Ethanol Withdrawal Syndrome Research Articles

Anti-anxiety and anti-depressive effects of Thai Mucuna pruriens seed aqueous extract against ethanol withdrawal syndrome in mice

BackgroundThai Mucuna pruriens (T-MP) has been used as a traditional medicine for treating many neurological conditions due to its antioxidant and neurorestorative properties. Aim of the studyThis study was to explore the effects of T-MP seed extract on ethanol withdrawal syndrome (EWS) in mice. MethodsMice were administered either normal saline solution (NSS) or 2 g/kg of 20% ethanol intraperitoneally once daily for 10 days. Behavioral symptoms of EWS were evaluated at 12-, 24-, and 36-hours after the last dose of ethanol using the elevated plus maze (EPM), light-dark box (LDB), and tail suspension test (TST). After determining the best time interval to detect EWS, a new set of mice were induced to have EWS, at 23 h after the last ethanol dose, mice were treated with either NSS (PO), diazepam (4 mg/kg, IP), or T-MP seed extract (600 mg/kg, PO). Behavioral tests were conducted one hour after treatment. ResultsIn the ethanol withdrawal mice, anxiety- and depressive-like behavior representing EWS were seen in LDB, EPM and TST, especially at the 24-hour after the final ethanol dose. At 36-hour after the final ethanol dose, although the anxiety-like behavior could be seen in LDB and EPM, whereas no significant depressive-like in TST was observed. Treatment with DZP or T-MP could significantly reduce the anxiety- and depressive-like symptoms of EWS at 24-hour after last dose of ethanol. In addition, treatment with T-MP, but not DZP, significantly reduced the total immobility time when compared to the control ethanol withdrawal group. ConclusionAccording to this study, it was discovered that T-MP seed extract could potentially offer a beneficial effect in managing anxiety- and depression-like behaviors in EWS in mice.

Anxiolytic effects of Dichrocephala integrifolia leaf aqueous extract on alcohol withdrawal-induced anxiety in mice: Involvement of the GABAergic pathway

Ethanol withdrawal syndrome is a life-threatening state that results from a sudden termination of chronic alcohol intake. One of the manifestations of ethanol withdrawal syndrome is anxiety. Dichrocephala integrifolia is a plant used in Africa in the treatment of alcohol use disorders. This study aimed to evaluate the effects of Dichrocephala integrifolia on ethanol withdrawal anxiety in mice. Young adult Swiss mice were arranged into seven groups of six mice each. Groups II to VII received ethanol in increasing concentration for 20 days. Following ethanol withdrawal, mice were administered distilled water (Group II), Dichrocephala integrifolia (25,50,100 and 200 mg/kg) (Groups III-VI) or diazepam (Group VII). Behavioural assessments were performed using the elevated plus maze, the open field and the hole board tests. Gamma-aminobutyric acid (GABA) concentration, GABA-Transaminase and glutamic acid decarboxylase activities were assessed in the brain. In the elevated plus maze, Dichrocephala integrifolia (100 mg/kg) significantly (p < 0.01) increased the percentage of open arms entries from 20.5 ± 1.56% in the negative control, to 65.3 ± 2.46%. In the hole board, the number of head dipping raised from 27.17 ± 0.60 in the negative control to 61.33 ± 2.82 (p < 0 0.01) at the dose 200 mg/kg of Dichrocephala integrifolia. Likewise, diazepam, Dichrocephala integrifolia (200 mg/kg) significantly (p < 0.01) raised GABA concentration from 267.70 ± 5.18 µg/g of tissue in the negative control to 395 ± 5.55 µg/g of tissue. The plant extract (200 mg/kg) reduced the activity of GABA-Transaminase from 101 ± 2.60 pg/min/mg of tissue in the negative control to 42.5 ± 2.35 pg/min/mg of tissue. From these results, we can conclude that, by enhancing the GABAergic neurotransmission, Dichrocephala integrifolia has anxiolytic activities against ethanol withdrawal anxiety and can therefore be a good drug candidate for the treatment of alcohol addiction.

