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The effect of lead acetate and 3-amino-1, 2, 4-triazole (AT) on ethanol-induced loss of righting reflex (LORR) and brain catalase activity was studied in an attempt to confirm earlier observations on the involvement of catalase in ethanol-induced effects. Lead acetate (0 or 100 mg/kg) or AT (0 or 500 mg/kg) was injected (acutely) into mice 7 days or 5 h before testing. Other mice were exposed to drinking fluid containing 500 ppm lead acetate for 60 days. On the test day, mice received an intraperitoneal injection of ethanol (4.0 or 4.5 g/kg) and the duration of LORR was recorded. Acute lead-treated animals demonstrated a reduction in the duration of the LORR. However, both chronic administration of lead acetate and AT treatment increased the duration of ethanol-produced LORR. Furthermore, brain catalase activity in acute lead pretreated animals showed a significant induction, whereas it was reduced in chronic lead and AT treated mice. These results suggest that brain catalase activity, and by implication centrally formed acetaldehyde, may modulate ethanol-induced LORR.

The present study deals with the effect of L-cysteine on the acute stimulating effects of ethanol. Swiss albino mice were pretreated with 0.0, 18.75, 37.50, or 75.00 mg/kg of cysteine simultaneously, 30 or 60 min, before the administration of saline or 0.8, 1.6, 2.4, or 3.2 g/kg of ethanol at 20% vol./vol. After these treatments, mice were left in the open-field chamber for 20 min, and locomotor activity was evaluated for the last 10 min. The specificity of the effects of L-cysteine was analyzed with the use of two drugs that also induce locomotor activity--d-amphetamine and methanol. Mice received L-cysteine (37.5 mg/kg), and 30 min after this treatment d-amphetamine (2 mg/kg) or methanol (2.4 g/kg) was injected. Data showed that L-cysteine at 37.5 mg/kg was able to increase locomotion induced by 2.4 and 3.2 g/kg of ethanol when it was administered 30 min before ethanol injection. The effects of L-cysteine are specific for the stimulation of ethanol on locomotion, because L-cysteine does not alter d-amphetamine-induced locomotor activity or methanol-induced locomotion. Moreover, blood ethanol levels were not affected by L-cysteine pretreatment. Therefore, the present findings demonstrated that ethanol-induced locomotor effects are enhanced by L-cysteine, in a manner similar to that of other sulfur amino acids.

In order to evaluate the effect of hypotaurine on ethanol-induced locomotion, different groups of mice received an injection of saline or 5.62, 8.45, 11.25, 16.87 or 33.75 mg/kg of hypotaurine 30 min prior to administering ethanol (2.4 g/kg). The duration of the effect of hypotaurine was explored by treating animals with ethanol 0, 30, 60 and 90 min after hypotaurine pretreatment. The effect of hypotaurine on acute stimulating ethanol locomotion was evaluated by pretreating animals with saline or 11.25 mg/kg of hypotaurine 30 or 60 min before ethanol (1.6, 2.4, 3.2 g/kg) or saline injections. Hypotaurine (11.25 mg/kg) required 30 min to boost, specifically ethanol-stimulated locomotion (2.4 g/kg). These results suggest a central locus for the interaction, firstly, because blood ethanol levels were not different between hypotaurine and saline pretreated mice, and, secondly, because a cotreatment with beta-alanine (22 mg/kg), a beta-amino acid that counteracts the transfer of hypotaurine across the blood-brain barrier (BBB), prevented the enhancement in ethanol-induced locomotion produced by hypotaurine.

