Cysteine sulfinic acid can enhance the central depressant effect of ethanol in mice.

The interaction between ethanol and cysteine sulfinic acid was examined in male Swiss-Webster mice. The loss of the righting reflex (LORR) was used as a measurement of central nervous system depression. In addition, the interaction between ethanol and cysteic acid, a metabolite of cysteine sulfinic acid, was studied. Immediately after the animals regained the righting reflex following ethanol injection (IP), mice were given an ICV injection of saline, cysteine sulfinic acid (1, 15 or 25 mumol/kg) or cysteic acid (1, 15, or 25 mumol/kg). There occurred a return to the LORR within 30 s after the ICV injection of drugs. The return to the LORR by the administration of the amino acids in the presence of ethanol occurred in a dose-dependent fashion. When cysteine sulfinic acid or cysteic acid (25 mumol/kg, ICV) was injected in the absence of ethanol, no loss of the righting reflex occurred. In other experiments, bicuculline methiodide was given ICV with cysteine sulfinic acid (25 mumol/kg), cysteic acid (25 mumol/kg), or GABA (25 mumol/kg) in the presence of ethanol. Bicuculline methiodide, a GABA antagonist, reduced the effects of the three amino acids to produce a return to the LORR in the presence of ethanol. These results indicate that cysteine sulfinic acid, an excitatory amino acid, and cysteic acid can enhance the central depressant properties of ethanol. Since bicuculline antagonized the effects of these two amino acids, a GABAergic mechanism may be involved in the interaction between ethanol and cysteine sulfinic acid or cysteic acid.     

Effect of taurine on ethanol-induced sleep time in mice genetically bred for differences in ethanol sensitivity

Long Sleep (LS) and Short Sleep (SS) mice were used in this study to investigate the interaction between ethanol and taurine. Sleep time (hypnosis) was selected as an index of ethanol-induced central nervous system depression. In order to achieve a similar degree of central nervous system depression with ethanol, SS and LS mice received 5.3 and 3.0 g/kg, IP, of ethanol, respectively. When taurine (7.5, 15 and 25 mumol/kg) was administered intracerebroventricularly (ICV) to LS and SS mice immediately after regaining the righting reflex following ethanol injection, a return to sleep time was produced. This effect of taurine was immediate in onset and occurred in a dose-dependent fashion. LS mice exhibited a greater effect from taurine administration than SS mice. In another experiment LS and SS mice were given ICV TAG, a taurine antagonist (6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide HCl), which significantly reduced the effect of taurine to produce a return to sleep time in the presence of ethanol. TAG did not affect ethanol-induced sleep time. In control experiments, in the absence of ethanol, neither taurine (25 mumol/kg, ICV) nor TAG (1 mumol/kg, ICV) caused a significant loss of the righting reflex (sleep time). When pentobarbital (50 mg/kg, IP) was injected instead of ethanol in the sleep time experiments, taurine (7.5, 15 and 25 mumol/kg, ICV) produced a return to sleep time in LS and SS mice that resembled the effect of taurine with ethanol in SS mice. These results indicate that taurine (ICV) can enhance the central depressant action of ethanol and pentobarbital and that the greatest effect of taurine occurred with LS mice in the presence of ethanol. It is possible that taurine may have some role in the central nervous system depressant properties of ethanol.     

Ethanol-induced sleep time: interaction with taurine and a taurine antagonist

In male Swiss-Webster mice sleep time (hypnosis) was used as an index of ethanol-induced central nervous system depression. Ethanol (4 g/kg, IP) was administered to animals and the onset to sleep time (loss of the righting reflex) and the duration of sleep time were recorded. At the end of the ethanol-induced sleep time, taurine (7.5, 15 or 25 mumol/kg, ICV) was injected. Immediately after the ICV injection of taurine the mice again lost the righting reflex. This effect of taurine occurred in a dose-dependent fashion. In the absence of ethanol, taurine (25 mumol/kg, ICV) did not produce a significant sleep time. In another experiment when TAG, 6-amino-methyl-3-4H-1,3,4-benzothiadiazine-1,1-dioxide HCl, (a taurine antagonist) was given to mice, TAG (0.9 mumol/kg, ICV) significantly reduced the effect of taurine (7.5, 15 and 25 mumol/kg, ICV) to reinstate a sleep time in the presence of ethanol. TAG, however, did not alter ethanol-induced sleep time. These results indicate that taurine (ICV) can enhance the central depressant action of ethanol and that this effect of taurine can be attenuated by TAG. The antagonism of taurine by TAG appears to be noncompetitive in nature.     