The Effect of Aqueous Extract of Gum Arabic on Hepato-renal Function During Ethanol Withdrawal Induced Stress in Wistar Rats

Background: Alcohol withdrawal syndrome (AWS) is a life-threatening condition affecting alcoholics who ceased or decreased their alcohol consumption. The synthetic drugs used to manage these consequences are not without undesirable effects; hence, the need for a natural and affordable approach is raised. Objectives: This study aimed at investigating the effect of aqueous extract of gum arabic (GA) on hepato-renal functions during ethanol withdrawal syndrome in Wistar rats. Methods: In phase I, dose-response for GA and alcohol for the study were determined. In phase II, the effect of GA on biomarkers during AWS was studied. A total of 60 male Wistar rats were used for the study. Blood and tissue samples were obtained at the end of stipulated periods of oral administration for biochemical and histological analysis, and biochemical parameters were analyzed by spectrophotometry. Results: In the dose-response study, there were no significant differences (P≥0.05) in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as in total bilirubin (TBIL), malondialdehyde (MDA), sodium ion (Na+), potassium ion (K+), and creatinine concentrations in groups treated with 200 mg/kg body weight (bw) and 400 mg/kg bw GA aqueous extract compared to the control group. However, significant alterations were observed in groups treated with 600 and 800 mg/kg bw GA extract. Furthermore, rats that received 5.5 mL/kg bw alcohol showed marked changes in biochemical parameters compared to the group that received 4.5 mL/kg bw and the control group. The results obtained in Phase II exhibited the hepato-renal protective effect of GA during ethanol withdrawal. Statistical analysis of the obtained results indicated a better response from the study groups that were pre-treated or co-administered with GA compared to the group that was post-treated. Conclusion: The result of this study suggests that GA aqueous extract offered better protection prophylactically than curatively.

Effect of 5-HT 1b/1d agonist on ethanol withdrawal syndrome and ethanol withdrawal induced anxiety.

Ethanol dependence and abuse is an important problem of public health worldwide and its withdrawal shows some severe behavioural complication. Management of ethanol withdrawal syndrome (EWS) is still a challenge, thus the presented report postulates the possible mechanism involved in the development of EWS. EWS was induced by administration of ethanol for 21 days and 5-hydroxytryptamine (5-HT) 1b/1d agonist treated group receives Zolmitriptan (ZMT) at 30 mg/kg i.p. 30 min prior to ethanol withdrawal. The effect of 5-HT 1b/1d receptor agonist on EWS was determined by estimating the change in the behaviour of withdrawal signs that included locomotor hyperactivity, agitation, tremor, tail stiffness, stereotyped behaviour, and wet dog shakes at 1, 2, 4, 6 and 12 h of ethanol withdrawal. Ethanol withdrawal induced anxiety was determined by using the elevated plus maze and levels of neurochemicals such as g-aminobutyric acid (GABA), glutamate and dopamine were determined in the brain of each group of rats. Data of the given report reveal that Zolmitriptan reverses ( p < 0.01) the behavioural changes induced due to EWS and also reduces the anxiety level in EWS rats. Moreover, Zolmitriptan was found to stimulate ( p < 0.01) the level of GABA and ameliorate the level of other neurochemicals in the brain of EWS rats. In conclusion, data of investigation reveal that 5-HT 1b/1d receptor involved in the EWS and treatment with its agonist prevents the behavioural changes in EWS by regulating the level of different neurochemicals.

Vanillin attenuates the ethanol withdrawal syndrome and ethanol withdrawal induced anxiety by regulating the neurochemical balance.

Ethanol abuse is a major public issue globally and withdrawal of ethanol after chronic exposure contributes to the development of behavioural changes. The present study evaluates vanillin effect against the ethanol withdrawal syndrome (EWS) and the associated anxiety. Rats were exposed to ethanol for 21 days at 7.2% concentration maximum with drinking water in a modified liquid diet. Vanillin at doses of 100 and 200 mg/kg were administered 30 min prior to ethanol withdrawal, and behavioural changes were observed at 1st, 2nd, 4th, 6th and 12th h of ethanol withdrawal. Moreover, the locomotor activity was assessed using the astrophotometer and level of anxiety by the elevated plus maze. The level of neurotransmitters and mRNA expression of corticotropin-releasing factor (CRF) and corticotropin releasing factor receptor 1 (CRFR1) were estimated in brain tissue of vanillin treated EWS rats. There was a significant improvement in the ethanol withdrawal behaviour in the vanillin treated group compared to EWS rats. The locomotor activity and level of anxiety was observed to be reduced significantly (p < 0.01) in the vanillin treated group compared to EWS rats. Treatment with vanillin ameliorates the altered level of g-aminobutyric acid (GABA), dopamine and glutamate and level of corticosterone in ethanol withdrawal rats. mRNA expression of CRF and CRFR1 was reduced significantly (p < 0.01) in brain tissue of the vanillin treated group compared to the EWS group of rats. In conclusion, data reveal that treatment with vanillin shows a beneficial effect against EWS and ethanol withdrawal associated anxiety by regulating CRF/CRFR1 expression.