It has been demonstrated that acute administration of lead to mice enhances brain catalase activity and ethanol-induced locomotion. These effects of lead seem to be related, since they show similar time courses and occur at similar doses. In the present study, in an attempt to further evaluate the relation between brain catalase activity and lead-induced changes in ethanol-stimulated locomotion, the interaction between lead acetate and 3-amino-1H,2,4-triazole (AT), a well-known catalase inhibitor, was assessed. In this study, lead acetate or saline was acutely injected intraperitoneally to Swiss mice at doses of 50 or 100 mg/kg 7 days before testing. On the test day, animals received an intraperitoneal injection of AT (0, 10, or 500 mg/kg). Five hours following AT treatment, ethanol (0.0 or 2.5 g/kg, ip) was injected and the animals were placed in open-field chambers, in which locomotion was measured for 10 min. Neither lead exposure nor AT administration, either alone or in combination, had any effect on spontaneous locomotor activity. AT treatment reduced ethanol-induced locomotion as well as brain catalase activity. On the other hand, ambulation and brain catalase activity were significantly increased by both doses of lead. Furthermore, AT significantly reduced the potentiation produced by lead acetate on brain catalase and on ethanol-induced locomotor activity in a dose-dependent manner. A significant correlation was found between locomotion and catalase activity across all test conditions. The results show that brain catalase activity is involved in the effects of lead acetate on ethanol-induced locomotion in mice. Thus, this study confirms the notion that brain catalase provides the molecular basis for understanding some of the mechanisms of the action of ethanol in the central nervous system.

Studies presented in this chapter show that: (1) in the brain, ethanol is metabolized by catalase to acetaldehyde, which condenses with dopamine forming salsolinol; (2) acetaldehyde-derived salsolinol increases the release of dopamine mediating, via opioid receptors, the reinforcing effects of ethanol during the acquisition of ethanol consumption, while (3) brain acetaldehyde does not influence the maintenance of chronic ethanol intake, it is suggested that a learned cue-induced hyperglutamatergic system takes precedence over the dopaminergic system. However, (4) following a prolonged ethanol deprivation, the generation of acetaldehyde in the brain again plays a role, contributing to the increase in ethanol intake observed during ethanol re-access, called the alcohol deprivation effect (ADE), a model of relapse behavior; (5) naltrexone inhibits the high ethanol intake seen in the ADE condition, suggesting that acetaldehyde-derived salsolinol via opioid receptors also contributes to the relapse-like drinking behavior. The reader is referred to glutamate-mediated mechanisms that trigger the cue-associated alcohol-seeking and that also contribute to triggering relapse., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

It has been suggested that the endogenous opioid system, especially b-endorphins (b-ep), can play a key role in the behavioral effects of ethanol. A single injection of estradiol valerate (EV) produces a neurotoxic effect on the b-endorphin cell population of the hypothalamic arcuate nucleus. In the present study we questioned whether mice pretreated with EV, exhibit any alterations in ethanol-induced behavioral effects. Female Swiss mice were pretreated with EV (2 mg/0.2 ml per mice) or vehicle and, 8 weeks later, these animals were challenged with ethanol (0.0-3.2 g/kg). Immediately after ethanol injection, mice were placed in the open field chambers and locomotor activity was assessed. EV administration did not produce any change in spontaneous locomotor activity but, conversely, blocked the locomotor activity induced by low (0.8 g/kg) and moderate (1.6 or 2.4 g/kg) doses of ethanol. Interestingly, the behavioral effects of higher doses of ethanol on locomotor activity as well as on the duration of the loss of righting reflex were unaffected by EV. Moreover, neither rota-rod performance or blood ethanol levels were affected by EV. In a second study, the effects of EV pre-treatment on caffeine- and 1-propanol-induced locomotor activity was tested. No differences were observed between groups in caffeine- or 1-propanol-induced locomotion. The results of the present study indicate that EV blocks ethanol-induced locomotor activity and that this effect can not be related with any difference in ethanol levels or nonspecific motor impairment. Furthermore, they suggest that b-ep containing neurons of the hypothalamic arcuate nucleus may play a role in some, but not all, behavioral effects of ethanol.

