear relationship among ethanol dosage, CSF ethanol concentration, and granule cell responses. It is likely that a generalized de-afferentation of the cerebellum from its mossy fiber afferents, followed by the subsequent development of acute tolerance may play major roles by which alcohol intoxication affects cerebellar functions.

An investigation of the behavioral actions of ethanol across adolescence in mice

The transition from adolescence into adulthood is characterized by rapid maturation of brain systems mediating reward and by increasing experimentation with drugs of abuse including ethanol (EtOH). Previous studies have found marked differences in sensitivity to the behavioral effects of EtOH in adolescent rats as compared to adults, but relatively few studies have been conducted in mice. The present study examined sensitivity to various behavioral effects of EtOH in C57BL/6J mice at various stages of adolescence/adulthood (4, 6, 8 weeks old). Ages were compared for locomotor stimulant (open field), anxiolytic-like (elevated plus-maze), memory-impairing (Pavlovian fear conditioning) and ataxic (accelerating rotarod) effects of EtOH, and the sedative/hypnotic (sleep time) effects of EtOH and pentobarbital. EtOH self-administration was compared using a two-bottle choice paradigm. Measures of EtOH metabolism were also obtained. Early adolescent mice exhibited increased sensitivity to locomotor stimulant (1.5 g/kg), anxiolytic-like (1.5 g/kg) and ataxic (1.5-2.5 g/kg), but not memory impairing (2.0 g/kg), effects of EtOH relative to adults. Early adolescent, and to some extent peri-adolescent, mice were less sensitive than adults to the sedative/hypnotic effects of EtOH (3.5-4.5 g/kg), but not pentobarbital (40-50 mg/kg). Early adolescent mice showed lower EtOH preference, but not EtOH consumption, than adults. Blood EtOH concentrations were higher at early time points and lower at later time points after (3.0 g/kg) EtOH injection in early and peri-adolescents relative to adults. Present data demonstrate that sensitivity to the acute intoxicating effects of EtOH changes across mouse adolescent development in a behavior-dependent manner.

Early Restoration of Cocaine-Induced Splanchnic Hypoperfusion in Anesthetized Dogs

Although cardiovascular effects of cocaine have been well studied, little is known about its effects on splanchnic perfusion. We studied systemic and regional hemodynamic effects of acute cocaine intoxication in dogs under volatile anesthesia. Mechanically ventilated beagle dogs, randomized at 1.5% halothane (n = 7) or 2.25% sevoflurane (n = 7) anesthesia, received an intravenous bolus of cocaine (12 mg/kg over 5 min) followed by 0.22 mg/kg/min infusion over 30 min. They were observed for 60 min thereafter. Cardiac index (CI), heart rate (HR), mean arterial pressure (MAP), portal blood flow (PBF), gastric PCO2 (gas tonometry), blood gases, and lactate and cocaine levels were assessed. Cocaine bolus promoted significant reductions in CI (∼ 50%), HR (∼ 20%), MAP (∼ 20%), and PBF (∼ 50%), accompanied by increase in systemic and splanchnic oxygen extractions and in gastric mucosal–arterial PCO2 gradient. Those changes were maintained during cocaine infusion and returned to baseline values parallel to plasmatic cocaine clearance. Unlike other shock states, regional parameters, including gastric mucosal–arterial PCO2 gradient, were restored before systemic variables. A possible local vasodilatory effect of volatile agents could play a role in this phenomenon. Cocaine infusion in anesthetized animals promoted marked systemic and regional hemodynamic derangement, which was rapidly reversible with decay of cocaine plasmatic concentration.