NMDA enhances the central depressant properties of ethanol in mice.

Male Swiss-Webster mice were used to examine the effect of NMDA on the ethanol-induced loss of the righting reflex (LORR). The LORR was used as a measure of CNS depression. Immediately after animals regained the righting reflex following ethanol injection (4.0 g/kg, IP) mice received an ICV injection of saline or NMDA (10, 50, 100, or 500 nmol/kg) in a volume of 5 microliters. Upon ICV injection of NMDA, mice again lost the righting reflex and this effect of NMDA in the presence of ethanol occurred rapidly and in a dose-dependent manner. In another experiment DL-2-amino-5-phosphonovaleric acid (APV), a competitive antagonist of NMDA, was given ICV with NMDA (50 nmol/kg) in the presence of ethanol. APV (10 and 100 nmol/kg, ICV) significantly attenuated the response of NMDA to enhance the depressant action of ethanol. When bicuculline methiodide, an antagonist of GABA, was given ICV with NMDA (50 nmol/kg), bicuculline methiodide reduced the effect of NMDA to produce a second loss of the righting reflex (return to the LORR) in the presence of ethanol. When NMDA (100 nmol/kg, ICV) was injected in the absence of ethanol into mice, NMDA by itself did not produce a loss of the righting reflex. In this investigation, the results suggest that NMDA can augment ethanol-induced depression possibly through an interaction between glutamatergic and GABAergeric systems in the CNS.     

Behavioral interactions of ethanol and methylxanthines

The effect of the methylxanthines caffeine, theophylline and isobutylmethylxanthine (IBMX) on ethanol-induced ataxia and loss of righting reflex was investigated in three strains of mice. A significant potentiation of ethanol-induced ataxia was produced in all strains of mice at 20, 45 and 75 min after ethanol in mice pretreated with 62.5 mg/kg caffeine and 12.5 mg/kg IBMX. In mice pretreated with 40 mg/kg caffeine potentiation of ethanol-induced ataxia was observed only at 20 min after ethanol. Theophylline pretreatment produced no alteration in ethanol-induced ataxia. The results of methylxanthine pretreatment on ethanol-induced ataxia were similar, regardless of a shorter (10 min) or longer (75 min) pretreatment time. The methylxanthines produced no effect on motor coordination or behavior when administered separately. Although ethanol-induced loss of righting reflex was shortened by theophylline, neither caffeine nor IBMX altered the duration of loss of righting reflex. It is possible that inhibition of adenosine uptake, a known effect of the methylxanthines, may be a more likely explanation for the modulation of the behavioral effects of ethanol.     

Calcium influence on neuronal sensitivity to ethanol in selectively bred mouse lines

Sensitivity to ethanol, as measured by blood ethanol concentration at loss of righting reflex, was increased significantly in SS but not LS mice following intracerebroventricular (ICV) administration of calcium chloride or A23187, a calcium ionophore. Magnesium chloride or lanthanum chloride, ICV, did not alter sensitivity to ethanol in either SS or LS mice, further indicating a specificity for calcium cation. Calcium was without effect on sensitivity to halothane narcosis in LS or SS mice. Endogenous brain calcium content was similar in these mouse lines, and ethanol administration either in vivo or in vitro did not alter brain calcium concentration. These results indicate that differences in brain sensitivity to ethanol are mediated, in part, by genetic differences in calcium-related processes and support the hypothesis that ethanol-induced narcosis may be due to alterations in calcium metabolism in the CNS.     

Methionine enhances alcohol-induced narcosis in mice.

