• Energy Research

The main objective of the present study is to investigate the possible effects of chronic ethanol consumption and ethanol withdrawal on cyclic guanosine 3', 5'-monophosphate (cGMP) levels in cerebral cortex, striatum, hippocampus and hypothalamus of rat brain. Ethanol was given to female Wistar rats (225-270g) by a liquid diet for 21 days. cGMP levels were measured in respective brain regions using an EIA kit at 7th, 14th and 21st days of ethanol ingestion and at 6th and 24th h of ethanol withdrawal. cGMP levels in cortex, striatum and hippocampus but not hypothalamus were found significantly increased at 14th and 21st days of ethanol consumption. The most prominent increase was observed in striatal tissues (approximately 350%). cGMP levels of striatum and hippocampus were still remaining significantly high at 6th h of ethanol withdrawal. Blood ethanol levels were found as 115.60, 50.0 and 7.0mg/dl just before and after 6 and 24h of ethanol withdrawal, respectively and audiogenic seizures also occurred at 6th h of ethanol withdrawal with an incidence of 75% in individual parallel groups. Our results suggest that changes of cGMP levels in cerebral cortex, striatum and hippocampus might participate in the mechanism of ethanol dependence and withdrawal in rats.

The effect of ethanol on rats was investigated at increasing rates of acceleration for bar rotation speed. Ethanol was given to rats by a liquid diet starting with 2.4% ethanol (v/v) for 3 days. Then the ethanol concentration was increased to 4.8% (v/v) for 3 days and finally to 7.2% (v/v) for 15 days. Accelerod performance was recorded before and throughout 20 days of ethanol intake. Mean blood ethanol levels were 266.34+/-13.11 and 285.20+/-9.77 mg/dl on the 7th and 15th days of ethanol (7.2% v/v) consumption, respectively, as measured in a parallel group of animals. Ethanol produced significant concentration-dependent impairments in the accelerod performance of rats. The motor impairment effect of ethanol was most prominent in the test using the greatest rate of acceleration (from 0 to 79 rpm within 2 min). The impairment effect of ethanol on accelerod performance occurred throughout the period of ethanol exposure. Our results indicate that motor impairment on the accelerod performance test produced by an ethanol liquid diet depends on the concentration of ethanol and the rate of acceleration. In addition, under free-access conditions accelerod performance may not be a suitable behavioral test for detecting tolerance development to ethanol 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.

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.

The effects of bromocriptine and haloperidol, either alone or in combination, on ethanol withdrawal syndrome (EWS) have been investigated in rats. Bromocriptine (5 mg/kg 1P) inhibited wet dog shakes behavior and catatonia but potentiated the intensity of abnormal gait. The latency of the audiogenic seizures was prolonged by bromocriptine treatment. Haloperidol (0.5 mg/kg SC) decreased the intensity of stereotyped behavior but potentiated catatonia and agitation. It did not antagonize the behaviors induced by bromocriptine when injected in combination except the increased latency of the audiogenic seizures. The total intensity score of the EWS was not significantly different from that in untreated control. The results suggest that brain dopaminergic system may be involved to a limited extent in mediating the EWS in rats.

In the present study, a possible sensitization development to a single injection of ethanol in mice was investigated. Subjects were adult male Swiss-Webster mice. Ethanol (0.5-4 g/kg) or saline (control) was intraperitoneally injected to mice. Horizontal, vertical and ambulatory locomotor activities were recorded for 30 min immediately following the ethanol or saline injections. After 2 weeks, each group of mice was randomly assigned to two groups. A single challenge dose of ethanol (1 g/kg) was administered to the first group, and saline was injected to the second group. Then, the locomotor activities were recorded for 30 min. In the first experiment, ethanol significantly increased the horizontal and ambulatory activities of the mice at the doses of 0.5 and 1 g/kg, but not at 2 g/kg, while they were decreased at the dose of 4 g/kg. Ethanol (0.5 g/kg) also significantly increased the vertical activity. After 2 weeks, the challenge injection of ethanol (1 g/kg) produced some significant increases in the horizontal and ambulatory activities of the group pretreated with ethanol (2 g/kg). It did not cause any significant change on the locomotor activities of the other three groups treated with lower (stimulant) or higher (depressant) doses of ethanol. In addition, there was no significant difference between locomotor activities of the groups challenged with saline. However, a two-way ANOVA of the data on the challenge injections did not indicate any sensitization development to the effects of ethanol on locomotor activities of the mice. Our results suggest that a locomotor sensitization did not develop to a single injection of ethanol after 2 weeks following the first injection in mice.

The objective of the present study was to examine the effects of prenatal exposure to ethanol on motor performance, emotionality, learning and memory in young-adult, male Wistar rats. Alcohol was delivered to the pregnant dams intragastrically, throughout gestation days (GD) 7-20, at the dose of 6 g/kg/day resulting in the peak blood alcohol concentration (BAC) of 350 mg/dl as assessed on GD 20. Isocaloric intubation and untreated control groups were included. Alcohol exposed rats were not impaired in the rotarod/accelerod tests. Their behavior in the open field and plus maze suggested increased neophobia. Hyperactivity was not observed. In the spatial-navigation task in the water maze, by the middle of the training, fetal alcohol rats showed a tendency towards a slower place acquisition compared to controls, but statistical analysis of the data did not yield between-group differences significant. Towards the end of the training, all rats reached a similar performance level. No detectable between-group differences were noted either in memory retention after a delay, in reversal learning, or in working memory task. Our findings demonstrate that the adverse behavioral effects of a binge-like alcohol administration during half of the first and throughout the second trimester equivalent are difficult to be disclosed in young-adult male Wistar rats. The possible reasons of the lack of significant behavioral deficits in the fetal-alcohol rats observed in the present study are discussed.

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.