Acute Ethanol Administration Research Articles

The Smoking Cessation Medication Varenicline Attenuates Alcohol and Nicotine Interactions in the Rat Mesolimbic Dopamine System

Varenicline was recently approved as an aid for smoking cessation. Patients treated with varenicline have reported a concomitant reduction in their alcohol consumption. This compound has also been demonstrated to reduce alcohol seeking and consumption in alcohol high-preferring rats. Based on the extensive coabuse of nicotine and alcohol, the aim of the present study was to explore whether interactions among varenicline, nicotine, and ethanol in the brain reward system could indicate the use of varenicline also for alcohol dependence. Using the in vivo microdialysis method, we investigated the effects of systemic injections of varenicline on the extracellular accumbal dopamine levels in response to a systemic challenge of ethanol, nicotine, or the combination of nicotine and ethanol in the experimental rat. Acute systemic coadministration of varenicline and ethanol counteracted each others' respective enhancing effect on dopamine levels in the nucleus accumbens. However, after 5 days of varenicline pretreatment, acute combined varenicline and ethanol administration raised dopamine levels to the same extent as either drug alone. Furthermore, after varenicline pretreatment an acute injection of varenicline antagonized the dopamine stimulatory effect of acute nicotine as well as that of systemic coadministration of ethanol and nicotine. In contrast, a pronounced additive dopamine increase was observed when nicotine and ethanol were coadministered in vehicle-pretreated rats. The antismoking agent varenicline exhibits properties with respect to its interaction with ethanol and nicotine in the brain reward system that may be beneficial for treating patients with alcohol dependence with (and possibly also without) concomitant nicotine dependence.

Mice Selectively Bred for High- or Low-Alcohol-Induced Locomotion Exhibit Differences in Dopamine Neuron Function

Elevated sensitivity to the euphoric or stimulant effects of ethanol is associated with higher levels of alcohol use in some human populations. Midbrain dopamine neurons are thought to be important mediators of both ethanol reward and locomotor stimulation. Patch-clamp recordings were used to examine the electrical properties of dopamine neurons in a genetic model of heightened (FAST) and reduced (SLOW) sensitivity to the locomotor-activating effects of ethanol. Pacemaker firing of dopamine neurons was faster in FAST than SLOW mice, as was the current density through I(H) channels. Acute administration of ethanol accelerated the firing of dopamine neurons to a greater extent in recordings from FAST than SLOW mice. Dopamine neurons from FAST mice also exhibited reduced GABA(A) receptor-mediated synaptic input, compared with SLOW mice. The results suggest that dopamine neuron I(H) channels, firing rate, and GABAergic input may play a role in sensitivity to the locomotor activation observed at early time points after ethanol administration and could underlie differences in sensitivity to alcohol relevant to risk for alcohol abuse.

