S-methyl-N,N-diethylthiolcarbamate: a disulfiram metabolite and potent rat liver mitochondrial low Km aldehyde dehydrogenase inhibitor

S-methyl-N,N-diethylthiolcarbamate-methyl ester (DETC-Me), a proposed disulfiram metabolite, was investigated both in vivo and in vitro for its effectiveness as a liver mitochondrial low Km aldehyde dehydrogenase (L Km ALDH) inhibitor. Male Sprague-Dawley rats were treated intraperitoneally with DETC-Me, killed at various times and L Km ALDH determined. DETC-Me was found to be a more potent in vivo inhibitor of L Km ALDH than either disulfiram, diethyldithiocarbamate (DDTC) or diethyldithiocarbamate-methyl ester (DDTC-Me). The ID50 for DETC-Me, DDTC-Me and disulfiram was 6.5, 15.5 and 56.2 mg/kg, respectively. The ID50 for DDTC was similar to DDTC-Me. Maximal inhibition of L Km ALDH occurred 30 minutes after DETC-Me administration. DETC-Me was ineffective as an in vitro inhibitor. DETC-Me produced a marked disulfiram-ethanol reaction (DER) at one-quarter of the dose of disulfiram or DDTC. Plasma DETC-Me in rats was greater after DETC-Me administration than after DDTC-Me, DDTC or disulfiram. In conclusion, DETC-Me is proposed to be a metabolite of disulfiram, and may be the immediate precursor of the chemical species responsible for L Km ALDH inhibition.     

Effect of diet and disulfiram on acetaldehyde blood levels after ethanol in UChA and UChB rats

Acetaldehyde (AcH) levels in blood samples taken from different zones of the vascular system 2 h after a p.o. dose of ethanol (2.76 g/kg) were studied in UChA (low ethanol consumer) and UChB (high ethanol consumer) rats fed a diet devoid of animal products, diet 1 (D₁), and a diet containing fish meal, diet 2 (D₂), and in rats pretreated with disulfiram (600 mg/kg p.o.).The results showed that, while there is no significant difference between UChA and UChB rats fed D₁ with respect to blood AcH levels and the basal activity of the hepatic mitochondrial high-affinity aldehyde dehydrogenase (AlDH), a significant strain difference was observed in rats fed D₂, which induced high blood AcH levels in UChA rats but not in UChB ones. No strain differences were observed in blood ethanol levels in the two groups of rats.When rats fed D₁ were pretreated with disulfiram, the raising of AcH blood levels induced by ethanol after disulfiram was significantly higher in UChA than in UChB rats in suprahepatic vein, femoral vein, and tail blood. This difference was concomitant with a greater inhibition of the hepatic mitochondrial high-affinity AlDH activity in UChA rats than in UChB ones, whether disulfiram was administered in vivo or in vitro, which excluded the possibility that the strain difference would be caused by a different bioavailability of disulfiram.     

Effect of ethanol on ascorbate release in the nucleus accumbens and striatum of freely moving rats.

An in vivo voltammetry technique was used to monitor the extracellular ascorbate (AA) concentration in the nucleus accumbens and striatum of unanesthetized, freely moving rats. A single injection of ethanol, 1.0 g/kg intraperitoneally (IP), induced a significant increase in extracellular AA concentration in both the nucleus accumbens and striatum. This effect was dose dependent within a dose range from 0.5-2.0 g/kg. 4-Methylpyrazole (50 mg/kg, IP), which inhibits alcoholdehydrogenase, could not prevent the increase in AA concentration, evoked by ethanol. Furthermore, systemic administration of acetaldehyde (20 mg/kg, IP), the main metabolite of ethanol, did not have any effect on the level of AA in the nucleus accumbens or striatum. These results show that ethanol can alter the brain extracellular AA levels and that this effect seems to be attributed to ethanol itself and not to acetaldehyde. Consequently, these results indicate that a role for AA in the action of ethanol in the brain should be considered.     