Methionine is an essential amino acid that has been used as a therapeutic drug in some disorders. In this study we questioned whether methionine affects ethanol-induced loss of righting reflex (narcosis). One hour after IP methionine administration (60, 120, 240, 480, 720, 960, and 1280 mg/kg), mice were injected with ethanol (4.0 g/kg), and the duration of loss of righting reflex was recorded. Methionine, at the higher doses (960 and 1280 mg/ kg), significantly increased this effect on ethanol-treated animals. A time-course study revealed that methionine increased the duration of the loss of righting reflex induced by ethanol until 4 h after being injected. Because methionine did not affect blood ethanol levels, no change in peripheral alcohol can explain the observed effects. This potentiation was not specific for ethanol because methionine increased 3-methyl-1-butanol (0.6 g/kg) and 1-propanol (2.4 g/kg)-induced loss of righting reflex as well. Therefore, the results obtained in this study suggest the need for further investigation into methionine-ethanol interactions prior to the use of methionine as an agent that can be used as an antidepressant and to prevent damage to organic tissue in alcoholism.     

Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c,C57BL/6, and DBA/2 mice

The effects of naltrexone on the increase in locomotor activity induced by a low dose (1.35 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (3.5 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice. Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice. Naltrexone, at a dose of 0.1 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice. The duration of loss of righting reflex was, however, differentially affected in all three strains by naltrexone. The BALB mice affected in all three strains by naltrexone. The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone. Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity.     

Potentiation of ethanol-induced loss of the righting reflex by ascorbic acid in mice: interaction with dopamine antagonists

The present investigation was carried out to determine the effect of ascorbic acid on ethanol-induced loss of the righting reflex (LORR) and the interactions between ascorbic acid and dopamine receptor antagonists in affecting this action of ethanol in mice. To test the effect of each drug on ethanol-induced LORR, ascorbic acid (31.25, 62.5, 125, 250, 500, 1000 mg/kg intraperitoneally [IP]) and dopamine receptor antagonists (haloperidol 0.5, 1.0 mg/kg; L-sulpiride 20, 40, 80 mg/kg; clozapine 0.625, 1.25, 2.5 mg/kg; SCH 23390 0.5, 1.0, 2.0 mg/kg subcutaneously [SC]) were administered, respectively, 30 min before ethanol (4.0 g/kg IP) administration. Ascorbic acid, at the dose of 1000 mg/kg, significantly potentiated ethanol-induced LORR in mice. Dopamine D(2) antagonists haloperidol (0.5, 1.0 mg/kg SC), and L-sulpiride (80 mg/kg SC) also significantly prolonged the duration of LORR induced by ethanol. Clozapine and SCH 23390, at the doses used, did not affect ethanol-induced LORR. In the interaction study, the synergistic effect of ascorbic acid (1000 mg/kg IP) on ethanol-induced LORR was significantly enhanced by dopamine D(2) antagonists haloperidol, L-sulpiride, and clozapine, and the highest dose of dopamine D(1) antagonist SCH 23390. These results suggest that ascorbic acid may potentiate ethanol-induced LORR partially via a mechanism mainly linked to blockade of dopamine D(2) receptors.     

Disulfiram enhances ethanol pharmacological activity and impairs its elimination

Disulfiram or diethyldithiocarbamate (DDC) significantly prolonged ethanol-induced loss of righting reflex in mice. The disappearance of ethanol from blood, and brain was significantly delayed in disulfiram-treated animals, suggesting an impairment in the activity of alcohol dehydrogenase in these animals. DDC, an active metabolite of disulfiram, inhibited mouse liver alcohol dehydrogenase (LADH) in vitro. Pyrazole, a known inhibitor of alcohol dehydrogenase, affected ethanol elimination and ethanol-induced loss of righting reflex in mice in a manner similar to that seen with disulfiram.     