Curative Effects of Dhatryadi ghrita Bioactive Extracts on Ethanol Withdrawal Syndrome in Wistar Rats

Background: Alcohol withdrawal syndrome leads to irritability, aggressiveness, body posture and motor abnormalities, sensory hyper reactivity and changes in various enzyme levels. Dhatryadi ghrita penetrates the blood-brain barrier to decrease the cravings for alcohol in this syndrome. Objective: To evaluate the effect of alcoholic extract of Dhatryadi ghrita on alcohol withdrawal syndrome in Wistar rats. Material &amp; Methods: A liquid diet with 7.2%, v/v ethanol was administered to the Wistar rats for 21 days. Control group animals received saline and normal diet. After alcohol withdrawal, rats were examined at 6th and 24th hour for anxiety and hyper locomotor activity as major withdrawal signs. Anxiety due to ethanol withdrawal was tested with the help of elevated plus maze, light and dark models. The hyper locomotor activity was assessed using Actophotometer. The hepatic enzymes level was determined with the help of the Bio-chemical Analyzer. ghrita extracts (100, 200,300 mg/kg, oral) were administered to different groups and diazepam as standard (2 mg/kg, i.p) was administered to the treatment group animals 30 minutes before alcohol withdrawal estimation. Drug treatment was administered 30 minutes before the second observation at the 24th hour. Results: Findings from the present study revealed that Ghrita extract treatment at doses 100, 200 and 300 mg/kg, oral in ethanol-dependent rats had a significant protective effect on signs and symptoms of ethanol withdrawal in alcohol-dependent rats. Conclusion: Dhatryadi extract acts effectively for the treatment of alcohol abstinence syndrome. The extract treatment has beneficial effects on ethanol withdrawal depressive-like behavior in rats.

Argan oil supplementation attenuates voluntary ethanol consumption and withdrawal syndrome promoted by adolescent intermittent ethanol in rat.

The present study investigates the potential neuroprotective effect of argan oil (AO), a natural vegetable oil, commonly used in folk Moroccan medicines, on adolescent intermittent ethanol intoxication (IEI), induced voluntary ethanol consumption, and withdrawal syndrome in rats. Animals were treated with ethanol (intraperitoneally [i.p.], 3g/kg body weight [bw]) in intermittent doses (2 days on; 2 days off, from postnatal day 30-43), with/without oral AO pre-treatment (10mL/kg/day bw, from postnatal day 21-121). A 2-bottle free access test was performed over 10 weeks to assess 10% ethanol consumption. Behavioral signs of withdrawal were observed after 2, 6, 24, 48, and 72h after ethanol removal. Anxiety-like behaviors in the elevated plus maze and the light/dark box tests were also evaluated at 72h of withdrawal. We found that AO pre-treatment significantly decreased the voluntary ethanol consumption induced by adolescent IEI. In addition, by establishing low ethanol consumption, AO pre-treatment counteracts negative effects of ethanol withdrawal and anxiety-like behaviors in ethanol-treated rats after 72h of abstinence. Following behavioral assays, oxidative stress markers were evaluated and histologic analysis of neurodegeneration was also performed. The results showed that the low ethanol drinking in the AO-supplemented rats was associated with inhibition of oxidative stress and neurodegeneration in the rats' brains. These findings provide evidence for the promising neuroprotective effect of AO supplementation in voluntary ethanol consumption and withdrawal syndrome, at least in part through counteracting oxidative stress markers and neurodegeneration.

