Ethanol Withdrawal In Mice Research Articles

Ethanol-Induced Suppression of G Protein–Gated Inwardly Rectifying K+–Dependent Signaling in the Basal Amygdala

BackgroundThe basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder. The GABABR (gamma-aminobutyric acid B receptor) is a promising therapeutic target for alcohol use disorder, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABABR-dependent signaling. The effect of ethanol on GABABR-dependent signaling in the BLA is unknown. MethodsGABABR-dependent signaling in the mouse BLA was examined using slice electrophysiology following repeated ethanol exposure. Neuron-specific viral genetic manipulations were then used to understand the relevance of ethanol-induced neuroadaptations in the basal amygdala subregion (BA) to mood-related behavior. ResultsThe somatodendritic inhibitory effect of GABABR activation on principal neurons in the basal but not the lateral subregion of the BLA was diminished following ethanol exposure. This adaptation was attributable to the suppression of GIRK (G protein–gated inwardly rectifying K+) channel activity and was mirrored by a redistribution of GABABR and GIRK channels from the surface membrane to internal sites. While GIRK1 and GIRK2 subunits are critical for GIRK channel formation in BA principal neurons, GIRK3 is necessary for the ethanol-induced neuroadaptation. Viral suppression of GIRK channel activity in BA principal neurons from ethanol-naïve mice recapitulated some mood-related behaviors observed in C57BL/6J mice during ethanol withdrawal. ConclusionsThe ethanol-induced suppression of GIRK-dependent signaling in BA principal neurons contributes to some of the mood-related behaviors associated with ethanol withdrawal in mice. Approaches designed to prevent this neuroadaptation and/or strengthen GIRK-dependent signaling may prove useful for the treatment of alcohol use disorder.

Attenuation of the levels of pro-inflammatory cytokines prevents depressive-like behavior during ethanol withdrawal in mice

Clinical studies indicate that alcohol-dependent patients may develop depressive symptoms during abstinence, which may increase the likelihood of relapse. It is known that both in alcohol exposure and depression, there is an increase in the levels of pro-inflammatory cytokines in the brain. However, the putative contribution of increased levels of pro-inflammatory cytokines in the development of depressive-like behavior during ethanol withdrawal has not been evaluated. In the present study, we aimed to investigate if ethanol withdrawal-induced depressive-like behavior is related to increased levels of pro-inflammatory cytokines in the brain. Male mice were treated with vehicle (saline 0.9%, v.o.) or ethanol (2 g/kg, v.o.) for 14 days. After 5 days of cessation of the ethanol treatment, mice were subjected to the forced swim test (FST), tail suspension test (TST), and open field test (OFT) and then sacrificed. Their brains were analyzed for the levels of pro-inflammatory cytokines. Ethanol withdrawal mice showed increased immobility time in the FST and TST than by the control group, indicating increased depressive-like behavior. No alterations in OFT were observed. Ethanol withdrawal increased the levels of tumor necrosis factor-alpha (TNF-α) in the hippocampus and striatum, interleukin-1 beta (IL-1β) in the hippocampus, and IL-6 in the prefrontal cortex and hippocampus. Treatment of mice with nimesulide (5 or 10 mg/kg/day), a cyclooxygenase-2 inhibitor, during ethanol withdrawal prevented the increase in immobility time in the TST. Similar results were observed in the FST upon nimesulide treatment, although with a higher dose. Nimesulide treatment (10 mg/kg) prevented the ethanol withdrawal-induced alterations in the levels of TNF-α, IL-1β, and IL-6 in the hippocampus, prefrontal cortex, and striatum. Treatment of mice with an atypical antidepressant drug, vilazodone (0.3 or 1 mg/kg) prevented the increase in depressive-like behavior induced by ethanol withdrawal in the TST. In the FST, the increase in immobility time was prevented only by 1 mg/kg vilazodone treatment. Vilazodone prevented the increase in the levels of TNF-α, IL-1β, and IL-6 in the hippocampus, IL-6 in the prefrontal cortex, and TNF-α in the striatum. In conclusion, these data indicate that increased levels of pro-inflammatory cytokines may play a role in the development of depressive-like behavior during ethanol withdrawal in mice.