Objective: The present experiments analyze the effects of the brain catalase inhibitor 3-amino-1,2,4-triazole (AT) on the locomotor activity induced by ethanol., Method: In the first experiment, mice received injections of either AT (0.5 g/kg) or saline (S) 5 hours prior to an ethanol injection (0, 0.8, 1.6, 2.4, 3.2 or 4 g/kg). In the second experiment, five different groups of mice received injections of AT (0, 0.010, 0.030, 0.060, 0.125, 0.250 or 0.500 g/kg) 5 hours prior to being injected with 1.6 g/kg of ethanol. In the third experiment, six groups of mice were treated with AT (0.5 g/kg), simultaneously, 2.5, 5, 10 or 20 hours before the administration of 1.6 g/kg of ethanol. Immediately after ethanol injection, mice were placed individually in the open-field apparatus for 20 minutes. In another set of experiments, the effects of AT on brain catalase activity were studied. Animals were injected with AT at 0, 0.010, 0.030, 0.060, 0.125, 0.250 or 0.500 g/kg, and 5, 10 or 20 hours following AT treatment mice were perfused and the brain was removed., Results: Pretreating mice with AT reduces ethanol-induced locomotor activity (1.6, 2.4 and 3.2 g/kg) without altering spontaneous locomotion. Pretreatment with AT (from 0.125 g/kg to 0.5 g/kg) produced a clear dose-dependent decrease of ethanol locomotion and brain catalase activity. The effect of AT was observed 5 and 10 hours after the injection of this drug, and it disappeared 20 hours following AT treatment., Conclusions: Current data showed a parallel property of AT in producing a remarkable dose- and time-dependent decrease in catalase activity and ethanol locomotion.

Several reports have demonstrated that acute lead acetate administration enhances brain catalase activity in animals. Other reports have shown a role of brain catalase in ethanol-induced behaviors. In the present study we investigated the effect of acute lead acetate on brain catalase activity and on ethanol-induced locomotion, as well as whether mice treated with different doses of lead acetate, and therefore, with enhanced brain catalase activity, exhibit an increased ethanol-induced locomotor activity. Lead acetate or saline was injected IP in Swiss mice at doses of 50, 100, 150, or 200 mg/kg. At 7 days following this treatment, ethanol (0.0, 1.5, 2.0, 2.5, or 3.0 g/kg) was injected IP, and the animals were placed in the open-field chambers. Results indicated that the locomotor activity induced by ethanol was significantly increased in the groups treated with lead acetate. Maximum ethanol-induced locomotor activity increase was found in animals treated with 100 mg/kg of lead acetate and 2.5 g/kg of ethanol. Total brain catalase activity in lead-pretreated animals also showed a significant induction, which was maximum at 100 mg/kg of lead acetate treatment. No differences in blood ethanol levels were observed among treatment groups. The fact that brain catalase and ethanol-induced locomotor activity followed a similar pattern could suggest a relationship between both lead acetate effects and also a role for brain catalase in ethanol-induced behaviors.

A role for brain catalase in the mediation of some psychopharmacological effects of ethanol has been proposed. In the present study, we investigated the effects of repeated cyanamide injections on the activity of brain catalase, as well as on the ethanol-induced locomotion of mice. Male Swiss mice were pre-treated with cyanamide (10 mg/kg; three times per day, 5 days) or saline. At different times (2, 3, 6 or 9 days) following this treatment, animals were injected with ethanol. Immediately following this ethanol challenge, animals were placed in the open field chambers and locomotor activity was assessed for 10 min. Results indicated an increase in ethanol-induced locomotion of mice pre-treated with cyanamide 2, 3 or 6 days before the ethanol challenge. Brain catalase activity showed an enhancement at the same time period and the two variables showed a significant correlation. No differences between pre-treatment groups on ethanol blood levels were observed at time of testing. In a second study, the effects of these cyanamide treatment conditions on d-amphetamine-induced locomotor activity were assessed. Results indicated no differences between pre-treatment groups in d-amphetamine-induced locomotion. Thus, these data suggest that repeated daily injections of cyanamide can simultaneously induce both brain catalase and locomotor activity, and that these effects may be strongly related. Furthermore, the present study provides further support for the notion that brain catalase activity may be a factor mediating some of the psychopharmacological effects of ethanol.

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.