IHT‐induced neuronal protection is mediated by the microglia

Neuronal damage is the main cause of disability after various brain injuries, including ischemic stroke and traumatic brain injury. Recent years, it is being reported that microglia, a resident immune cell in the brain, shows dual edge roles. Intermittent hypoxic training (IHT) was introduced as a potential preventive or treatment program for the ischemic stroke and ethanol withdrawal syndrome. This study showed the effect of IHT on the function of microglia along with neuronal protection.MethodsEOC20, microglia, were randomly assigned to the following groups; 1) normoxic control, 2) oxygen‐glucose deprivation (OGD)‐reoxygenation, 3) IHT, and 4) IHT+ OGD‐reoxygenation. 3 days of IHT that consists of 5–8 daily and 5–10 min cycles of hypoxia with intervening 4 min of reoxygenation was applied to the microglia. OGD (0.1% O2, 90 min) and reoxygenation (24 hours) was used to simulate ischemic stroke and reperfusion. Additionally, the DMEM in which either normoxic or IHT‐treated microglia were grown was used to culture the neuronal cells. After word, the cell viability of neuronal cell exposed to the OGD and reoxygenation was measured. Calcein AM and the LDH assays have been used to compare the cell viability between groups. The microglia were characterized with staining CD45, 11b, CD68, and CD208 and by flow cytometry. Phagocytic activity of microglia was tested by using latex bead coated with FITC. ROS generation was also monitored by DCFDA assay. Both pro‐ and anti‐inflammatory cytokines were examined with commercial ELISA assay kits. Finally, the one‐way ANOVA followed by post hoc test was done to determine the statistical significance. The p‐value less than 0.05 was considered as a meaningful data.ResultsOGD and reoxygenation significantly decreased cell viability of microglia and interestingly, survived microglia from OGD and reoxygenation increased its phagocytic activity, which might benefit from the activated microglia. IHT was able to salvage the microglia from OGD and reoxygenation but also even more enhanced its phagocytic activity vs. OGD and reoxygenation group. This beneficial effect of IHT should be associated with increased antiinflammatory cytokine and shift of M1 to M2 stereotype. Last, it was observed that when neuronal cells were cultured in the DMEM in which microglia underwent 3 days of IHT, were able to be protected against OGD and reoxygenation. This might indicate humoral factors including cytokine released from microglia during IHT were an essential factor in maintaining cerebral circumstance, including neuron.ConclusionThis preliminary study suggests that microglia play a pivotal role in the neuronal damage in the ischemic stroke and can be a key target in developing ischemic stroke treatment. Furthermore, global intermittent hypoxic training might be potential and/or better intervention than an intervention that targets single cell type or organ in developing a treatment program for the ischemic stroke victims.Support or Funding InformationFaculty Development Grant, Tarleton State Univ Basic Research Program Grant, UNTHSCThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Correlation between the epigenetic modification of histone H3K9 acetylation of NR2B gene promoter in rat hippocampus and ethanol withdrawal syndrome.

Patients with alcohol use disorder may develop acute ethanol withdrawal syndrome (EWS). Previous studies showed that an epigenetic modification of the N-methyl-D-aspartate (NMDA) receptor, especially NMDA receptor 2B subunit (NR2B), was involved in the pathological process of EWS. However, the relationship between the epigenetic regulation of the NR2B gene in the rat hippocampus region and EWS were inconsistent. The purpose of this study was to explore the role of the histone H3K9 acetylation of the NR2B gene in the rat hippocampus region in EWS. A rat model of chronic ethanol exposure was established. EWS score and the behavioral changes were recorded at different time points. The NR2B expression levels and the histone H3K9 acetylation level in the NR2B gene promoter region were measured using qRT-PCR, Western blot, immunofluorescence, and chromatin immunoprecipitation, respectively. Finally, the relationship between the epigenetic modification of histone H3K9 acetylation of NR2B gene promoter and EWS were examined. Our ultimate results showed that the EWS score was increased at 2h, peaked at 6h after withdrawal of ethanol, and reduced to the level parallel to the normal control group at day 3 after ethanol withdrawal. The NR2B mRNA expression and protein levels showed similar patterns. Further correlation analyses indicted that both histone H3K9 acetylation in NR2B gene promoter and the expression levels of NR2B were positively associated with EWS. Our results suggest that chronic ethanol exposure may result in epigenetic modification of histone H3K9 acetylation in NR2B gene promoter in rat hippocampus, and the expression levels of NR2B were found to be positively correlated with ethanol withdrawal syndrome.