Taurine and ethanol interactions: behavioral effects in mice

Taurine is an abundant amino acid in the brain that shares pharmacological effects and similar potency with ethanol. Recently, taurine-containing beverages have been reported to enhance the euphoric effects of ethanol, though the extent of this effect and the role of taurine remain speculative. The present study was designed to explore interactions between taurine and ethanol on several behaviors including locomotion, ataxia, and loss of righting. Two strains of mice, C57BL/6J and DBA/2J mice, were used to examine potential strain differences. In the first experiment, effects of various doses of taurine (0.3-3.0 g/kg), ethanol (1.0-4.2 g/kg), or taurine in combination with ethanol were assessed in a within-subjects design. Although taurine did not appear to alter effects of ethanol on any measure in either strain, the development of tolerance to locomotor effects and sensitization to ataxic effects of ethanol in DBA/2J mice complicated interpretation of these results. In a second experiment, drug-na?ve mice were assigned to one of four treatment groups: saline+saline, saline+ethanol (1.78 g/kg), taurine (1.78 g/kg)+saline, or ethanol+taurine. In this experiment, taurine pretreatment significantly attenuated the locomotor-stimulating effect of ethanol in both strains (but to a greater extent in C57BL/6J mice) and appeared to reduce the ataxic effects of ethanol in C57BL/6J mice. In conclusion, the interaction between taurine and ethanol is subtle. Further, results are inconsistent with the notion that taurine plays a major role in the locomotor, ataxic, or loss of righting effects of ethanol.     

The effects of neurotensin, β-endorphin and bombesin on ethanol-induced behaviors in mice

The effects of the three peptides neurotensin, beta-endorphin, and bombesin on ethanol-induced behaviors were studied in mice. Intracisternal administration of these peptides to mice prolonged the duration of sleep induced by ethanol (5.2 g/kg). Neurotensin and beta-endorphin also enhanced ethanol-induced hypothermia. None of the peptides, when administered alone, produced sleep. However, all three compounds impaired the aerial righting reflex and induced sleep when followed by an IP dose of ethanol (3.5 g/kg), which alone did not induce sleep. These results, taken together with previous findings, suggest that neuropeptides may be involved in the complex mechanisms of action of ethanol on the CNS.     

Pharmacological and Metabolic Interactions between Ethanol and Methyl n-Butyl Ketone, Methyl Isobutyl Ketone, Methyl Ethyl Ketone, or Acetone in Mice

Methyl n-butyl ketone (MnBK), methyl isobutyl ketone (MIBK),methyl ethyl ketone (MEK), and acetone are widely used industrialsolvents to which certain groups of workers are exposed. Pharmacologicaland metabolic interactions between these solvents and ethanolwere explored in male CD-1 mice. The effects of these solventson the duration of ethanol-induced loss of righting reflex andon ethanol elimination in mice were studied. The solvents weredissolved in corn oil and injected intraperitoneally 30 mm beforeethanol 4 g/kg ip. The four solvents prolonged significantlythe duration of ethanol-induced loss of righting reflex whengiven in the following doses (m mol/kg): MnBK, 3.75 and 5; MIBK,5; MEK, 5 and 10, acetone, 20 and 40. This prolongation wasdose related and increased as the dose of the solvent was increased.The concentrations of ethanol in blood or brain on return ofthe righting reflex were similar in solvent-treated and controlanimals, with the exception of the group of mice treated with40 mmol/kg acetone in which the ethanol concentrations weresignificantly lower than in control animals. The mean eliminationrate of ethanol was markedly reduced in mice treated with MnBK5 mmol/kg, MEK 15 mmol/ kg, and acetone 40 mmol/kg. All foursolvents reduced the activity of mouse liver alcohol dehy-drogenasein vitro. It is concluded that enhancement of the ethanol-inducedloss of righting reflex by these solvents in mice is well correlatedto reduced elimination rate of ethanol.     

Effects of calcium channel ligands on anaesthetic properties of ethanol in mice.

This study has examined the effect of two calcium channel antagonists--nifedipine, verapamil and a calcium channel agonist BAY K 8644 on duration of ethanol-induced anaesthetic activity measured as the loss of the righting reflex (LORR) in mice. Nifedipine (5 and 10 mg/kg, i.p.) and verapamil (10 and 20 mg/kg, i.p.) potentiated the acute general anaesthetic effect of ethanol (3.5 g/kg, i.p.). BAY K 8644 (2 mg/kg, i.p.) shortened the duration of ethanol-induced LORR. This action of BAY K 8644 was prevented by the pretreatment with nifedipine (2.5 mg/kg, i.p.) but not with verapamil (5 mg/kg, i.p.). Injections of both calcium channel blockers--nifedipine (2.5 mg/kg) and verapamil (5 mg/kg) did not influence the ethanol-induced hypnotic activity themselves. Our results suggest that the calcium ions are involved in the central depressant effects of acute ethanol administration at high doses. It can be supposed that the modification of the activity of voltage-dependent calcium channels plays an important role in the anaesthetic action of ethanol.     

