Ethanol Withdrawal Syndrome In Rats Research Articles

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.

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.

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.

The relationship between baseline prepulse inhibition levels and ethanol withdrawal severity in rats

Baseline prepulse inhibition (PPI) of the acoustic startle reflex is thought to reflect the functioning of the sensorimotor gating system in the brain. The current literature indicates that similar neurotransmitter systems may play roles both in the regulation of PPI and in the development of ethanol withdrawal syndrome (EWS). The aim of the present study was to test if individual baseline PPI levels have any relationship to the behavioral and neurochemical consequences of EWS in rats. A batch of rats (n = 30) was sorted according to baseline PPI levels and classified as either high-inhibitory (HI) or low-inhibitory (LI) rats (n = 10 in each group). Ethanol was administered in a liquid diet for 21 days. On the 22nd day, ethanol was removed from the diet, and EWS was induced. At the 2nd, 4th, and 6th hours of EWS, locomotor activity and behavioral symptoms were evaluated. Brain tissue concentrations of dopamine, serotonin and noradrenaline in hippocampus, cortex, and striatum were measured after the 6th hour of EWS testing. Another batch of rats (n = 30) was classified using the same procedure and fed with regular diet. On the 22nd day, rats were decapitated and neurochemical measurements were repeated. HI and LI rats consumed similar amounts of ethanol. However, EWS signs such as stereotyped behaviors, wet-dog shakes, and tremor were more intense in LI rats compared to their HI counterparts. Audiogenic seizures occurred in both groups in a similar manner. Although the catecholamine concentrations in the brains of both groups were parallel under baseline conditions, dopamine levels increased in the cortex of LI and in the striatum of HI rats, whereas striatum serotonin levels decreased only in LI rats after the 6th hour of EWS. In conclusion, the data suggest that the behavioral symptoms and neurochemical changes observed in EWS may be associated with baseline PPI levels.

Effects of Clozapine on Ethanol Withdrawal Syndrome in Rats

Co-morbid substance use in schizophrenic patients is common, and an important factor affects the outcome of disease. On the other hand, drug dependence is a predictive factor for psychosis. Alcohol is one of the most frequently abused psychoactive substances and may contribute psychotic symptoms in several conditions, such as withdrawal syndrome. The present study was designed to investigate the effects of clozapine 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 by a liquid diet for 14 days. An isocaloric liquid diet without containing ethanol was also given to control rats. Clozapine (2.5, 5 and 10 mg/kg) and its vehicle (0.1% acetic acid) were injected to rats subcutaneously at the 1.5th and 5.5th hours of ethanol withdrawal. At 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min and withdrawal signs that included locomotor hyperactivity, agitation, tremor, tail stiffness, stereotyped behaviour and wet dog shakes were recorded or rated. Following the observations at 6th hour, subjects were tested for audiogenic seizures. Clozapine significantly and dose-dependently inhibited the EWS-induced locomotor hyperactivity, wet dog shake, stereotyped behaviour, tremor and tail stiffness. However, it did not produce any significant effect on agitation and audiogenic seizures. Doses of clozapine used in the present study did not produce any significant change on locomotor activities of naïve rats. Our results suggest that clozapine had some significant beneficial effects on EWS in rats. Thus, this drug may be helpful for controlling some withdrawal signs in ethanol-dependent patients.

Effects of olanzapine on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of olanzapine, a serotonin–dopamine antagonistic atypical antipsychotic agent, on 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 21 days. Control rats were pair fed with an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. After 2nd, 4th and 6th h of ethanol withdrawal, rats were observed for 5 min, afterwards withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, tremor, wet dog shakes, abnormal posture and abnormal gait were recorded or rated. Olanzapine (0.5, 1 and 2 mg/kg) and saline were injected to the rats intraperitoneally 30 min before ethanol withdrawal assessment. A second series of injections was also given 30 min before the 6th-h-observation, and subjects were then tested for audiogenic seizures. Olanzapine (2 mg/kg) produced significant inhibitory effects on stereotyped behaviors and wet dog shakes at the 6th h of ethanol withdrawal. Contrary, the same dose caused some increases in the intensity of posture and gait impairments at the 2nd h of ethanol withdrawal. In addition, that dose was found to be ineffective on agitation, tremor, tail stiffness and audiogenic seizures. Our results suggest that acute olanzapine treatment has beneficial effects on stereotyped behavior and wet dog shakes, but it also has some adverse effects on posture and gait during ethanol withdrawal in rats. Overall, olanzapine does not seem to be an adequate and suitable drug in controlling of ethanol withdrawal syndrome.