The Prophylactic and Therapeutic Effects of Saffron Extract and Crocin on Ethanol Withdrawal Syndrome in Mice.

ObjectivesEthanol withdrawal following its chronic use is a serious outcome and challenging to treatment. The chronic use of ethanol induces a progressive neuroplasticity in different reigns of brain. In this study we evaluated the effects of aqueous extract of Crocus sativus L. (saffron) and its active compound, crocin, on the withdrawal behavior induced after repeated administration of ethanol, in two regimens of prophylactic (administration of drugs concomitant with the induction of dependence) and treatment (administration of drugs during the period of ethanol withdrawal) in mice which received ethanol.MethodsEthanol dependence was induced by oral administration of 10% v/v ethanol (2 g/kg) for 7 days. The aqueous extracts of saffron (40, 80 and 160) and crocin (10, 20 and 40 mg/kg) were administered to mice in two regimens of prophylactic (along with ethanol) and treatment (during withdrawal period). Diazepam (1 mg/kg) was used as a positive control. Six hours after discontinuation of the ethanol, seizure was evaluated by the sub-convulsive dose of pentyleneltetrazole (PTZ) (30 mg/kg). The open field test and Rota rod test were used for evaluation of locomotor activity and motor incoordination, respectively.ResultsBoth extracts and crocin increased the number of crossed lined in the open field test. PTZ kindling seizure was inhibited in animals received extract (80 and 160 mg/kg) in both regimens. Motor incoordination was only improved following administration of crocin.ConclusionThe aqueous extract of saffron and crocin can be considered as safe agents and reliable alternative to diazepam in management of ethanol withdrawal syndrome.

Intermittent Normobaric Hypoxic Training Protects the Brain by Regulating Microglia Phenotype

IntroductionEthanol Withdrawal (EW) syndrome is an etiologically important factor linked to the ischemia and reperfusion injuries, including ischemic stroke. In the US, ischemic stroke is the 4th leading cause of death and the first cause of adult disability. Previously we showed that intermittent normobaric hypoxic training (IHT) protects the brain from EW syndrome by reducing ROS and increasing protective proteins. Pro‐inflammatory microglia has been studied in various CNS diseases. However, the function of microglia in the IHT‐induced brain protective mechanism is not yet thoroughly explored. In here, we focused on how IHT influence on regulating the phenotype of microglia, a pivotal resident phagocytic cell in the brain, in the in vitro IHT model.MethodsMouse microglia cells, EOC20 cell, underwent three days of IHT program which composed of 5–7 cycles of hypoxia/normoxia. O2 concentration was gradually decreased from 2.5% to 2 % each daily training cycle. Two sessions of EW treatment was done as following; EtOH (100 mM) for 16 hrs followed by 6 hrs of EtOH cessation. Cells were assigned into four groups; 1) non‐treated control, 2) IHT, 3) EW, 4) IHT+EW. Cell viability was evaluated by Calcein AM assay. Immunocytochemistry and flow cytometry were applied to determine the phenotype of microglia; CD 68 (M1), CD 206 (M2). The expression of mRNA of pro‐ and anti‐inflammatory cytokines were examined with quantitative real‐time rt‐PCR. Additionally, protein contents, which play a role in cerebral protection, were quantified by immunoblot assays. Data were expressed as mean ± SEM. Two factor ANOVA analysis and Tukey's multiple comparison test was used. P value &lt; 0.05 was considered as a significant value.ResultsEW reduced cell viability and IHT was able to salvage the microglia from EW stress. IHT‐induced protection was mediated by increased HIF‐1α and activated Erk, an anti‐apoptotic protein kinase. The expression of CD 68 was not reduced with IHT vs. EW, but CD 206 was significantly increased in the IHT group vs. non‐IHT groups. An increased pro‐inflammatory phenotype of microglia was observed in the flow cytometry. IHT significantly decreased the expression of TNF‐α and IL‐6, pro‐inflammatory cytokines.ConclusionIHC drives the microglia toward anti‐inflammatory phenotype, which could be an important factor in the IHC‐induced cerebral protective mechanism.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Where is the contre-coup? Atypical localization of occipital brain contusion