Evaluation of anxiety-like behaviors following ethanol withdrawal in mice: effects of cannabidiol

The abrupt interruption of ethanol consumption increases anxiety-like behaviors in rodents and may reflect different aspects of ethanol dependence in humans. Measuring emotional behaviors resulting from ethanol withdrawal may aid in testing potential pharmacological agents for the treatment of ethanol dependence. In the present study, we used forced expositon to ethanol 20% during 10 days to mice, followed by abrupt withdrawal of the substance. The animals were evaluated 7, 24 and 35 h after ethanol withdrawal in three different behavioral paradigms, i.e., the open field (OF), light dark (LD) transition and elevated plus maze (EPM), tests usually used to measure anxiety-like behaviors. This was done with the aim of identifying the best interval as well as the most appropriate behavioral test to detect the effects of drugs that can relieve anxiety induced by ethanol withdrawal in mice. We also evaluated the effect of cannabidiol (CBD 10, 30 and 60 mg/kg) in ethanol withdrawn mice because it has been shown to alliviate drug addicton and present anti-anxiety effects. Our results show significant behavioral changes at 24 h following ethanol withdrawal. Diazepam (4 mg/kg), used as a positive control, counteracted the effects of ethanol withdrawal in OF, LD box and EPM. Cannabidiol attenuated anxiety-like behavior produced at 24 h after abstinence from ethanol exposure only in the EPM test.

Electroacupuncture inhibits CB1 upregulation induced by ethanol withdrawal in mice

CB1R play a role in alcohol withdrawal and in some effects of acupuncture. Interestingly, acupuncture has been used to alleviate alcohol withdrawal. Here, we investigated electroacupuncture (EA) effects during ethanol withdrawal on CB1R immunoreactivity. Male Swiss mice were daily injected with ethanol (2g/kg, i.p) (EtOH group), for 21days. EA was performed daily during 4days of ethanol withdrawal. The stimuli of 2 or 100Hz were provided in two acupoints combination: Ea1 [(ST-36/Zusanli) and (PC-6/Neiguan)] or Ea2 [(DU-14/Dazhui) and (DU-20/Baihui)]. The specificity of the acupoints were assessed by the inclusion of three additional groups, Ea3 [(ST 25/Tianshu – acupoints used to other non-related disorders)], Sham1 and Sham2 (transdermic stimulation nearly to the respective acupoints). EtOH group were only handled during withdrawal and Saline group was chronically treated with Saline and handled similarly to EtOH group. One day after withdrawal the animals were perfused and their brains processed for immunohistochemistry. There was an increase of CB1R in the prefrontal cortex, striatum, hippocampus, amygdala and ventral tegmental area. The procedures used in the 2HzEa1 and 100HzEa2 groups were the most effective and specific to inhibit this CB1R upregulation. Therefore, EA inhibits CB1R upregulation seen in ethanol withdrawn mice. The specificity of acupoints stimulation depends of the encephalic nuclei, acupoints association and frequency of stimulation.

Substantia nigra pars reticulata is crucially involved in barbiturate and ethanol withdrawal in mice

Sedative-hypnotic CNS depressant drugs are widely prescribed to treat a variety of disorders, and are abused for their sedative and euphoric effects. Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force that sustains their use/abuse and may contribute to relapse in dependent individuals. Although no animal model duplicates depressant dependence, models for specific factors, like withdrawal, are useful for identifying potential neural determinants of liability in humans. Recent analyses implicate the caudolateral substantia nigra pars reticulata (clSNr) in withdrawal following acute and repeated ethanol exposures in mice, but did not assess its impact on withdrawal from other sedative-hypnotics or whether intrinsic neurons or fibers of passage are involved. Here, we demonstrate that bilateral chemical (ibotenic acid) lesions of the clSNr attenuate barbiturate (pentobarbital) and ethanol withdrawal. Chemical lesions did not affect convulsions in response to pentylenetetrazole, which blocks GABAA receptor-mediated transmission. Our results demonstrate that the clSNr nucleus itself rather than fibers of passage is crucial to its effects on barbiturate and ethanol withdrawal. These findings support suggest that clSNr could be one of the shared neural substrates mediating withdrawal from sedative-hypnotic drugs.