Effects of chronic ethanol intoxication on aldehyde dehydrogenase in mouse liver.

Effects of chronic ethanol treatment with liquid diet (ethanol constituted 28% of the calories) on hepatic aldehyde dehydrogenase (ALDH) isozymes were studied in mice. One week of ethanol feeding caused 66% loss of mitochondrial low Km ALDH activity and 80% loss of mitochondrial high Km ALDH activity, compared with the control-fed group. However, these decreases recovered after 4 weeks of ethanol feeding. The cytosolic ALDH activity increased up to 140% after 10 weeks of ethanol feeding, compared with the control-fed group. Effects of acute ethanol injection on ALDH activity after prolonged ethanol feeding were studied. The severe acute ethanol injection (4.5 g/kg body wt) after 4 weeks of ethanol feeding caused a drastic decrease of the mitochondrial low Km ALDH activity; however, that did not affect the ethanol-fed group. After 10 weeks of ethanol feeding, acute ethanol injection (4.5 g/kg body wt) caused about twofold increase in mitochondrial low Km ALDH activity. From the agarose IEF study, it was found that ethanol intoxication does not affect the number and pI value of ALDH isozymes.     

Ferrous sulfate combined with ascorbic acid does not significantly reduce acetaldehyde accumulation in the blood of alcoholized rats treated with disulfiram or betalactam antibiotics

Adult female SPF Sprague-Dawley rats treated orally by gavage with disulfiram (1 g/kg b.wt.) or betalactam antibiotics (3.38 mmol/kg b.wt.) with a 1-methyltetrazole-5-thiol side chain (cefmenoxime, latamoxef, cefotetan, cefoperazone, cefamandole) produced a marked, statistically significant rise of acetaldehyde in the blood 1 and 3 hr following IP administration of ethanol [2 g/kg b.wt., 20% (g/v) solution]. This accumulation of blood acetaldehyde remained unchanged or was reduced only very slightly by a mixture of iron sulfate [Fe(II)SO4.7H2O, 2.64 mg/kg b.wt.] and ascorbic acid (6.67 mg/kg b.wt.) injected intravenously. This slight decrease is considered to be due to a formation of a complex between ferrous sulfate and agents (disulfiram and the betalactam antibiotics as well as their metabolites) producing acetaldehyde by inhibition of acetaldehyde metabolizing enzymes. A possible coaction of ascorbic acid cannot be explained satisfactorily; ascorbic acid may support cellular redox potentials. The combination of ferrous sulfate and ascorbic acid was used for examination since both chemicals are recommended to reduce adverse symptoms of an ethanol incompatibility reaction in the course of a therapy with the mentioned antibiotics or disulfiram. Since acetaldehyde augmentation in the blood is regarded as a cause of complaints and because the acetaldehyde rise was not depressed significantly by ferrous sulfate and ascorbic acid it can be concluded that these two agents are not potent enough for a rational therapy of ethanol incompatibility symptoms initiated by the investigated drugs.     

Effects of benzodiazepines on aldehyde dehydrogenase activity

The reported ability of benzodiazepines to increase human erythrocyte aldehyde dehydrogenase (ALDH) activity and reverse the disulfiram-induced inhibition of ALDH was reexamined. When ALDH activity assays were carried out spectrophotometrically on a hemoglobin-free lysate of human erythrocytes with propionaldehyde as substrate, addition of diazepam (10 μmol/1) did not affect the enzyme activity. When assays were carried out on intact or hemolysed erythrocytes using high performance liquid chromatographic technique with 3,4-dihydroxyphenylacetaldehyde as substrate, no significant increase in erythrocyte ALDH activity was found in the presence of chlordiazepoxide, oxazepam, diazepam, or desmethyldiazepam in the concentration range 1–20 μmol/1. Rather, a significant decrease (about 50%) in activity was obtained when lysed cells were incubated with 20 μmol/1 chlordiazepoxide. Diazepam inhibited the rat liver mitochondria! low Km ALDH activity by about 50%. Disulfiram inhibited the ALDH activity almost completely in assays on human erythrocyte or rat liver mitochondrial ALDH. The ALDH activity was not regained by the subsequent addition of diazepam, nor was the effect of disulfiram reduced when diazepam was added prior to disulfiram. In an alcoholic subject who was followed during onset of disulfiram (Antabuse) therapy, the concurrent use of diazepam did not prevent a rapid decline in blood ALDH activity. The present results suggest that benzodiazepines do not increase ALDH activity in vitro, nor interfere with the inhibition of ALDH by disulfiram.     