Interactions between cannabinoids and alcohol

Event Abstract Back to Event Interactions between cannabinoids and alcohol Fernando Rodriguez-de-Fonseca1* 1 Hospital Carlos Haya, Avenida Carlos Haya 82, Laboratorio de Medicina Regenerativa, Fundación IMABIS, Spain The endogenous cannabinoid anandamide participates in the neuroadaptations associated with chronic ethanol exposure and serves as a link between exogenous cannabinoid administration and alcohol actions. While cannabinoid exposure favors alcohol intake, cannabinoid CB1 receptor antagonist reduces both alcohol intake and cue-induced relapse to alcohol selfadministration. Thus, intraperitoneal administration of the cannabinoid CB1 receptor antagonist SR141716A (0.03, 1.0 and 3.0 mg/kg) markedly inhibits ethanol selfadministration and conditioned reinstatement of ethanol-seeking behavior in both Wistar and Marchegian-Sardinian Alcohol preferring rats (mSp). ED50 analysis showed significantly higher sensitivity (p<0.05) to the effect of SR141716A in msP rats compared to heterogeneous Wistar rats. On the other side, acute peripheral administration of ethanol (4 gr/kg, i.p.) decreased anandamide in the cerebellum, the hippocampus and the ventral striatum, as well as in plasma and adipose tissue. Parallel decreases of a second acylethanolamide, palmithylethanolamide were observed in the brain. Effects were observed 45-90 min after ethanol administration. In vivo studies revealed that anandamide decreases were associated with a remarkable inhibition of the release of both anadamide and glutamate release in the ventral striatum. There were no changes in the expression and enzimatic activity of the main enzyme that degradates anandamide, the fatty acid amidohydrolase. Acute ethanol did not change neither the activity of n-acyltransferase, the enzyme that catalyzes the synthesis of the anandamide precursor, nor the expression of NAPE-PLD, the enzyme that releases anandamide from membrane phospholipid precursors. These results suggest that receptor-mediated release of acylethanolamide is inhibited by the acute administration of ethanol, and that this effect is not derived of increased fatty acid ethanolamide degradation. In conclusion, we provide clear evidence that the endogenous cannabinoid system participates in alcohol-seeking behavior in rats, and that alcohol directly modulates endocannabinoid production. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 02 – Cannabinoids and brain reward processes Citation: Rodriguez-de-Fonseca F (2009). Interactions between cannabinoids and alcohol. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.009 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Nov 2009; Published Online: 18 Nov 2009. * Correspondence: Fernando Rodriguez-de-Fonseca, Hospital Carlos Haya, Avenida Carlos Haya 82, Laboratorio de Medicina Regenerativa, Fundación IMABIS, 13331 Marseille, Spain, fernando.rodriguez@ibima.eu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Fernando Rodriguez-de-Fonseca Google Fernando Rodriguez-de-Fonseca Google Scholar Fernando Rodriguez-de-Fonseca PubMed Fernando Rodriguez-de-Fonseca Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Saponins isolated from the root of Platycodon grandiflorum protect against acute ethanol-induced hepatotoxicity in mice

The protective effects of saponins isolated from the root of Platycodon grandiflorum (Changkil saponins: CKS) against alcoholic steatosis in liver injury induced by acute ethanol administration were investigated. Pretreatment with CKS prior to ethanol administration significantly prevented the increases in serum alanine aminotransferase activity, hepatic TNF-α level, hepatic lipid peroxidation and hepatic triglyceride level. CKS prevented ethanol-induced steatosis and necrosis, as indicated by liver histopathological studies. Additionally, CKS protected against ethanol-induced depletion of hepatic glutathione levels. CYP2E1 has been suggested as a major contributor to ethanol-induced oxidative stress and liver injury. The concurrent administration of CKS efficaciously abrogated the CYP2E1 induction and CYP2E1-dependents hydroxylation of aniline as compared to the individual treatment at higher doses. These findings suggest that CKS may prevent ethanol-induced acute liver injury, possibly through its ability to block CYP2El-mediated ethanol bioactivation and its free radical scavenging effects.

Acute Ethanol Effects on Local Cerebral Glucose Utilization in Select Central Nervous System Regions of Adolescent Alcohol‐Preferring (P) and Alcohol‐Nonpreferring (NP) Rats

Alcohol abuse among adolescents is a major health and developmental problem. The 2-[(14)C]deoxyglucose (2-DG) technique allows for the in vivo quantification of local cerebral glucose utilization (LCGU) as a measure of functional neuronal activity. Local cerebral glucose utilization rates were examined after acute ethanol administration within selected brain regions of adolescent alcohol-preferring (P) and -nonpreferring (NP) rats. Postnatal day 45 male P and NP rats were injected with saline or 1.0 g/kg ethanol, i.p., 10 minutes prior to an intravenous bolus of [(14)C]-2-deoxyglucose (125 microCi/kg). Image densities were determined using quantitative autoradiography and LCGU values calculated. Acute ethanol injection significantly decreased LCGU rates in select brain regions including the olfactory tubercles, the frontal cortex (Fr), and subregions of the posterior hippocampus (pCA1 and pCA3). Acute ethanol had no significant effects on LCGU rates in any region of the adolescent NP rats. Significant basal LCGU rate differences were apparent between the rat lines in a nearly global fashion with adolescent P rats having much higher basal LCGU rates compared with adolescent NP rats. These findings suggest that the adolescent P and NP rats are less sensitive to the effects of acute ethanol than their adult counterparts. The adolescent P rat is relatively more sensitive to the initial effects of acute ethanol in select brain regions as compared with the adolescent NP rat. Additionally, the innate hyper-excited state of the adolescent P central nervous system is a likely factor in the development of their high alcohol drinking behaviors.