Alcohol Withdrawal‐Induced Hippocampal Neurotoxicity In Vitro and Seizures In Vivo are Both Reduced by Memantine

The ethanol withdrawal (EWD) syndrome is typically treated using benzodiazepines such as diazepam. However there is concern that benzodiazepines may not prevent neurotoxicity associated with EWD. Antagonists of glutamate/N-Methyl-D-Aspartate receptors (NMDARs) such as MK801 have been shown to be effective against both EWD-induced neurotoxicity in vitro and seizures in vivo. However, most of these agents have adverse side effects. An exception is the moderate affinity NMDAR channel blocker memantine, used in Alzheimer's dementia. The present studies examined the ability of memantine to protect against EWD-related toxicity in vitro and seizures in vivo. Organotypic hippocampal slice cultures from neonatal rat pups were treated starting at 15 days in vitro with 100 mM ethanol for 10 days followed by a 24-hour EWD period. During the 24-hour EWD period cultures were treated with memantine (15 or 30 microM). MK801 (10 microM) was utilized as a positive control. For the in vivo studies, the ability of memantine (2, 5, 10, and 15 mg/kg) to reduce convulsions was analyzed in Swiss-Webster mice using the handling induced convulsion test paradigm. In vitro studies demonstrated that memantine is effective at blocking EWD-induced neurotoxicity. In vivo experiments showed that memantine also significantly reduced convulsions induced by EWD in mice. Memantine may be of therapeutic value during alcohol detoxification by virtue of its having neuroprotective effects in addition to anti-seizure activity. The potential role of memantine in treatment of alcoholism is deserving of further study.

Motor impairment: a new ethanol withdrawal phenotype in mice

Alcoholism is a complex disorder with genetic and environmental risk factors. The presence of withdrawal symptoms is one criterion for alcohol dependence. Genetic animal models have followed a reductionist approach by quantifying various effects of ethanol withdrawal separately. Different ethanol withdrawal symptoms may have distinct genetic etiologies, and therefore differentiating distinct neurobiological mechanisms related to separate signs of withdrawal would increase our understanding of various aspects of the complex phenotype. This study establishes motor incoordination as a new phenotype of alcohol withdrawal in mice. Mice were made physically dependent on ethanol by exposure to ethanol vapor for 72 h. The effects of ethanol withdrawal in mice from different genetic backgrounds were measured on the accelerating rotarod, a simple motor task. Ethanol withdrawal disrupted accelerating rotarod behavior in mice. The disruptive effects of withdrawal suggest a performance rather than a learning deficit. Inbred strain comparisons suggest genetic differences in magnitude of this withdrawal phenotype. The withdrawal-induced deficits were not correlated with the selection response difference in handling convulsion severity in selectively bred Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant lines. The accelerating rotarod seems to be a simple behavioral measure of ethanol withdrawal that is suitable for comparing genotypes.

Effects of the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on handling-induced convulsions during ethanol withdrawal in mice