Polymorphism of aldehyde dehydrogenase and ethanol elimination

The influence of polymorphism of aldehyde dehydrogenase (ALDH) on ethanol elimination was investigated. Japanese healthy male volunteers were divided into two groups, i.e., a normal ALDH group of 52 subjects with the low Km isozyme of ALDH, and a deficient group of 48 subjects without it. The subjects of the normal group were given 0.4, 0.8, 1.2, 1.6 or 2.0 g/kg of ethanol, while those in the deficient group ingested 0.4, 0.8 or 1.2 g/kg of ethanol. Widmark's factors (beta 60, Co and r) and ethanol elimination rate (ER) were compared between the two groups. In the deficient group, beta 60 and ER were not clearly elevated with the increase of ethanol dose, while those in the normal ALDH group increased depending on the blood ethanol level. Blood acetaldehyde level was elevated with the increase of the ethanol dose in the deficient group, but not in the normal group. In the experiment of the repeated ingestion of ethanol in the deficient group, the second peak of blood acetaldehyde level was lower than that of the first one.     

Microbes and mucosa in the regulation of intracolonic acetaldehyde concentration during ethanol challenge

— Aims: The bacteriocolonic pathway for ethanol oxidationleads to high intracolonic levels of carcinogenic acetaldehyde.The respective roles of colonic mucosal cells and gut florain the regulation of intracolonic acetaldehyde concentrationare not known. Disulfiram inhibits hepatic acetaldehyde oxidationand may have an effect on colonic mucosal cells. On the otherhand, metronidazole treatment leads to overgrowth of acetaldehyde-producingaerobic flora in the large intestine. The aim of this studywas to characterize by means of disulfiram and metronidazolethe contribution of colonic mucosal cells and intracolonic microbesto the regulation of intracolonic acetaldehyde concentrationduring ethanol oxidation in rats. Methods: Forty male Wistarrats were used. Three groups of 10 rats each received metronidazole,disulfiram, or both for 5 days, and a fourth group of 10 ratsserved as controls and did not receive any premedication. Faecalsamples were taken for the ALDH (aldehyde dehydrogenase) determinationbefore the injection of ethanol, after which all rats receivedethanol (1.5 g/kg) 2 h prior to taking samples from blood, liver,colonic mucosa and colonic contents. Results: Disulfiram decreasedsignificantly hepatic and colonic mucosal ALDH activities, andresulted in increased blood and intracolonic acetaldehyde levels.In disulfiram-treated rats, mean intracolonic acetaldehyde levelwas 8-fold higher than that in the blood. Metronidazole inhibitedonly colonic mucosal high K_M ALDH and increased intracolonic,but not blood, acetaldehyde levels. Faecal ALDH activity wasnot detectable in any of the groups. Conclusions: This studydemonstrates that during ethanol challenge, intracolonic acetaldehydelevel is regulated not only by intracolonic microbes, but alsoby colonic mucosal cells.     