Ethanol for cardiac ischemia: the role of protein kinase c

The physiological effects of ethanol are dependent upon the amount and duration of consumption. Chronic excessive consumption can lead to diseases such as liver cirrhosis, and cardiac arrhythmias, while chronic moderate consumption can have therapeutic effects on the cardiovascular system. Recently, it has also been observed that acute administration of ethanol to animals prior to an ischemic event provides significant protection to the heart. This review focuses on the different modalities of chronic vs. acute ethanol consumption and discusses recent evidence for a protective effect of acute ethanol exposure and the possible use of ethanol as a therapeutic agent.

Oxidative DNA Damage Induced by Ethanol in Mouse Peripheral Leucocytes

It is suggested that reactive oxygen species produced during ethanol intake may induce oxidative DNA damage. The present study, by the use of single cell gel electrophoresis (comet assay), investigated the potential genotoxicity of acute and long-term ethanol administration in mouse peripheral leucocytes. Urinary 8-hydroxy-2'-deoxyguanosine and total antioxidant capacity and reactive oxygen species in whole blood were also detected. Acute or long-term administration of ethanol, at the dose of 2.5 or 5.0 g/kg intraperitoneally, for 30 days, could induce significant DNA damage in peripheral leucocytes, which could be repaired at least 3 days after ethanol withdrawal in long-term ethanol treatment. A significant increase of urinary 8-hydroxy-2'-deoxyguanosine and generations of reactive oxygen species in whole blood after ethanol administration were observed, which demonstrated the ethanol-induced oxidative DNA damage. Interestingly, it was found that the total antioxidant capacity was significantly increased in whole blood after long-term ethanol administration compared to the control group, which suggested enhancement in the activities of the antioxidative defence system against oxidative tissue damage caused by excessive ethanol consumption. Thus, the present studies provide a clear evidence that ethanol induced DNA damage in peripheral leucocytes, which might result from ethanol-induced oxidative stress in the body.

Effects of acute ethanol on opioid peptide release in the central amygdala: an in vivo microdialysis study

There is experimental evidence that indicates that the endogenous opioid system of the central nucleus of the amygdala (CeA) may mediate some of the reinforcing effects of ethanol. However, the precise interactions of ethanol with the endogenous opioid system at the level of the CeA have not been investigated. The aim of the current study was to investigate the hypothesis that acute systemic ethanol administration will increase the release of endogenous opioid peptides at the level of the CeA in a time- and dose-dependent manner. Rats were implanted with a unilateral guide cannula to aim microdialysis probes at the CeA. Intraperitoneal injections of saline and various doses of ethanol (0.8, 1.6, 2.0, 2.4, and 2.8 g ethanol/kg body weight) were administered to the rats. Dialysate samples were collected at 30-min intervals at distinct time points prior to and following treatment. Radioimmunoassays specific for beta-endorphin, met-enkephalin, and dynorphin A1-8 were used to determine the effect of ethanol on the content of the opioid peptides in the dialysate. We report that the 2.8-g/kg dose of ethanol induced a long-lasting increase in beta-endorphin release from 60 min onwards following administration and, later, an ongoing increase in dynorphin A1-8 release. None of the ethanol doses tested elicited significant changes in dialysate met-enkephalin content compared to the saline treatment. Acute systemic ethanol administration induced a dose- and time-dependent increase in beta-endorphin and dynorphin A1-8 release at the level of the CeA, which may be involved in ethanol consumption.