In alcoholic patients, ethanol is often consumed in a repeated cyclic pattern of intoxication followed by abstinence and the emergence of withdrawal symptoms. Repeated cycles of ethanol intoxication and withdrawal lead to a sensitization of central nervous system hyperexcitability as a result of an imbalance between inhibitory GABAergic transmission and excitatory glutamatergic transmission. Symptoms of alcohol withdrawal are usually treated pharmacologically with either benzodiazepines or anticonvulsant medications. However, recent evidence suggests that inhibition of glutamate transmission by stimulation of presynaptic inhibitory metabotropic glutamate receptors (i.e., mGluR2/3 receptors) or inhibition of mGluR5 receptors produces anticonvulsant effects. Therefore, the present study was designed to determine the effects the mGluR2/3 agonist LY379268 and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on ethanol withdrawal-induced seizure activity. Adult male C3H/He mice received chronic 16 h of ethanol vapor exposure in inhalation chambers followed by 8 h of withdrawal daily for 4 consecutive days. During the final (fourth) withdrawal cycle, mice were evaluated hourly for handling-induced convulsions (HIC), and were treated with vehicle, LY379268 (0.3, 1, and 3 mg/kg) or MPEP (1, 3, and 10 mg/kg) treatment at 4 and 8 h into withdrawal. Significant reductions in overall HIC activity were not observed following administration of either compound. These results suggest that inhibition of glutamate transmission by mGluR2/3 agonists or mGluR5 antagonists does not alter HIC activity during withdrawal from repeated ethanol exposure, and as such these compounds may have limited usefulness in the treatment of central nervous system hyperexcitability during alcohol withdrawal.

Anxiolytic activity of Atrial Natriuretic Peptide and ß-Endorphin during acute Ethanol withdrawal in mice

Tumor angiogenesis and PI3K/Akt/mTOR pathway are two major molecular objectives for the treatment and management of breast cancer. Here we first time report the molecular mechanism of a marine sponge alkaloid derivative 4-chloro fascapysin (4-CF) for its anticancer and antiangiogenesis potential. It simultaneously targets multiple cancer and angiogenesis dynamics, such as proliferation, chemotaxis cell migration, and invasion, growth factors signaling cascade, autophagy and apoptosis in HUVEC and MDAMB-231 breast cancer cells. It inhibited the VEGF mediated microvessel sprouting and blood vessel formation in the matrigel plug of C57/BL6J mice. It inhibits the tumor growth in ET (solid) mouse tumor model. It significantly inhibited cell survival through PI3K/Akt/mTOR pathway, with attendant effects on key pro-angiogenesis factors like HIF-1α, eNOS and MMP-2/9. The cytotoxicity of 4-CF was reversed by co-treatment with the VEGF and Akt inhibitors sunitinib and perifosine, respectively or by the addition of neutralizing VEGF antibodies. The apoptotic potential of 4-CF was through mitochondrial dependent as illustrated through loss of mitochondrial membrane potential. The safety profile of 4-CF was acceptable as it exhibits five times high cytotoxic IC50 value in normal cells as well as no apparent toxicities in experimental tumor mice at therapeutic doses.

Double-blind study of cyamemazine and diazepam in the alcohol withdrawal syndrome

Cyamemazine is an original phenothiazine derivative which showed similar efficacy and tolerability to lorazepam during ethanol withdrawal in mice. This study investigated cyamemazine for its efficacy and tolerability in alcohol-dependent patients electing an alcohol withdrawal procedure, in comparison with diazepam. A multicenter, randomized, double-blind study in 89 alcohol-dependent patients (CIWA-Ar score between 10 and 30), electing an alcohol withdrawal procedure, was used to find effective doses of cyamemazine and to compare it with diazepam for efficacy and tolerability. On day 1 (D(1)), cyamemazine or diazepam (50 mg and 10 mg capsule, respectively) were administered at hourly intervals to reduce CIWA-Ar = 5, up to a maximum of eight administrations. Starting from D(2), the compounds were given twice a day in progressively decreasing doses during a maximum period of 13 days (D(end)). At h(8) (8 h after the first treatment of D(1)), therapeutic success (CIWA-Ar score </= 5) was achieved in 32 out of 43 ITT patients treated with cyamemazine (74.4%), a value very similar to that of diazepam (32/44; 72.7%). Most such patients (29/32) were controlled with 2-6 capsules of cyamemazine (100-300 mg). In the PP population, cyamemazine (n = 28) was significantly non-inferior to diazepam (n = 33), with a threshold of 10% for non-inferiority bound and 2.5% for one-sided type I error rate. Such therapeutic similarity was confirmed by the analysis of other efficacy criteria. Safety analysis did not show substantial differences between the two treatments. Cyamemazine showed similar efficacy and tolerability to diazepam for the treatment of alcohol withdrawal symptoms at therapeutic doses in the range 100-300 mg.