Acute and Chronic Alcohol–Cocaine Interactions in Rats

The widespread combined use of alcohol and cocaine across the United States underscores the importance of understanding how the actions of those two agents interact upon important physiological regulatory processes. In an experiment exploring acute ethanol–cocaine interactions, 16 rats were given 2.0 g/kg (IP) doses of ethanol at time zero. Two hours later, half of the rats were given cocaine (20 mg/kg, IP), while the other half were given injections of saline. The group given cocaine displayed a prolongation of the hypothermia condition induced by ethanol injection. In a chronic experiment, three groups of rats (n = 6–8) were exposed for an 11-day period to daily IP injections of 10 mg/kg cocaine, 20 mg/kg of cocaine, or saline. On day 12 these groups did not differ in their response to loss of the righting reflex induced by a 3.0 g/kg dose of ethanol. However, recovery from ethanol hypothermia was more rapid in the rats exposed to chronic cocaine. In summary, these initial studies provide evidence for exacerbation of the acute hypothermic effects of ethanol when a cocaine challenge is given 2 h after ethanol. In contrast, ethanol hypothermia was observed to be reduced when tested on day 12 after an 11-day chronic regimen of cocaine. Other dosage regimens and response measures need to be tested to understand the full scope of acute and chronic cocaine–ethanol interactions and the possible health consequences.     

Acetaldehyde-reinforcing effects: differences in low-alcohol-drinking (UChA) and high-alcohol-drinking (UChB) rats.

It has been suggested that acetaldehyde has a biphasic effect on voluntary alcohol consumption. At low brain concentration, it might exert reinforcing effects, whereas high acetaldehyde levels would be predominantly aversive. The objective of the current study was to compare the effect of an intraperitoneal dose of acetaldehyde (50 mg/kg) in high-alcohol-drinking (UChB) and low-alcohol-drinking (UChA) rat lines, which differ in the activity of the brain mitochondrial class 2 aldehyde dehydrogenase (ALDH2) as a consequence of differences in their ALDH2 genotypes. A classical place-conditioning procedure was used to determine the reinforcing or aversive (or both) effects of acetaldehyde in ethanol-naive UChB and UChA rats. Environmental cues were paired with an intraperitoneal 50-mg/kg injection of acetaldehyde. On 10 consecutive days, each rat received one place conditioning per day; the acetaldehyde-pairing was alternated with saline-pairing. Results showed that conditioning with the 50-mg/kg dose of acetaldehyde induced place preference in UChB rats and place aversion in UChA rats. In a second experiment, UChB and UChA rats, pretested for ethanol preference, were injected with one 50-mg/kg dose of acetaldehyde or saline and tested for their voluntary ethanol consumption during 4 weeks. Results showed that the acetaldehyde dose induced a persistent and long-lasting enhancement of ethanol intake in UChB rats, but not in UChA rats. These results, together with the finding that after administration of a 50-mg/kg dose of acetaldehyde cerebral venous blood acetaldehyde levels in UChA rats were consistently higher than levels in UChB rats, support the suggestion that differential acetaldehyde levels, differential brain ALDH2 activity, or both were responsible for the different effects of acetaldehyde in the two rat lines.     

Ethanol feeding can produce secondary alterations in aldehyde dehydrogenase isozymes

Depressed hepatic aldehyde dehydrogenase (ALDH) activity levels have been observed in alcoholics, but whether the deficit is primary or secondary in nature remains controversial. In this study, we examined liver ALDH in rodent (rat) and primate (baboon) animal models pair-fed nutritionally adequate ethanol or isocaloric carbohydrate containing liquid diets. Both species show qualitative changes in ALDH isozymes after ethanol consumption. The changes include alterations in isozyme patterns seen upon electrofocusing and decreased responsiveness to the ALDH inhibitor, disulfiram. The subcellular locus of most of the changes is cytosolic in the baboon and mitochondrial in the rat. Study of partially purified (enriched) baboon cytosolic ALDH confirmed changes seen in the original cytosols and kinetic characterization of the enriched enzyme revealed a 9-fold higher Km for acetaldehyde in ALDH from an ethanol treated animal. We note that qualitative and quantitative changes secondary to ethanol treatment in the primate model closely parallel those described in human alcoholics.     