Ethanol-induced changes in tyrosine hydroxylase activity in brains of mice selectively bred for differences in sensitivity to ethanol

The effects of ethanol on tyrosine hydroxylase (TH) activity in five brain areas were analyzed in two lines of mice selectively bred for their differences in sensitivity to ethanol. Following a 4.1 g/kg dose of ethanol, intraperitoneally, short sleep (SS) mice lose their righting reflex for a duration of 20 minutes and long sleep (LS) mice fail to regain their righting reflex until 120 minutes. A significant increase in TH activity occurred in the striatum, locus coeruleus and frontal cortex in both lines of mice approximately 25 minutes following ethanol administration. A decrease in TH activity occurred in the substantia nigra of SS mice at 5 minutes following ethanol administration. However, there was no significant difference in TH activity in any of these four brain regions between LS and SS mice at any time following ethanol administration. In contrast, hypothalamic TH activity was significantly increased at 25 minutes in the SS mice and at 125 minutes in the LS mice following the administration of ethanol, times which coincided with the regaining of the righting reflex. These data suggest that activation of TH in the hypothalamus of LS and SS mice in response to ethanol is associated with arousal from ethanol induced narcosis.     

Neonatal monosodium glutamate lesions alter neurosensitivity to ethanol in adult mice

A number of studies have indicated a relationship between brain peptide activity and sensitivity to the behavioral effects of ethanol. Specifically, it has been suggested that ethanol effects are mediated by changes in the endogenous opioid peptides derived from the proopiomelanocortin (POMC) precursor. Most cell bodies containing brain POMC-derived peptides are found in the arcuate nucleus of the hypothalamus. Neonatal administration of monosodium glutamate (MSG) has been reported to destroy cell bodies of the arcuate nucleus. We treated WSC strain mice on postnatal Day 4 with a single SC injection of 4 mg/g MSG or saline. When adult, MSG and control mice were challenged with an IP injection of ethanol and its effect on body temperature, open field activity, or duration of loss of righting reflex was assessed. Blood ethanol concentration (BEC) was measured and the hypothalamic content of beta-endorphin like immunoreactivity (beta-EP) was determined by radioimmunoassay. beta-EP was markedly reduced in both females and males by MSG treatment. MSG-treated animals of both sexes showed significantly less ethanol-induced hypothermia than controls. BEC was higher in MSG-treated animals of both sexes than in controls, so the differences were not due to ethanol pharmacokinetics. beta-EP was generally lower in males. Duration of righting reflex was prolonged in MSG treated animals, and the reduction in open field activity was potentiated. These latter effects may be in part attributable to the higher BECs achieved in lesioned animals. These data suggest that beta-EP cell bodies in the arcuate nucleus of the hypothalamus mediate neurosensitivity to some effects of ethanol in mice, but further experiments will be necessary to implicate beta-EP specifically.     

Effects of cyanamide and acetaldehyde accumulation on the locomotor stimulant and sedative effects of ethanol in mice

Ethanol administration induces both locomotor stimulant and sedative effects depending upon blood ethanol concentrations. Recent studies in rats and mice suggest that acetaldehyde, the first product of ethanol metabolism, might be involved in the expression of both the stimulant and the sedative effects of ethanol. A number of studies have used the drug cyanamide in an attempt to clarify the role of acetaldehyde in the behavioral effects of ethanol. The results of such studies are, however, difficult to interpret because cyanamide is an inhibitor of the enzymes catalase and aldehyde dehydrogenase, two enzymes with opposite effects on brain acetaldehyde concentrations. This study was aimed at clarifying the effects of cyanamide on ethanol-induced locomotor stimulant and sedative effects in Swiss mice. The locomotor stimulant effects of ethanol were measured in standard activity boxes, whereas the sedative effects of ethanol were quantified using the loss of righting reflex procedure. Cyanamide prevented the locomotor stimulant effects of 2 g/kg ethanol, although this was mainly due to a potentiation of the inhibitory effects of ethanol as evidenced by a prolongation of ethanol-induced loss of righting reflex. Additionally, 4-methylpyrazole, an inhibitor of the enzyme alcohol dehydrogenase, prevented these effects of cyanamide. It is concluded that in vivo the effects of cyanamide are predominantly due to the inhibition of the enzyme aldehyde dehydrogenase, rather than to its effects on catalase.     