Serotonergic anti-depressants and ethanol withdrawal syndrome: A review

To review laboratory findings on the effects of anti-depressant agents that interact with the serotonergic system on signs of ethanol withdrawal syndrome in rats. Adult Wistar rats received a modified liquid diet to produce ethanol dependence. Signs of ethanol withdrawal, locomotor hyperactivity, stereotyped behaviour, tremor, wet dog shakes, agitation, and audiogenic seizures, were evaluated for the first 6 h of ethanol withdrawal. The effects of the anti-depressants fluoxetine, venlafaxine, escitalopram, tianeptine, and extract of Hypericum perforatum (St. John's wort) (HPE) were examined. Some beneficial effects of fluoxetine, tianeptine, HPE, escitalopram and venlafaxine on ethanol withdrawal signs were observed, ranked as follows: fluoxetine = tianeptine > HPE > escitalopram > venlafaxine. Tianeptine and fluoxetine seem to be potent pharmacologically active agents on ethanol withdrawal syndrome in rats. Thus, these anti-depressants may be useful in treatment of ethanol withdrawal syndrome in patients with alcoholism. In addition to serotonergic effects, interactions with nitrergic, glutamatergic, and adenosinergic systems may also provide a significant contribution to the beneficial effects of these drugs on ethanol withdrawal syndrome.

P.6.b.004 Effects of clozapine on ethanol withdrawal syndrome in rats

P.6.b.004 Effects of clozapine on ethanol withdrawal syndrome in rats

Attenuation of ethanol withdrawal syndrome by extract of Hypericum perforatum in Wistar rats

The effects of Hypericum perforatum (St John's wort) on ethanol withdrawal syndrome have been investigated in ethanol-dependent rats. Adult male Wistar rats were subjects. Ethanol (7.2% v/v) was given to rats by a liquid diet for 15 days. Hypericum perforatum extract (HPE) (25-200 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After second, fourth and sixth hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, stereotyped behavior and tremors were recorded or rated. A second series of injections was given at 6 h after the first one, and subjects were then tested for audiogenic seizures. HPE (25-200 mg/kg) produced some dose-dependent and significant inhibitory effects on locomotor hyperactivity at second and sixth hour of ethanol withdrawal. In addition, it significantly reduced the number of stereotyped behaviors at the same dose range. HPE (50 and 100 mg/kg) produced some significant inhibitory effects on tremor and audiogenic seizures during withdrawal period. These results suggest that HPE has some beneficial effects on ethanol withdrawal syndrome in rats.

Effects of escitalopram on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of escitalopram, a selective serotonin reuptake inhibitor, on ethanol withdrawal syndrome in rats. Adult male Wistar rats (266–278 g) were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed with an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Escitalopram (2.5, 5 and 10 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the second and sixth hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes, tremors and audiogenic seizures were recorded or rated. A second series of injections was given 30 min before sixth hour of withdrawal test. Effects of escitalopram on the locomotor activities of the naïve (no ethanol-dependent) rats were also evaluated. Escitalopram (5 mg/kg) reduced the increased stereotyped behaviors at the sixth hour of ethanol withdrawal. It inhibited tremors at the second hour of ethanol withdrawal at doses of 5 and 10 mg/kg. Escitalopram (2.5 and 5 mg/kg) also produced some significant attenuations in the incidence of wet dog shakes at the second and sixth hours of the observation period. It was found ineffective on locomotor hyperactivity, agitation and audiogenic seizures. Escitalopram (2.5 and 5 mg/kg) did not cause any significant effect on locomotor activities of the naïve rats. Our results suggest that acute escitalopram treatment has some limited beneficial effects on ethanol withdrawal syndrome in rats.

Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats

Effects of acute and chronic tianeptine treatments on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Acute or chronic (twice daily) tianeptine (5, 10 and 20 mg/kg) and saline were administered to rats intraperitoneally. Acute and last chronic tianeptine injections and saline were done 30 min before ethanol withdrawal testing. After 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, tremor, wet dog shakes, stereotyped behavior and audiogenic seizures were recorded or rated. Locomotor activity in naive (no ethanol-dependent rats) was also tested after acute tianeptine treatments. Acute but not chronic tianeptine treatment attenuated locomotor hyperactivity and agitation in ethanol-dependent rats. Both acute and chronic tianeptine treatment produced some significant inhibitory effects on tremor, wet dog shakes, stereotyped behaviors and audiogenic seizures during the ethanol withdrawal. Our results suggest that acute or chronic tianeptine treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

P.6.b.005 Effects of olanzapine on ethanol withdrawal syndrome in rats

Changes in dopaminergic and serotonergic levels and metabolites in cerebral cortex, corpus striatum and hippocampus were investigated during the first 6-h of withdrawal in ethanol-dependent Wistar rats. Ethanol was given by a liquid diet for 21 days. The concentration of ethanol was 7.2% (v/v) for the last 15 days of the exposure. After 2, 4 and 6 h of ethanol withdrawal, and after audiogenic stimulus (100 dB for 60 s) at 6 h of ethanol withdrawal, various brain regions were assayed for levels of dopamine (DA), DOPAC, HVA, serotonin (5-HT) and 5-HIAA. Behavioral signs of ethanol withdrawal and blood ethanol levels were also evaluated in other parallel groups of ethanol-dependent rats. Significant decreases in 5-HT levels and significant increases in HVA levels in striatum were found during the first 6 h of ethanol withdrawal and after the audiogenic seizures. In hippocampus, 5-HIAA levels were significantly reduced after 2 h of ethanol withdrawal and after the audiogenic seizures. 5-HIAA levels significantly increased after 2 h of ethanol withdrawal in cerebral cortex. Significant increases in both DA and 5-HT levels were also found in cerebral cortex after the audiogenic seizures. The results suggest that the levels of DA, 5-HT and their metabolites are altered by ethanol withdrawal. Furthermore, this may suggest that DA and 5-HT may be involved in the first 6 h of ethanol withdrawal syndrome in rats.

Effects of venlafaxine on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), on ethanol withdrawal syndrome in rats. Adult male Wistar rats (187-319 g) were used for the study. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair-fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Venlafaxine (5, 10, 20 and 40 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behaviour and wet dog shakes were recorded or rated. A second series of injections was given at the 6th hour after the first one, and rats were then tested for audiogenic seizures. Venlafaxine produced some inhibitory effects on locomotor hyperactivity, stereotypic behaviours and wet dog shakes. However, a two-way anova of the data did not indicate any significant effect. It reduced the incidence of the audiogenic seizures at the 6th hour of ethanol withdrawal. Venlafaxine (20 mg/kg) also prolonged the latency of the seizures significantly. Our results suggest that acute venlafaxine treatment has limited beneficial effects on ethanol withdrawal syndrome in rats.

Effects of fluoxetine on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of fluoxetine, a selective serotonin reuptake inhibitor, on ethanol withdrawal syndrome in rats. Adult male Wistar rats (218–255 g) were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Fluoxetine (2.5, 5 and 10 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes and tremor were recorded or rated. A second series of injections was given at 6 h after the first one, and subjects were then tested for audiogenic seizures. Fluoxetine produced some dose-dependent and significant inhibitory effects on all the signs of ethanol withdrawal during ethanol withdrawal period. Our results suggest that acute fluoxetine treatment has some beneficial effects on ethanol withdrawal in rats. Thus, this drug may be useful for treatment of ethanol withdrawal syndrome.

P.5.045 Effects of venlafaxine on ethanol withdrawal syndrome in rats

The genes that encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1, which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, we genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. This can be accounted for by linkage disequlibrium between ADH3*1 and ADH2*2 ALDH2*2 homozygosity, regardless of the ADH2 genotypes, was fully protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (ORs 0.04–0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk associated with the ADH2*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH2*1/*2-ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that afforded by ALDH2*2.