Effects of acute and short-term administration of tryptophan plus ethanol on noradrenaline and serotonin metabolites in the locus coeruleus.

The effects of acute and short-term administration of tryptophan or tryptophan plus ethanol on serotonin [5-hydroxytryptamine (5-HT)] and two of its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus were investigated in rats by using the microdialysis method. In addition, the acute effects of these drugs on noradrenaline and its metabolite 4-hydroxy-3-methoxymandelic acid (HMMA) were addressed. A single co-administration of tryptophan (50 mg/kg, i.p.) and ethanol (1.25 g/kg, i.p.) did not change the concentrations of either noradrenaline or its metabolite in the locus coeruleus. In contrast, administration of tryptophan (50 mg/kg, i.p.) for three consecutive days caused an increase in the concentration of 5-HIAA, but not that of 5-HT, in the locus coeruleus. Combined administration of tryptophan plus ethanol for 3 days resulted in marked increases in 5-HIAA concentrations in the locus coeruleus, but not in 5-HTPL concentrations. However, administration of ethanol (1.25 g/kg) for 3 days had no effect on the concentrations of 5-HT and its metabolites. The increased 5-HIAA concentration that resulted with combined tryptophan plus ethanol administration was remarkably suppressed by disulfiram. Moreover, in comparison with tryptophan-treated rats, the behavioral sign of teeth-chattering was significantly detected in tryptophan plus ethanol-treated rats, but the enhancement of behavioral signs with combined treatment was markedly suppressed by disulfiram. Results of the current study seem to indicate that the stimulation of 5-HT metabolism in locus coeruleus serotonergic neurons by tryptophan was strengthened by the simultaneous administration of ethanol in short-term experiments, and that the increased 5-HIAA concentrations in the locus coeruleus are responsible for behavioral activation.     

Developmental Differences in the Acquisition of Tolerance to Ethanol

This study was designed to compare the development of tolerance to ethanol in adolescent and adult rats. Rats were pretreated with ethanol (4 g/kg) twice daily by intragastric gavage for 3 or 7 days, and then challenged with a single IP dose of ethanol (5 g/kg). Throughout the pretreatment period body temperature was measured before and after the morning dosage. During the IP challenge test we measured body temperature, duration of the loss of righting reflex, and blood ethanol level upon regaining the righting reflex. The adolescent rats that were pretreated for 7 days developed greater tolerance to the effects of ethanol on body temperature during the pretreatment period. No tolerance was observed in animals that received only 3 days of pretreatment. Ethanol decreased body temperature to a greater extent in adolescent animals than adults in response to the IP challenge dose, but there was no significant difference between control and pretreated animals in either age group. The time to regain the righting reflex was lower in adolescent rats than in adults. Post hoc analyses indicated that 7 days of ethanol pretreatment diminished the effects of the IP ethanol challenge on the loss of righting reflex in adolescent but not adult rats. Although adolescent rats regained the righting reflex with higher blood ethanol levels than adults, there was no significant effect of ethanol pretreatment on that measure. These findings indicate that the development of tolerance to the temperature regulatory effects of ethanol is more marked in the adolescent rat than in the adult. This developmental difference in ethanol sensitivity is consistent with other recent findings and suggests that adolescence may be a period of unique sensitivity to a number of the behavioral and physiological effects of ethanol.     

Abecarnil and alprazolam reverse anxiety-like behaviors induced by ethanol withdrawal.