Expression profiling identifies strain-specific changes associated with ethanol withdrawal in mice.

Mice that exhibit characteristics of physical dependence following ethanol exposure serve as useful models of alcoholism in humans. The DBA/2J and C57BL/6J inbred strains differ in their behavioral response to ethanol withdrawal. Alterations in gene expression are believed to underlie neuroadaptation to ethanol dependence and tolerance. Therefore, the differences in ethanol withdrawal severity observed between the DBA/2J and C57BL/6J strains may be related to differential regulation of gene expression. We have used cDNA microarrays to determine the gene expression profile in the hippocampus of DBA/2J and C57BL/6J mice during withdrawal after chronic and acute ethanol exposure. Of the 7634 genes surveyed, approximately 2% were consistently differentially expressed by at least 1.4-fold in DBA/2J mice during chronic ethanol withdrawal. Less than 1% of the genes showed altered expression in C57BL/6J mice under the same conditions, or in DBA/2J mice during acute ethanol withdrawal. Strain- and treatment-specific patterns of altered expression were observed for multiple genes associated with the Janus kinase/signal transducers and activators of transcription and the mitogen activated protein kinase pathways. Genes associated with both pathways are regulated in DBA/2J mice during chronic ethanol withdrawal, and to a lesser extent during acute ethanol withdrawal. Only those genes associated with the mitogen-activated protein kinase (MAPK) pathway exhibited changes in expression in C57BL/6J mice during ethanol withdrawal. Furthermore, genes associated with retinoic acid-mediated signaling show differential expression exclusively in C57BL/6J mice. These findings represent significant differences in cellular adaptation to ethanol between the DBA/2J and C57BL/6J strains.

Correlation between increases in dihydropyridine binding in vivo and behavioural signs of ethanol withdrawal in mice.

Increased ligand binding to dihydropyridine receptors in the central nervous system after chronic ethanol consumption is thought to contribute to the withdrawal syndrome. Previous studies demonstrated such changes when the binding was measured in vitro, which, as the receptors are voltage-sensitive, may not accurately reflect the binding in vivo. In the present study, dihydropyridine binding was measured in vivo in mice, after intravenous administration of the radioligand. The aim was to determine whether there was any correlation between such binding and measurements of behavioural hyperexcitability at different times during the withdrawal phase and after two different methods of alcohol administration. Measurements were made of the binding in vivo of [3H]nitrendipine, at intervals after withdrawal from chronic ethanol administration, and of the severity of withdrawal as measured by response to gentle handling. An increase in the in vivo binding to [3H]nitrendipine was seen after cessation of chronic ethanol consumption by liquid diet. The binding was significantly increased at 4 h, when the behavioural changes were maximal, but not immediately after withdrawal, when the responses to handling were unchanged. By 24 h after cessation of the ethanol treatment, no differences in the binding were found, compared with control values; at this time the withdrawal hyperexcitability had ceased. When alcohol was given chronically by inhalation, the in vivo dihydropyridine binding was increased at 3 h from withdrawal of the ethanol, the time of maximal behavioural hyperexcitability, but no change was seen 30 min after withdrawal, when no changes in the ratings of behaviour were found. There was a significant positive correlation in individual mice between the ratings of handling-induced behaviour at the 3 h interval and the amount of in vivo binding. These data support the hypothesis that the sites labelled by [3H]nitrendipine play an important role in withdrawal hyperexcitability.

Cyamemazine decreases ethanol intake in rats and convulsions during ethanol withdrawal syndrome in mice.