The Influence of the Nitric Oxide Synthase InhibitorL-NOARG on the Effects of Ethanol in Rats after Acute Ethanol Administration

Abstract: The aim of this work was to study the effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NOARG) on the sedative and toxic effects of ethanol in rats. Ethanol at a dose of 3 g/kg, intraperitoneally induced sleep in rats (sleep time: 111.2±10.3 min.). Administration of the nitric oxide synthase inhibitor L-NOARG (20 and 40 mg/kg, intraperitoneally) 30 min. before ethanol significantly increased the duration of ethanol-induced sleep. L-NOARG at doses of 20 and 40 mg/kg reduced the exploratory activity of rats in the open-field test and significantly enhanced the sedative effect of ethanol in this test. It is possible that this effect is not caused by the interaction of ethanol with nitric oxide pathways but by synergistic CNS depression caused by ethanol and L-NOARG. L-NOARG (20 and 40 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (2 and 3 g/kg). Moreover, the combined administration of ethanol (2 g/kg) and L-NOARG (20 and 40 mg/kg) caused a decrease in the body weight of animals, observed for 14 days. Also, livers of these rats were studied for necrosis and connective tissue reaction. In histological studies L-NOARG at a dose of 40 mg/kg had no effect on hepatic necrosis caused by the acute administration of ethanol but strenghtened connective tissue reaction. L-NOARG is widely used in pharmacological studies, including those concerning the effects of ethanol. However, on the basis of our data the possibility of toxic interactions with ethanol should be considered.

Influence of hormonal status on behavioral responses to an acute ethanol challenge during ethanol withdrawal in male and female rats

We previously reported significant sex differences in ethanol withdrawal (EW) recovery as well as in sensitivity to GABA A receptor modulators during EW. The aim of the present study was to determine if hormonal status moderated behavioral responses to an acute ethanol challenge in EW animals comparing two different behaviors. An initial set of experiments explored motor-incoordinating effects of the acute ethanol injection during EW at either 1 day or 3 days of withdrawal. EW male, but not female, rats showed a decrease in coordination compared to controls that persisted through 3 days EW. Female rats displayed tolerance to the motor-incoordinating actions of the acute ethanol challenge at 1 day EW whereas tolerance was more evident in EW male rats at 3 days. In contrast, EW animals generally remained responsive to the anticonvulsant actions of ethanol, irrespective of hormonal status. While EW by itself did not significantly alter seizure latency, duration or severity, it increased seizure-induced mortality especially at 3 days EW. There was some evidence of tolerance to the anticonvulsant effect of the acute ethanol challenge at the lowest dose employed (0.62 g/kg), which varied by sex condition and time of EW. All sex conditions displayed marked sensitivity to the anticonvulsant effects of the ethanol challenge at the two higher doses studied. Overall, ovariectomized females showed the greatest response to the acute ethanol administration. These findings provide additional evidence of a divergence in behavioral responses during EW and suggest that multiple neuroadaptations moderate various responses to ethanol during EW, with minor contributions of hormonal status.

Genetic and pharmacological manipulations of the CB1 receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice

Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB(1) receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB(1) receptor significantly reduced the ethanol preference. Although the stimulation of the CB(1) receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB(1) receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB(1) -/- mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB(1) receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB(1) receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB(1) receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB(1) receptor may have therapeutic potential in the treatment of ethanol dependence.

Acute ethanol administration causes malformations but does not affect cranial morphometry in neonatal mice

Ethanol is a known teratogen and has been implicated in the etiology of human fetal alcohol syndrome (FAS), which is characterized by distinct craniofacial abnormalities such as microcephaly, agnathia, and ocular aberrations. Attempts at quantifying the craniofacial anomalies arising from ethanol exposure have largely been limited to radiographic evaluation in postnatal rats. Such studies discount the role of the cranial soft tissue in the morphology of FAS. We present a study whose aim was to conduct measurements of the entire head including soft and hard tissue in full-term fetuses of mice by means of a digital analyzer, while at the same time comparing stained skeletal tissues in treated and untreated animals. Thirteen pregnant C57BL/6J mice were fed with 25% ethanol (vol/vol) on gestation days (E) 6, 7, and 8, whereas 10 pregnant mice received water only. Fetuses were retrieved from the animals just before delivery on E18, digitally photographed, measured, and assessed for abnormalities. Ethanol-exposed mice showed a number of abnormalities such as anophthalmia and agnathia, but these were not significantly increased over those from nontreated fetuses ( P = .5). Birth weight ( P = .5), crown-rump length ( P = .8), and mandibular length ( P = .9) were also not significantly reduced compared to control fetuses. However, defects in some cranial bones and degrees of ossification that trailed same-stage controls were observed in treated animals, at a nonstatistically significant level ( P = .14). Acute maternal ingestion of alcohol in mice during pregnancy may not cause a significant increase in craniofacial or skeletal defects when evaluated at term. However, these effects may be latent, manifesting postnatally. The postnatal ability of mice for recovery from alcohol-induced birth defects deserves further investigation.