This study investigated the effects of a benzodiazepine partial agonist, abecarnil, and a full agonist, alprazolam, on ethanol withdrawal-induced anxiety-like behaviors in rats. Anxiety was assessed in two models: elevated plus maze and pentylenetetrazol (GABA(A) antagonist) discrimination assay. Male rats received an ethanol-containing (4.5%) liquid diet for 7 to 10 days and were tested for withdrawal symptoms 12 h after termination of the diet. In the elevated plus maze, ethanol-withdrawn rats displayed less open arm activity and total arm entries than pair-fed rats. Abecarnil (0.08-0.32 mg/kg, IP) and alprazolam (0.08-1.25 mg/kg, IP) each produced a dose-dependent, full reversal of ethanol withdrawal-induced reduction of open arm activity, but only alprazolam increased the total arm entries. In the pentylenetetrazol assay, ethanol-withdrawn rats selected the pentylenetetrazol lever (100%) over the salin-lever. Abecarnil (0.04-0.32 mg/kg, IP) and alprazolam (0.08-0.32 mg/kg, IP) dose dependently reduced pentylenetetrazol-lever responding to control levels (10-20%). Alprazolam was more potent than abecarnil in reversing ethanol withdrawal-induced decrease in open arm activities, but showed comparable potency and efficacy to abecarnil in blocking the pentylenetetrazol-like ethanol withdrawal stimulus. These results suggest that abecarnil and alprazolam may have therapeutic potential for treatment of ethanol withdrawal-induced anxiety-like symptoms.     

ACETALDEHYDE METABOLISM: DIFFERENCES BETWEEN UChA AND UChB RATS

In order to explore the influence of acetaldehyde (AcH) metabolismon the voluntary ethanol intake of genetically low (UChA) andhigh (UChB) ethanol consumer rats, the AcH disappearance rate(ADR) after incubation with homogenates and subcellular fractionsfrom liver and brain was determined. In addition, the effectof disulfiram pretreatment on AcH metabolism was studied. Maleadult rats of both strains were used. ADR was assayed in totalhomogenates, and in mitochondrial as well as 9000 g supernatantfractions of liver and brain. AcH was measured by gas chromatography.In some experiments, rats were pretreated with disulfiram (300mg/kg po) 24 hr before the studies. The result showed no straindifference in ADR in homogenates or subcellular fractions ofliver from untreated rats, but for disulfiram pretreated ratsa significantly lower decrease of ADR in samples from UChB comparedto UChA rats was observed. This result is consistent with alower peak AcH level in UChB compared to UChA rats after a loadof ethanol (60 mmole/kg ip). Concerning brain homogenates, ahigher ADR was observed in homogenates and crude mitochondrialfractions of UChB than of UChA rats. This difference was notobserved when the incubation was performed without adding NADor in the absence of oxygen. These results provide evidenceof strain differences in mitochondrial AcH metabolism, the natureand origin of which deserve further study.     

Study on the role of glycine,strychnine-insensitive receptors (glycineB sites) in the discriminative stimulus effects of ethanol in the rat

Several recent studies indicate that both competitive and noncompetitive NMDA receptor antagonists substitute for ethanol in a drug discrimination procedure. In the present study we examined compounds from another class of NMDA receptor antagonists—glycine, strychnine-insensitive, receptor (glycine_B site) antagonists in rats trained to discriminate between IP-administered 1.0 g/kg ethanol (10% v/v) and saline. When the animals met the discriminative criteria, substitution tests were conducted with the noncompetitive NMDA receptor antagonist, memantine (3.0–12.0 mg/kg, IP) and selective, glycine_B site antagonists—L-701,324 (0.3–3.0 mg/kg, IP) and MRZ 2/576 (0.1–10.0 mg/kg, IP). Memantine completely substituted for ethanol at the dose of 6.0 mg/kg, which significantly suppressed the rate of responding. L-701,324 substituted for ethanol at the dose of 3.0 mg/kg, which only tended to decrease the response rate. MRZ 2/576 produced maximal ethanol-appropriate responding (50%) at the dose of 5.0 mg/kg, which did not affect the rate of responding. Glycine (200–800 mg/kg, IP) did not antagonize the ethanol stimulus. These results indicate thatglycine, strychine-insensitive, site antagonists may induce some ethanol-like stimulus effects in the rat.     