Several reports have demonstrated that chronic lead administration decreases brain catalase activity in animals. Other reports have shown a role of brain catalase on ethanol-induced behaviors. In the present study, we questioned whether mice treated chronically with lead, and therefore functionally devoid of brain catalase activity, exhibit some alterations in ethanol-induced behaviors. Swiss-Webster mice were exposed to drinking fluid containing either 500 ppm lead acetate or sodium acetate (control group) for 0, 15, 30, or 60 days before an acute ethanol administration. Following ethanol injection (2.5 g/kg, i.p.), animals were placed in open field chambers and locomotor activity was measured. Lead exposure had no effect on spontaneous locomotor activity. However, a reduction in ethanol-induced locomotor activity was found at all periods of lead exposure. After 60 days of treatment, the lead group demonstrated 35% less activity than the control group. Brain catalase activity was significantly reduced in the lead group following 60 days of exposure. This reduction in ethanol-induced locomotor activity and in brain catalase activity persisted after 40 days of lead withdrawal. The fact that brain catalase and ethanol-induced locomotor activity followed a similar pattern could suggest a relationship between both lead acetate effects and also a role for brain catalase in ethanol-induced behaviors.

The involvement of brain catalase in modulating the psychopharmacological effects of ethanol was investigated by examining ethanol-induced locomotor activity in sodium azide-treated mice. Mice were pretreated with i.p. injections of the catalase inhibitor sodium azide (5, 10, or 15 mg/kg) or saline. Following this treatment, animals received i.p. injections of ethanol (0.0, 1.6, 2.4, or 3.2 g/kg). Ten minutes after ethanol administration, locomotor activity was recorded during a 10-min testing period in open-field chambers. The time effect between the two treatments (0, 30, 60, or 90 min) was also evaluated. Results indicated that sodium azide alone did not change spontaneous locomotor activity. However, this catalase inhibitor significantly reduced ethanol-induced locomotor activity when it was injected simultaneously or 30 min before ethanol injections. Moreover, perfused brain homogenates of mice treated with sodium azide also showed a significant reduction of catalase activity. No differences in blood ethanol levels were observed between sodium azide and saline pretreated animals. Results of an additional experiment showed that sodium azide (10 mg/kg, at 30 min) did not produce an effect on d-amphetamine- (2 mg/kg) or tert-butanol- (0.5 g/kg) induced locomotor activities. A specific interaction between ethanol and sodium azide at the level of the central nervous system is suggested. These results provide further support for the involvement of brain catalase in ethanol-induced behavioral effects. They also support the notion that acetaldehyde may be produced directly in the brain by catalase and that it may be an important regulator of ethanol's locomotor effects.

It has been proposed that brain catalase plays a role in the modulation of some psychopharmacological effects of ethanol. The acute administration of lead acetate has demonstrated a transient increase in several antioxidant cell mechanisms, including catalase. In the present study, we investigated the effects of acute lead acetate administration on ethanol-induced behavior, brain catalase activity, and the relation between both effects. Lead acetate (100 mg/kg) or saline was injected intraperitoncally in mice. At different intervals of time (1, 3, 5, 7, 9, or 11 days) after this treatment, ethanol (2.5 g/kg) was injected intraperitoneally and the mice were placed in open field chambers. Results indicated that the locomotor activity induced by ethanol was significantly increased. Maximum ethanol-induced locomotion increase (70% more activity than control animals) was found in animals treated with lead acetate 7 days before ethanol administration. Total brain catalase activity in lead-pretreated animals also showed a significant induction, which was maximum 7 days after lead administration. A significant correlation was found between both effects of locomotor and catalase activity. In a second study, the effect of lead administration on d-amphetamine (2.0 mg/kg) and tert-butanol-(0.5 g/kg) induced locomotor activity was investigated. Lead acetate treatment did not affect the locomotion induced by these drugs. These data suggest that brain catalase is involved in ethanol's effects. They also provide further support for the notion that acetaldehyde may be produced directly in the brain via catalase and that it may be a factor mediating some of ethanol's central effects.