Actin Dynamics and Ethanol Sensitivity

The risk of alcoholism has been associated with resistance to the acute intoxicating effects of alcohol, leading researchers to explore model systems that might give insight into the molecular factors that modulate ethanol sensitivity. Two studies suggest that ability to regulate the actin cytoskeleton could influence sensitivity to alcohol. Rothenfluh et al . found that mutations of the Drosophila RhoGAP18B locus, which was predicted to encode three RhoGAP18 proteins that shared only the guanosine triphosphatase (GTPase) activating protein (GAP) domain, led to resistance to ethanol-induced sedation (assessed by the loss-of-righting test and locomotor tracking) that was specifically associated with loss of the RhoGAP18B-RC transcript. Experiments with dominant-negative or constitutively active Rho GTPases and loss-of-function alleles suggested that the effects of RhoGAP18B-RC on ethanol-induced sedation were mediated though Rho1 or the Rac GTPases (or both) but not through Cdc42. In contrast to RhoGAP18B-RC , the RhoGAP18B-RA transcript appeared to be involved in mediating ethanol’s stimulant effects. As Sordella and Van Aelst note, the Rho GTPases have been implicated in regulation of actin dynamics; the second study, by Offenhäuser et al ., investigated ethanol resistance in mice of Eps8, which is also involved in regulating actin dynamics. Mice lacking Eps8 ( Eps8 -KO mice) showed increased ethanol consumption and were less sensitive to the sedative and motor-incoordinating effects of ethanol but not to its stimulation of locomotor activity. Eps8 was observed in dendritic articulations of cerebellar granule neurons (CGNs); it was present in cerebellar postsynaptic density fractions, and it coimmunoprecipitated with the N -methyl-𝒟-aspartate (NMDA)-type glutamate receptor (NMDAR). Electrophysiological recordings from CGNs in cerebellar slices indicated that the NMDA component of the composite excitatory postsynaptic current was increased in Eps8 -KO compared with that of wild-type mice and was less sensitive to inhibition by 400 mM ethanol. Introduction of Eps8 into Eps8 -KO neurons reduced NMDAR-mediated currents, as did latrunculin (which disrupts actin filaments). Eps8 was present in F-actin-rich clusters in the neurites of cultured CGNs; glutamate or NMDA treatment led to a decrease in cofilin phosphorylation and a loss of F-actin from these structures, effects that were attenuated in Eps8 -KO neurons. Ethanol treatment also elicited a loss of F-actin from these structures and in cerebellar slices, effects to which Eps8 -KO neurons were resistant. Thus, both Drosophila and mouse studies suggest that disruption of the mechanisms involved in regulating actin dynamics affects sensitivity to ethanol. A. Rothenfluh, R. J. Threlkeld, R. J. Bainton, L. T.-Y. Tsai, A. W. Lasek, U. Heberlein, Distinct behavioral responses to ethanol are regulated by alternate RhoGAP18B isoforms. Cell 127 , 199-211 (2006). [PubMed] N. Offenhäuser, D. Castelletti, L. Mapelli, B. E. Soppo, M. C. Regondi, P. Rossi, E. D'Angelo, C. Frassoni, A. Amadeo, A. Tocchetti, B. Pozzi, A. Disanza, D. Guarnieri, C. Betsholtz, G. Scita, U. Heberlein, P. P. Di Fiore, Increased ethanol resistance and consumption in Eps8 knockout mice correlates with altered actin dynamics. Cell 127 , 213-226 (2006). [PubMed] R. Sordella, L. Van Aelst, Driving actin dynamics under the influence of alcohol. Cell 127 , 37-39 (2006). [PubMed]

Increased Ethanol Resistance and Consumption in Eps8 Knockout Mice Correlates with Altered Actin Dynamics

Dynamic modulation of the actin cytoskeleton is critical for synaptic plasticity, abnormalities of which are thought to contribute to mental illness and addiction. Here we report that mice lacking Eps8, a regulator of actin dynamics, are resistant to some acute intoxicating effects of ethanol and show increased ethanol consumption. In the brain, the N-methyl-D-aspartate (NMDA) receptor is a major target of ethanol. We show that Eps8 is localized to postsynaptic structures and is part of the NMDA receptor complex. Moreover, in Eps8 null mice, NMDA receptor currents and their sensitivity to inhibition by ethanol are abnormal. In addition, Eps8 null neurons are resistant to the actin-remodeling activities of NMDA and ethanol. We propose that proper regulation of the actin cytoskeleton is a key determinant of cellular and behavioral responses to ethanol.