Abstract Most traumatic brain injuries with occipital impact cause frontal and temporal contre-coup lesions, while patients with coagulopathies are more susceptible to such lesions. We present the case of a chronic ethylic patient with thrombocytopenia, who was treated for ethanol withdrawal syndrome at a psychiatric service. The head CT scan revealed an occipital contusion with atypical localization and the absence of fronto-temporal contre-coup lesions. In conclusion, it is recommended a head CT scan to chronic alcoholic patients with psychiatric manifestations, especially in the context of systemic coagulopathies related to excessive alcohol consumption. In the case of chronic ethylic patients that frequently display systemic coagulation disorders, the head CT scan is necessary at the first psychiatric manifestations.

Protective effect of Ocimum sanctum Linn. leaf extract on ethanol withdrawal syndrome in Wistar rats

Objective: To evaluate the effects of Oscimum sanctum L (O. sanctum), an important medicinal herb, on alcohol withdrawal syndrome in Wistar rats. Methods: Liquid diet with 7.2%, v/v ethanol was administered to the rats for 21 d. Control group animals received sucrose as an isocaloric liquid diet. After alcohol withdrawal, rats were examined at 6th and 24th hour for major withdrawal signs that included anxiety and hyper locomotor activity. Ethanol withdrawal anxiety was tested using elevated plus maze, light and dark model; the hyper locomotor activity using actophotometer. O. sanctum leaf extract (100, 200 and 300 mg/kg, oral) and diazepam (2 mg/kg, i.p) were administered to the treatment group animals 30 min before alcohol withdrawal estimation. Drug treatment was also given 30 min before the second observation at 24th hour. On the last day of the protocol, rats were sacrificed by cervical dislocation liver, kidney and brain were isolated and preserved in formalin for further histopathological examination. Results: Findings from the present study revealed that O. Sanctum leaf extract treatment at doses 100, 200 and 300 mg/kg, oral had a significant protective effect on signs and symptoms of ethanol withdrawal in alcohol-dependent rats. However, no remarkable pathological and microscopic alterations were observed in histopathological examination. Conclusions:O. sanctum seems to be an active drug for the treatment of alcohol abstinence syndrome.

Induced Locomotor Hyperactivity on Ethanol Withdrawal Syndrome in Rats is Inhibited by Quetiapine

Our aim is to investigate the effects of two atypical antipsychotics; quetiapine and olanzapine on locomotor activity that is a sign of ethanol withdrawal syndrome in rats. Adult male Wistar rats were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 30 days. Control rats were pair fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Quetiapine (10 mg/kg), olanzapine (5 mg/kg) and saline were injected to the rats intraperitoneally 7 days after ethanol withdrawal syndrome and the last one 30 min before ethanol withdrawal testing. After 2nd hour of ethanol withdrawal, rats were observed for 5 min and withdrawal signs that included locomotor hyperactivity were recorded. We have found increased vertical and horizontal locomotor activity in ethanol withdrawal group to control and reduced vertical and horizontal locomotor activity in quetiapine-injected rats. In olanzapine injected rats were seen no reduced locomotor activity. Significant inhibitory effects were produced by quetiapine on the signs of ethanol withdrawal. Our results suggest that acute quetiapine treatment has some beneficial efects on ethanol withdrawal in rats. Thus, this drug may be useful for treatment of ethanol withdrawal syndrome.

Chronic Simvastatin Treatments Attenuate Ethanol Withdrawal Syndrome in Rats

Rodent models of ethanol withdrawal-induced anxiety have been used to explore the neurobiology underlying withdrawal and to evaluate the utility of therapeutic agents aimed at reducing withdrawal severity. Of the many tests of anxiety-like behavior, the elevated plus maze and open field are the most commonly used. In general, ethanol withdrawal decreases most or all of the individual behaviors recorded in these tasks, indicating the occurrence of an anxiogenic-like effect of withdrawal in rodents. Effects of sub-chronic simvastatin treatments on ethanol withdrawal syndrome were inves- tigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Sub-chronic (once daily) simvastatin (1 or 10 mg/kg) or saline were administered to rats by oral gavage. After 24 hours of ethanol withdrawal on the simvastatin treatment rats were observed in behavior tests. The increases the time open arms entries in the elevated plus-maze and grooming in the open-field through the exposure to sub-chronic treatment with simvastatin in rats submitted to ethanol intake, indicating beneficial effects on ethanol withdrawal syndrome. Our results suggest that sub-chronic simvastatin treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