以葛根提取物和藤茶粉为主要材料的配方的醒酒功能研究

目的 探讨并比较以葛根提取物和藤茶粉为主要材料的两种天然产物配方对急性酒精中毒小鼠乙醇脱氢酶（ADH）和乙醛脱氢酶（ALDH）活性的影响。方法 将18～22 g SPF级雄性KM小鼠随机分为AL[A配方低剂量：470mg/（kg·bw）]、AH[A配方高剂量：1 400 mg/（kg·bw）]、BL[B配方低剂量：400 mg/（kg·bw）]、BH[B配方高剂量：1 200 mg/（kg·bw）]、空白对照组、模型对照组、阳性对照组[海王金樽：1 500 mg/（kg·bw）]共7组,A、B配方组和阳性对照组按照受试物对应剂量灌胃14 d,模型对照组和空白对照组灌胃双蒸水[灌胃剂量：20 ml/（kg·bw）],第15 d除空白组外其余组灌胃52°白酒[灌胃剂量：22 ml/（kg·bw）]后观察翻正反射消失时间;酒精灌胃后的1、2和3 h分别进行眼眶取血检测血乙醇、乙醛含量变化趋势;取肝脏测定ADH和ALDH活性以及HE染色观察肝脏病理变化。结果 AH、BL、BH组ADH活性高于模型组（P=0.002;P=0.003;P=0.003）;A、B高低剂量ALDH活性高于模型组（P<...     

Hypothermia as an index of the disulfiram-ethanol reaction in the rat

Decreased core temperature in female rats was investigated as one possible index of the disulfiram-ethanol reaction (DER). Core temperature was decreased in rats in a dose-dependent manner when ethanol was administered to rats treated with disulfiram 8 hours before the ethanol challenge. The decrease in temperature began within 20 minutes after ethanol administration, reaching a maximal decrease between 60 and 120 minutes post ethanol. The core temperature returned to normal 300 minutes after ethanol. The blood pressure (carotid cannulation) decreased along with the core temperature. Maximal hypotension was found 120 minutes post ethanol, and returned to normal 300 minutes after ethanol. Heart rate increased initially and returned to normal 40 minutes after ethanol challenge.     

Effects of 7-keto dehydroepiandrosterone on voluntary ethanol intake in male rats

Administration of dehydroepiandrosterone (DHEA), a neurosteroid that can negatively modulate the GABA_A receptor, has been shown to decrease voluntary intake of ethanol in rats. In vivo, DHEA can be metabolized to a variety of metabolites, including 3β-acetoxyandrost-5-ene-7,17-dione (7-keto DHEA), a metabolite without the prohormonal effects of DHEA. This study compared the effectiveness of 7-keto DHEA with DHEA for reducing ethanol intake in the same group of rats. The subjects, previously trained to drink ethanol using a saccharin-fading procedure, had access to ethanol for 30 min daily and the amount consumed was recorded. Subjects were administered 10 and 56 mg/kg of DHEA or 7-keto DHEA intraperitoneally 15 min before drinking sessions. Subjects received each particular dose daily until one of two criteria was met, that is, either ethanol intake did not differ by more than 20% of the mean for 3 consecutive days or for a maximum of 8 days. Both 10 and 56 mg/kg of 7-keto DHEA significantly reduced the dose of ethanol consumed. Although 10 mg/kg of 7-keto DHEA produced decreases similar to those found with DHEA, the 56-mg/kg dose of 7-keto DHEA was significantly more effective at decreasing the dose of ethanol consumed than the same dose of DHEA. These results show that 7-keto DHEA is comparable with, or possibly more effective than, DHEA at decreasing ethanol consumption in rats, and that 7-keto DHEA is a compound deserving further investigation as a possible clinical treatment for alcohol abuse without the prohormonal effects of DHEA.