The effect of cyamemazine a dopamine D2 receptor antagonist on voluntary ethanol consumption in rats and on ethanol withdrawal in mice was examined. Male Sprague-Dawley rats were tested in a free choice (water and 10% ethanol) experiment and consumed 5 g/kg ethanol daily. Rats were treated daily IP with cyamemazine (0.5, 1, or 2 mg/kg) or acamprosate (100 mg/kg) during 2 weeks. Both acamprosate and 1 mg/kg cyamemazine significantly decreased ethanol intake by 45% without affecting either fluid or food intake. The lowest dose of cyamemazine had no effect on alcohol intake but increased food intake. The highest dose had no effect on any variables. During the post-treatment period, only 1 mg/kg cyamemazine decreased both ethanol and fluid intakes. Mice were made dependent on alcohol using a chocolate fluid diet containing increasing concentrations of alcohol and withdrawn after 9 days. Mice were treated with cyamemazine (1 or 0.5 mg/kg, respectively) or with the same doses of lorazepam acutely on the day of withdrawal or chronically (during alcohol treatment). Both chronic and acute cyamemazine and lorazepam treatments decreased convulsions during ethanol withdrawal. Both acute treatments decreased locomotor activity in control and alcohol dependent mice. Chronic treatment had no effect on locomotor activity. We suggest that cyamemazine could reduce alcohol consumption by antagonizing the activation of the dopaminergic pathways during the induction of alcohol dependence. The action of cyamemazine on 5-HT3 receptors could also explain its effect on alcohol convulsions during withdrawal convulsions.

Chronic ethanol administration alters activity in ventral tegmental area neurons after cessation of withdrawal hyperexcitability

The present study investigated the activity of neurons in the mesolimbic dopamine system after the end of the acute phase of the behavioural signs of ethanol withdrawal in mice. This was designed to provide a comparison with earlier behavioural studies, in which greater development of sensitisation to amphetamine and cocaine, but no change in the initial effects of these compounds, or in the behaviour in the absence of drug treatment, was seen when repeated injection of these psychostimulants were given after chronic ethanol consumption. In the present study, single unit recordings were made from dopamine-sensitive neurons in the ventral tegmental area in perfused midbrain slices prepared 24 h after cessation of chronic ethanol consumption. Profound decreases in firing of the ventral tegmental area (VTA) neurons were seen in slices prepared after the ethanol treatment. Firing rates increased after application of N-methyl- dl-aspartate, but still remained lower and more variable after the ethanol treatment. Application of dopamine or amphetamine, following stimulation of firing with a low concentration of N-methyl- dl-aspartate, also resulted in lower firing rates in slices from ethanol-treated mice. No changes were seen in release of tritiated dopamine, in response to applied KCl or amphetamine, from slices of striatum or cerebral cortex, prepared 24 h after cessation of the chronic ethanol consumption, compared with control values. The results demonstrate that very substantial decreases in firing rate, and in the number of active cells, occur in VTA neurons at a time when withdrawal hyperexcitability was no longer apparent and overt changes in behaviour were not seen.

The benzodiazepine receptor inverse agonist RO15-4513 exacerbates, but does not precipitate, ethanol withdrawal in mice

RO15-4513, an imidazobenzodiazepine that has been reported to antagonize several behavioral and biochemical actions of ethanol, was given to C3H mice at various times during withdrawal from chronic (72 hours) continuous exposure to ethanol vapor. When administered immediately following chronic ethanol exposure, RO15-4513 (6 or 12 mg/kg) did not influence the withdrawal response. However, when given at subsequent times (3, 5, and 8 hours postethanol withdrawal), RO15-4513 significantly increased the severity of the withdrawal response in ethanol-exposed mice. Moreover, this exacerbation was completely reversed by pretreatment with the benzodiazepine receptor antagonist RO15-1788. Thus, these data indicate that the benzodiazepine inverse agonist, RO15-4513, is capable of exacerbating, but not precipitating, ethanol withdrawal.

Ethanol withdrawal in mice precipitated and exacerbated by hyperbaric exposure.