Withdrawal from repeated treatment with ethanol induces a protracted decrease in novelty-seeking behavior and enhancement of environmental habituation in mice

Ethanol withdrawal syndrome is characterized by somatic and behavioral symptoms, including increased anxiety and anhedonia. In animal models, however, there are many studies on the anxiogenic effects occurring during the first 24h after ethanol withdrawal, while anhedonia has been overlooked. Recently, we have found that amphetamine withdrawal reduced novelty seeking and enhanced environmental habituation in mice, two motivation-related behaviors. We now investigate the effects of withdrawal from ethanol, a drug of abuse with a different pharmacological profile, on these two motivation-related behaviors. Swiss male mice (3months old) were treated with 1.8g/kg ethanol for 21 consecutive days in their home cages. Seven days after ethanol withdrawal, mice were tested in a free-choice novelty apparatus containing one familiar and one novel compartment. Novelty-seeking behavior was assessed by comparing time spent in the novel compartment versus the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time–response curve of total locomotion (novel+familiar). Novelty seeking was decreased and environmental habituation was enhanced during ethanol withdrawal. These anhedonic responses were not associated with concurrent changes in the anxiety-like behavior of mice (as confirmed in the elevated plus-maze test). We propose that the concomitant evaluation of novelty-seeking behavior and environmental habituation can be useful to study the behavioral consequences not only of amphetamine withdrawal but also of ethanol withdrawal. Furthermore, the present data support recent clinical findings that suggest the occurrence of protracted anhedonia well beyond the limited period immediately following the abrupt cessation of ethanol intake.

Atypical Antipsychotic Drugs and Ethanol Withdrawal Syndrome: A Review

Alcoholism and psychosis are known to have common neurochemical substrates. The aim of this review is to assess the reports involved in the effects of some atypical antipsychotic agents on the signs of ethanol withdrawal syndrome (EWS) in rats. Thus, both effectiveness of these drugs in ethanol withdrawal and the association between the drug effects and the signs have been investigated here on the same animal model. Adult Wistar rats were used as subjects. Ethanol was given to rats by modified liquid diet technique for inducing ethanol dependence. Clozapine, olanzapine, risperidone, quetiapine and ziprasidone were the drugs tested. Effects of these drugs on the signs of ethanol withdrawal such as locomotor hyperactivity, stereotyped behavior, tremor, wet dog shakes, tail-stiffness, abnormal posture and gait, agitation and audiogenic seizures were evaluated for the first 6 h of ethanol withdrawal. Although some beneficial effects of all the drugs on ethanol withdrawal signs were observed, olanzapine precipitated abnormal posture and gait in the animals. Effectiveness rank of the used atypical antipsychotics was as follows: risperidone = quetiapine > ziprasidone > klozapine > olanzapine. Our results suggest that risperidone and quetiapine seem to be potent and pharmacologically more active agents on EWS in rats. Thus, these drugs may be beneficial in treatment of EWS in patients with alcoholism. Ziprasidone and clozapine also seem to be useful drugs in treatment of ethanol withdrawal.

Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway

The dorsal striatum has been proposed to contribute to the formation of drug-seeking behaviors, leading to excessive and compulsive drug usage, such as addiction. The current study aimed to investigate the involvement of extracellular signal-regulated kinase (ERK) pathway in the modification of striatal synaptic plasticity. Ethanol was administered to rats in drinking water at concentration of 6% (v/v) for 30 days. Rats were sacrificed on day 10, 20, or 30 during ethanol intake or on withdrawal day 1, 3, or 7 following 30-d ethanol intake. The striata were removed either for electrophysiological recording or for protein immuno-blot analysis. Extracellular recording technique was used to record population spikes (PS) induced by high-frequency stimulation (HFS) in the dorsolateral striatum (DLS). Corticostriatal long-term depression (LTD) was determined to be dependent upon ERK signaling. Chronic ethanol intake (CEI) attenuated ERK phosphorylation and LTD induction, whereas withdrawal for one day (W1D) potentiated ERK phosphorylation and LTD induction. These results showed that the impact of chronic ethanol intake and withdrawal on corticostriatal synaptic plasticity was associated with ethanol's effect on ERK phosphorylation. In particular, pharmacological inhibition of ERK hyper-phosphorylation by U0126 prevented LTD induction in the DLS and attenuated ethanol withdrawal syndrome as well. In rat DLS, chronic ethanol intake and withdrawal altered LTD induction via ERK signaling pathway. Ethanol withdrawal syndrome is mediated, at least partly, by ERK hyper-phosphorylation in the DLS.

Acupuncture Attenuates Anxiety‐Like Behavior by Normalizing Amygdaloid Catecholamines during Ethanol Withdrawal in Rats

Previously, we demonstrated acupuncture at acupoint HT7 (Shen-Men) attenuated ethanol withdrawal syndrome by normalizing the dopamine release in nucleus accumbens shell. In the present study, we investigated the effect of acupuncture on anxiety-like behavior in rats and its relevant mechanism by studying neuro-endocrine parameters during ethanol withdrawal. Rats were treated with 3 g kg−1day−1 of ethanol (20%, w/v) or saline by intraperitoneal injections for 28 days. The rats undergoing ethanol withdrawal exhibited anxiety-like behavior 72 h after the last dose of ethanol characterized by the decrease of time spent in the open arms of the elevated plus maze compared with the saline-treated rats (P < .05). Radioimmunoassay exhibited there were notably increased concentrations of plasma corticosterone in ethanol-withdrawn rats compared with saline-treated rats (P < .05). Additionally, high performance liquid chromatography analysis also showed the levels of norepinephrine and 3-methoxy-4-hydroxy-phenylglycol were markedly increased while the levels of dopamine and 3,4-dihydroxyphenylacetic acid were significantly decreased in the central nucleus of the amygdala of ethanol-withdrawn rats compared with saline-treated rats (P < .01). Acupuncture groups were treated with acupuncture at acupoint HT7 or PC6 (Nei-Guan). Acupuncture at HT7 but not PC6 greatly attenuated the anxiety-like behavior during ethanol withdrawal as evidenced by significant increases in the percentage of time spent in open arms (P < .05). In the meantime, acupuncture at HT7 also markedly inhibited the alterations of neuro-endocrine parameters induced by ethanol withdrawal (P < .05). These results suggest that acupuncture may attenuate anxiety-like behavior during ethanol withdrawal through regulation of neuro-endocrine system.

Effects of risperidone, quetiapine and ziprasidone on ethanol withdrawal syndrome in rats

Comorbid substance use in schizophrenic patients is common, and substance dependence is a predictive factor for psychosis. The present study was designed to investigate the effects of risperidone, quetiapine and ziprasidone, atypical antipsychotic drugs, on ethanol withdrawal syndrome (EWS) in rats. Adult male Wistar rats were used in the study. Ethanol (7.2%, v/v) was given to rats via a liquid diet for 21 days. An isocaloric liquid diet without ethanol was given to control rats. Risperidone (1 and 2 mg/kg), quetiapine (8 and 16 mg/kg), ziprasidone (0.5 and 1 mg/kg) and vehicle were injected into rats intraperitoneally at 1.5 and 5.5 h of ethanol withdrawal. At the 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, stereotyped behaviors, abnormal gait and posture, tail stiffness and agitation were recorded or rated. Following the observations at the 6th hour, the rats were tested for audiogenic seizures. All three drugs had some significant inhibitory effects on EWS-induced behavioral signs beginning at the 2nd hour of withdrawal. The drugs also significantly reduced the incidence of audiogenic seizures. Overall, risperidone and quetiapine seemed to be more effective than ziprasidone in ameliorating the withdrawal signs. Doses of the drugs used in the present study did not produce any significant changes in locomotor activities of naïve rats. Our results suggest that risperidone, quetiapine and ziprasidone had beneficial effects on EWS in rats. Thus, these drugs may be helpful for controlling withdrawal signs in ethanol-dependent patients.