Ethanol-induced Changes in Proenkephalin mRNA Expression in the Rat Nigrostriatal Pathway

Endogenous opioid systems have been suggested to play a key role in ethanol reinforcement mechanisms and alcohol-drinking behavior. Ethanol induces differential alterations in opioid peptide expression in brain areas of the reward circuits, which may be linked to the reinforcing effects of ethanol. In addition, ethanol-induced alterations in opioidergic nigrostriatal transmission could be involved in brain sensitivity to ethanol and play a role in addictive processes. The aim of this work was to study the effects of acute ethanol administration on proenkephalin (proenk) mRNA expression in the rat substantia nigra and caudate-putamen (CP) for up to 24 h post treatment. Male Wistar rats received ethanol (2.5 g/kg) or distilled water by intragastric administration, and proenk mRNA expression was studied by in situ hybridization and densitometry. Ethanol transiently increased proenk mRNA expression in the CP 1 h after drug administration. Proenk mRNA levels remained elevated 2 h post treatment in the anterior-medial and medial-posterior regions of the CP. In contrast, ethanol decreased proenk mRNA expression in the substantia nigra pars compacta and pars reticulata 2 h after drug exposure. Alterations in enkephalin expression in the substantia nigra and CP in response to ethanol exposure could be involved in the mechanisms underlying brain sensitivity to the drug.

Ethanol Abolishes Ischemic Preconditioning in Humans

This study sought to assess the effect of acute alcohol intake on ischemic preconditioning (IPC) in humans using the clinical model of 2 sequential balloon inflations during a percutaneous coronary intervention (PCI). Ischemic preconditioning is the most potent form of endogenous myocardial protection from irreversible ischemic injury. Experimental observations suggest that acute ethanol administration might abolish IPC. We studied 30 consecutive patients (22 men, mean age 65 years) undergoing elective coronary angioplasty who were randomized to receive an oral dose of 40 g ethylic alcohol (administered as 149 ml of Gordon's Gin) or 149 ml of water 30 min before PCI. Intracoronary electrocardiogram was continuously monitored to assess the greatest ST-segment elevation or depression from baseline. In placebo-treated patients, the change of ST-segment shift during the second inflation was significantly smaller than that during the first inflation (19.3 +/- 9.1 vs. 15.7 +/- 8.7, p = 0.005). In contrast, in gin-treated patients, the change of ST-segment shift during the second inflation was significantly greater than that during the first inflation (18.7 +/- 7.2 vs. 22 +/- 10, p = 0.03). The group-inflation interaction for ST-segment changes was highly significant (p < 0.001). This randomized, prospective study in humans shows that administration of a moderate dose of ethanol abolishes IPC occurring during sequential episodes of myocardial ischemia and is associated with worsening ischemia. Based on our study, intake of moderate to high doses of alcoholic beverages should be avoided in patients at high risk of acute myocardial infarction.