P.5.048 Effects of fluoxetine on ethanol withdrawal syndrome in rats

P.5.048 Effects of fluoxetine on ethanol withdrawal syndrome in rats

Attenuation of ethanol withdrawal signs by high doses of L-arginine in rats.

Effects of l-arginine, a nitric oxide (NO) precursor, on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to rats by a liquid diet for 16 days. l-Arginine (250, 500 and 1000 mg/kg) or saline were injected into rats intraperitoneally 20 min before ethanol withdrawal. All injections were repeated 30 min before the 6th h of the observation period. The effects of l-arginine on ethanol withdrawal syndrome were evaluated during the first 6 h of ethanol withdrawal. l-Arginine (250 mg/kg) potentiated significantly vertical and ambulatory locomotor activities at only the 30th minute of the observation period. l-Arginine (500 and 1000 mg/kg) inhibited behavioural signs of ethanol withdrawal significantly. l-Arginine (1000 mg/kg) also prolonged the latency and attenuated the intensity of audiogenic seizures. This dose of l-arginine also reduced both vertical and ambulatory locomotor hyperactivity of the rats from the 2nd hour of ethanol withdrawal. l-Arginine (1000 mg/kg) did not produce any significant change in the locomotor activities of the naive (non-ethanol-dependent) rats. Our results indicate that l-arginine at high doses alleviates the signs of ethanol withdrawal syndrome in rats.

Effects of agmatine on ethanol withdrawal syndrome in rats

Effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of l-arginine, have been investigated on the ethanol withdrawal syndrome in rats. Adult male Wistar rats were used in the study. Ethanol (7.2% v/v) was given to the rats by a liquid diet for 21 days. Agmatine (20, 40, 80 and 160 mg/kg) and saline were injected to rats intraperitoneally 30 min before ethanol withdrawal testing. After 30th min, 2nd and 6th h of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes and tremor were recorded or rated. A second series of injections was given at 6 h after the first one, and subjects were then tested for audiogenic seizures. Agmatine caused dose-dependent and significant inhibitory effects on stereotyped behaviors, wet dog shakes and tremors during the observation period. It did not cause any significant change in motor coordination of naive (not ethanol-dependent) rats. Our results suggest that agmatine attenuates withdrawal syndrome in ethanol-dependent rats; thus, this drug may be beneficial in the treatment of ethanol dependence.

Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs

Changes in dopaminergic and serotonergic levels and metabolites in cerebral cortex, corpus striatum and hippocampus were investigated during the first 6-h of withdrawal in ethanol-dependent Wistar rats. Ethanol was given by a liquid diet for 21 days. The concentration of ethanol was 7.2% (v/v) for the last 15 days of the exposure. After 2, 4 and 6 h of ethanol withdrawal, and after audiogenic stimulus (100 dB for 60 s) at 6 h of ethanol withdrawal, various brain regions were assayed for levels of dopamine (DA), DOPAC, HVA, serotonin (5-HT) and 5-HIAA. Behavioral signs of ethanol withdrawal and blood ethanol levels were also evaluated in other parallel groups of ethanol-dependent rats. Significant decreases in 5-HT levels and significant increases in HVA levels in striatum were found during the first 6 h of ethanol withdrawal and after the audiogenic seizures. In hippocampus, 5-HIAA levels were significantly reduced after 2 h of ethanol withdrawal and after the audiogenic seizures. 5-HIAA levels significantly increased after 2 h of ethanol withdrawal in cerebral cortex. Significant increases in both DA and 5-HT levels were also found in cerebral cortex after the audiogenic seizures. The results suggest that the levels of DA, 5-HT and their metabolites are altered by ethanol withdrawal. Furthermore, this may suggest that DA and 5-HT may be involved in the first 6 h of ethanol withdrawal syndrome in rats.

P.5.001 Dopaminergic turnover changes on various brain regions during ethanol withdrawal syndrome in rats

P.5.001 Dopaminergic turnover changes on various brain regions during ethanol withdrawal syndrome in rats