Mice were fed an ethanol-containing liquid diet for 9 days. On removal of the diet, exposure to 12 atmospheres absolute of a mixture of helium and oxygen precipitated earlier withdrawal, increased withdrawal scores for the first 6 hours, and increased the peak withdrawal intensity compared to dependent animals exposed to control conditions. The enhanced withdrawal did not appear to reflect alterations in ethanol elimination, oxygen or helium partial pressures, body temperature, or general excitability. These results extend to chronically treated animals the evidence that hyperbaric exposure antagonizes the membrane actions of ethanol.

Striatal and hypothalamic neurotransmitter changes during ethanol withdrawal in mice

The alterations in striatal and hypothalamic GABA, DA and its metabolites DOPAC and HVA, and in hypothalamic NE were investigated immediately after ethanol removal and during the withdrawal phase following 10 or 30 days of chronic ethanol administration. After 10 days of ethanol, GABA levels were increased immediately after ethanol removal in both the corpus striatum and the hypothalamus. The concentration of striatal DA was increased at days 2 and 3 of withdrawal and was unchanged at any other time. There was no change in the concentration of DOPAC and HVA in the hypothalamus at any time during withdrawal. Striatal DOPAC and HVA levels were increased only at day 7 of withdrawal after 10 and 30 days of ethanol feeding which was associated with a return of striatal DA to control levels. The concentration of NE in the hypothalamus was increased at days 1, 2 and 7 of withdrawal. After 30 days of ethanol, striatal GABA was increased only at day 7 of withdrawal whereas striatal DA levels were only increased at days 2 and 3 of withdrawal. Hypothalamic NE was markedly increased at days 2, 3 and 7 of withdrawal. The increase in DA concentration associated with no change in DOPA accumulation following inhibition of DOPA decarboxylase and a decrease in the striatal disappearance of DA after alphamethylparatyrosine (α-MT) suggests the presence of a hypodopaminergic state. On the other hand an increase in the disappearance of NE in the hypothalamus after α-MT suggests an increased NE turnover and a hyperadrenergic state during withdrawal. The increase in striatal GABA at day 7 of withdrawal after 30 days of ethanol may be a rebound phenomenon and may reflect the presence of a hypogabaergic state which has been shown to occur during ethanol withdrawal.

Effect of delta-THC on ethanol withdrawal in mice.

Delta-THC (10 mg/kg, i.p.) administered to mice immediately after withdrawal from a 3-day exposure to ethanol vapor was found to intensify withdrawal reactions. No effect was seen when delta-THC was administered chronically during the exposure to ethanol.

Electroencephalographic correlates of audiogenic seizures during ethanol withdrawal in mice.

C57BL/6Bg mice had silver bead electrodes chronically implanted on the surface of the cortex and had their cortical EEG recorded during audiogenic seizures following ethanol withdrawal. For 7 days, the experimental groups were fed a liquid diet containing 6% v/v ethanol ad lib as the only source of food and water. The control group was fed a similar diet containing an isocaloric amount of sucrose. The cortical EEG's of experimental and control groups before, during, and after treatment were virtually identical. Only the experimental group was susceptible to audiogenic seizures. During audiogenic seizures, the cortical EEG showed no sign of spike waves or paroxysmal activity. This is in contrast to picrotoxin convulsions with these same mice as well as to spontaneous convulsions in animals following ethanol withdrawal. Similar EEG observations have been reported on audiogenic seizures from genetic and acoustically primed susceptibilities. Consequently, we suggest that all audiogenic seizure responses, including those during ethanol withdrawal, are a type of subcortical epilepsy.

Morphine suppression of ethanol withdrawal in mice.

The acute administration of morphine, alcohol or dopamine results in a pronounced suppression of the convulsions produced by alcohol in mice. The suppressive action of morphine on alcohol withdrawal in the mouse apparently is not a product of morphine intoxication, but rather to some other specific interaction between alcohol and morphine in the central nervous system. The conclusion suggest that dopamine may play a significant role as a modulator in convulsions produced during alcohol withdrawal.