アルコールと脳内微量元素

When men drink excessive amounts of alcohol over a prolonged period, they may develop neurological diseases, such as peripheral neuropathy, Wernicke encephalopathy, and alcohol-induced cerebellar degeneration. Trace elements in the brain can lead to the increased expression of receptors, enzymes for the synthesis and metabolism of the neurotransmitter, and proteins that modulate function, ets. It is possible that various neurological symptoms occur when trace elements in the brain are affected by excessive consumption of alcohol, even though the trace elements in the brain are maintained at a constant level. Drinking excessive levels of alcohol increases the level of zinc in the brain, while lower levels of zinc in blood are seen in men with signs of chronic excessive alcohol consumption, such as with alcoholic cirrhosis. It is speculated that increased free radicals by acute alcoholic intake, cause zinc to be increased in the brain in response to this phenomenon. Copper is closely related to neurological diseases, such as Wilson′s disease or Menkes disease, but there have been no reports regarding encephalopathy induced by changes in copper and its metabolites in the brain due to drinking. About 80% of manganese in the brain exists within the astrocytes, and is involved in glutamine metabolism. However, there have not been many reports concerning the relation between alcohol and manganese. Low levels of manganese in the blood are observed in chronic alcoholics and these patients exhibit delirium tremens, tetany, convulsions, athetosis and involuntary movement. The level of iron in the blood increases with chronic excessive alcohol drinking, but there have been no reports indicating that iron levels in the brain are modified by alcohol intake. Metal-lothionein (MT) contributes significantly to zinc and copper metabolism and functions as a protective protein, but MT in the brain is increased when the MT-I overexpressing transgenic mouse (MT-I*) is administered 4 g/kg of ethanol by a gastric tube. Acute ethanol administration can generate oxygen free radicals and cause oxidative stress in the brain. The mechanism of induction of MT in the brain after oral ethanol administration may be associated with oxidative stress caused by ethanol or its metabolites, and can be considered a protective mechanism against ethanol toxicity.

Differential Modulation of Ethanol‐Induced Sedation and Hypnosis by Metabotropic Glutamate Receptor Antagonists in C57BL/6J Mice

Emerging evidence implicates metabotropic glutamate receptor (mGluR) function in the neurobiological effects of ethanol. The recent development of subtype specific mGluR antagonists has made it possible to examine the roles of specific mGluRs in biochemical and behavioral responses to ethanol. The purpose of the present study was to determine if mGluRs modulate the acute sedative-hypnotic properties of ethanol in mice. C57BL/6J mice were tested for locomotor activity (sedation) and duration of loss of the righting reflex (hypnosis) following acute systemic administration of ethanol alone or in combination with the mGluR5-selective antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), the mGluR1-selective antagonist, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), or the mGluR2/3-selective antagonist (2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495)). MPEP (10 and 30 mg/kg) significantly enhanced both the sedative and hypnotic effects of ethanol, while LY341495 (10 and 30 mg/kg) significantly reduced the sedative-hypnotic effects of ethanol. CPCCOEt had no effect at any concentration tested. Further loss of righting reflex experiments revealed that LY341495 (30 mg/kg) significantly reduced hypnosis induced by the gamma-aminobutyric acid type A (GABAA) positive modulators, pentobarbital (50 mg/kg) and midazolam (60 mg/kg), and the N-methyl-d-aspartate (NMDA) receptor antagonist, ketamine (150 mg/kg), while MPEP (30 mg/kg) only significantly enhanced the hypnotic properties of ketamine (150 mg/kg). These findings suggest that specific subtypes of the metabotropic glutamate receptor differentially modulate the sedative-hypnotic properties of ethanol through separate mechanisms of action, potentially involving GABA(A) and NMDA receptors.

Acute Ethanol Potentiates the Clock‐Speed Enhancing Effects of Nicotine on Timing and Temporal Memory

Acute ethanol administration potentiates some of the behavioral effects of nicotine, although the extent of this effect is unknown. The present investigation assessed the ability of ethanol to potentiate nicotine's effect on the overestimation of multisecond durations as a result of an increase in the speed of an internal clock. Adult male rats were exposed to the acute effects of ethanol (0.0, 0.5, 1.5, and 3.0 g/kg; IG) which was given 10 minutes prior to the administration of nicotine (0.0, 0.3, 0.6, and 1.0 mg/kg; IP). The effects of these combined treatments on timing and temporal memory were assessed using 18- and 36-second peak-interval procedures with separate visual/spatial cues for responding. When administered alone, ethanol had no consistent effect on peak time, but decreased peak rate, and increased peak spread as a function of dose. In contrast, nicotine alone shifted the peak times of the response distributions leftward in a proportional manner as a function of dose. When administered after pretreatment with ethanol, nicotine's effect on the horizontal placement of the peak functions was potentiated. The observation that ethanol pretreatment potentiates the clock-speed enhancing effects of subsequently administered nicotine is discussed in terms of the role of alpha7-nicotinic acetylcholine receptors and dopamine-glutamate interactions in cortico-striatal circuits thought to subserve interval timing.