Apomorphine effects on behavioral response to ethanol in mice selectively bred for differential sensitivity to ethanol

Two lines of mice selectively bred for differences in response to a hypnotic dose of ethanol were administered apomorphine alone or in combination with ethanol. When administered by itself, apomorphine produced similar dose-dependent depression of locomotor activity and increases in stereotypy in the two lines. Doses of apomorphine (0.5 microM/kg and 2 microM/kg) thought to bind only presynaptic dopamine receptors blocked the slight locomotor activation to 1.5 g/kg ethanol in the ethanol-sensitive Long-Sleep (LS) mice; in the ethanol-insensitive Short-Sleep (SS) mice which show marked activation to all subhypnotic doses of ethanol, these doses of apomorphine only attenuated the activation. A higher apomorphine dose (8 microM/kg) antagonized the locomotor depressant effects of 2.0 and 2.5 g/kg of ethanol in LS mice but did not alter the shape of the SS ethanol dose response curve for locomotor activity. Apomorphine (2 and 8 microM/kg) potentiated ethanol-induced loss of the righting reflex in LS mice in a dose dependent fashion, but did not alter this soporific effect of ethanol in SS mice. These findings extend the data base suggesting a role for dopamine both in the mechanism(s) differentiating the LS and SS mice and the stimulant and intoxicating properties of ethanol.     

Deletion of vanilloid receptor (TRPV1) in mice alters behavioral effects of ethanol

The vanilloid receptor TRPV1 is activated by ethanol and this may be important for some of the central and peripheral actions of ethanol. To determine if this receptor has a role in ethanol-mediated behaviors, we studied null mutant mice in which the Trpv1 gene was deleted. Mice lacking this gene showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wild type littermates. Null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol (2 g/kg). However, there were no differences between null mutant and wild type mice in severity of ethanol-induced acute withdrawal (4 g/kg) or conditioned taste aversion to ethanol (2.5 g/kg). Two behavioral phenotypes (decreased sensitivity to ethanol-induced sedation and faster recovery from ethanol-induced motor incoordination) seen in null mutant mice were reproduced in wild type mice by injection of a TRPV1 antagonist, capsazepine (10 mg/kg). These two ethanol behaviors were changed in the opposite direction after injection of capsaicin, a selective TRPV1 agonist, in wild type mice. The studies provide the first evidence that TRPV1 is important for specific behavioral actions of ethanol.     

Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade

The role of the adenosine A_2A receptor in the hypnotic effects of ethanol was assessed in mice. The duration of the loss of righting reflex following acute ethanol administration was shorter for A_2A receptor-deficient mice (A_2AR KO) than for wild-type mice (A_2AR WT), whereas the fall in body temperature was not different between the two phenotypes. In contrast, the duration of the loss of righting reflex was increased in A_2AR KO mice versus controls after administration of pentobarbital. Dipyridamole, an inhibitor of adenosine uptake, increased the sleep time observed following administration of ethanol in CD1 mice and in A_2AR WT but not in A_2AR KO mice. SCH 58261, a selective A_2A receptor antagonist, unlike DPCPX, a selective A₁ receptor antagonist, shortened the duration of the loss of righting reflex induced by ethanol, thus mimicking the lack of receptor in deficient mice. Finally, the non-selective adenosine receptor antagonist caffeine (25 mg/kg) reduced ethanol-induced hypnotic effects. These results indicate that the activation of A_2A receptors that follows an increase in extracellular adenosine levels caused by the administration of high doses of ethanol plays a role in its hypnotic effects. Thus, A_2A receptor antagonists may be useful therapeutic agents for alleviating ethylic coma.