Time dependent alterations on tyrosine hydroxylase, opioid and cannabinoid CB 1 receptor gene expressions after acute ethanol administration in the rat brain

The aim of this study was to examine the differential regulation after acute ethanol administration on tyrosine hydroxylase, proenkephalin and cannabinoid CB 1 receptor gene expressions in selected areas of the rat brain. Rats received an intragastric administration of 3 g/kg ethanol and were killed by decapitation at 1, 2, 4, 8 and 24 h. The results showed an activation of tyrosine hydroxylase gene expression in the ventral tegmental area and the substantia nigra, increased proenkephalin gene expression in the caudate–putamen, nucleus accumbens core and shell, central and medial amygdala, ventromedial hypothalamic nucleus and the paraventricular hypothalamic nucleus. In contrast, a significant decrease in the cannabinoid CB1 receptor gene expression was found in caudate–putamen, central amygdala and ventromedial hypothalamic nucleus. In conclusion, the results suggest that an acute dose of ethanol induces neuroplastic alterations in proenkephalin, tyrosine hydroxylase and cannabinoid CB1 receptor gene expressions that may contribute to trigger the rewarding effects of ethanol consumption.

The impact of gonadectomy and adrenalectomy on acute withdrawal severity in male and female C57BL/6J and DBA/2J mice following a single high dose of ethanol.

Steroid hormones can influence neuronal excitability and subsequent seizure susceptibility through genomic and nongenomic mechanisms. For example, there are proconvulsant steroids such as estradiol and corticosterone and anticonvulsant steroids such as testosterone, progesterone, and their GABAergic metabolites. Recent findings indicated that a single, acute administration of ethanol increased levels of GABAergic steroids and that the source of this increase was peripheral organs such as the adrenals and gonads. Thus, the purpose of the present study was to determine the impact of removal of the adrenals and/or gonads on withdrawal severity following a single high dose of ethanol in 2 genotypes that differ in ethanol withdrawal severity. Male and female C57BL/6J (B6) and DBA/2J (D2) mice were either left intact (SHAM), adrenalectomized (ADX), gonadectomized (GDX), or underwent ADX/GDX surgery. Seven days following surgery, baseline handling-induced convulsions (HICs) were measured prior to administration of a 4 g/kg dose of ethanol. HICs were assessed following the ethanol injection, then hourly for 12 hours and at 24 hours. A separate group of mice were used to measure the impact of surgical status on ethanol metabolism at 30, 60, 120, and 240 minutes after a single 4 g/kg dose of ethanol. ADX and ADX/GDX treatments in male B6 and D2 mice increased ethanol withdrawal severity following a single dose of ethanol, measured by area under the withdrawal curve and peak HIC scores. Acute ethanol withdrawal also was increased in female D2 mice that had undergone ADX/GDX. In contrast, surgical status did not alter ethanol withdrawal severity in female B6 mice. Surgical status had only minor effects on ethanol metabolism. Removal of peripherally derived steroids with anticonvulsant properties significantly increased HIC scores during acute ethanol withdrawal following a single dose of ethanol in male and female D2 mice and in male B6 mice. These increases were not due to changes in ethanol metabolism.

Ethanol alters acetylcholinesterase activity and gene expression in zebrafish brain

Alcohol abuse is a health problem throughout the world and alcohol consumption is linked to the occurrence of several pathological conditions. Acute ethanol administration exerts a variety of actions on the central nervous system (CNS). Zebrafish has been used as an attractive model system to investigate behavioral and neurochemical changes promoted by alcohol intoxication. Here we investigated the in vitro and in vivo effects promoted by ethanol and its metabolites on zebrafish brain acetylcholinesterase (AChE). There was a significant increase of AChE (33%) activity after acute 1% ethanol exposure. However, ethanol in vitro did not alter AChE activity. Acetaldehyde, the first metabolite of alcohol metabolism, promoted a dose-dependent decrease (15%, 27.5% and 46.5%) at 0.25%, 0.5% and 1%, respectively. Acetate, a product of acetaldehyde degradation, did not change AChE activity. Furthermore, the acute ethanol exposure was able to inhibit AChE transcripts at 0.5% and 1%. These findings suggest that the alterations on zebrafish AChE could reveal molecular mechanisms related to cholinergic signaling in alcoholism.