The present study was designed in an attempt to assess a previously suggested role of brain catalase activity in ethanol-induced behaviour by examining ethanol-induced locomotor activity in cyanamide-treated mice. Mice were pretreated with IP injections of the catalase inhibitor cyanamide (3.75, 7.5, 15, 30 or 45 mg/kg) or saline. Following this treatment, animals in each group received IP injections of ethanol (0.0, 1.6, 2.4 or 3.2 g/kg) and locomotion was recorded. Several time intervals (0, 5, 10, 15, 20 or 25 h) between the two treatments were also evaluated. Results indicated that cyanamide administration produced a dose-dependent decrease in ethanol-induced locomotor activity that depends on the time between treatments. However, cyanamide did not change spontaneous or d-amphetamine-induced locomotor activity. Moreover, an additive effect of cyanamide and another brain catalase inhibitor, 3-amino-1,2,4-triazole (AT), on the reduction of ethanol-induced locomotor activity was observed. Perfused brain homogenates of mice treated with cyanamide, AT or cyanamide+AT showed a significant reduction of brain catalase activity. The dose and time patterns of both effects were closely related and a significant correlation between them was obtained. These results suggest that cyanamide could reduce locomotor activity through its inhibition of brain catalase, giving further support to the notion that brain catalase may be an important regulator of some ethanol-induced behavioural effects.

The effect of isethionic acid, a central metabolite of taurine, on ethanol-induced locomotor activity was investigated in rodents. Ten minutes following an (i.p.) simultaneous administration of ethanol (0.0, 1.5, 2.0, 2.5, 3.0, 3.5 g/kg) and isethionic acid (0.0, 22.5, 45.0, 90.0, 180.0 mg/kg), mice were placed in the open-field chambers and locomotor activity was measured during a ten-minute testing period. A significant interaction was found between isethionic acid and ethanol. Isethionic acid pre-treated mice (45.0, 90.0 and 180.0 mg/kg) showed a higher locomotor activity than the saline group at 2.5 and 3 g/kg of ethanol. In a second study, isethionic acid (45 mg/kg) and ethanol (1 g/kg) were simultaneously injected to rats. Ten minutes after the two treatments, rats were placed in the open-field chamber for a 30-minute period. The depressant effects that ethanol produced on rat locomotion were amplified by the same dose of isethionic acid as it affected ethanol-induced locomotion in mice (45 mg/kg). However, isethionic acid did not change the spontaneous locomotion at any of the doses tested in mice or rats. Since no differences in blood ethanol levels were detected in both mice and rats, the interaction between isethionic acid's action and ethanol-related locomotion does not seem to be due to different rates of absorption of ethanol or any other pharmacokinetic process related to ethanol levels. The current study displayed that isethionic acid, administered intraperitoneally, behaves in a similar way to its immediate precursor, taurine, by amplifying ethanol-induction of the locomotor activity.

This review represents an attempt to assess the available data on the role of catalase in the mediation of the behavioral actions of ethanol and the regulation of voluntary ethanol consumption. It is argued that acetaldehyde may be formed in brain through the peroxidatic activity of catalase. Furthermore, acetaldehyde formed centrally through the activity of this enzyme, may be responsible, at least in part, for some of the motivational, behavioral and neurotoxic effects of ethanol.

Nitric oxide has been implicated in mediating the neurotoxic effects of ischemia in the brain. However, studies of the effects of nitric oxide inhibition with nitric oxide synthase inhibitors have provided controversial results. One of the reasons for the controversy may be related to the specificity of the nitric oxide synthase inhibitors, such as Nw-nitro-L-arginine methylester (L-NAME), which has recently been questioned. The present work investigated the possible interaction of L-NAME with the enzyme catalase in vitro. Catalase is an iron containing enzyme which could potentially interact with the iron-binding groups of L-NAME. Since the normal function of catalase in the brain is to remove excess hydrogen peroxide, the inhibition of this process could have potentially toxic effects. L-NAME was found to attenuate the catalase inhibiting effects of the known catalase inhibitor cyanamide in vitro, suggesting a competition between cyanamide and L-NAME for catalase. In addition, L-NAME by itself attenuated catalase activity in vitro. These results indicate that in addition to inhibiting nitric oxide synthase, L-NAME may have effects on catalase activity.

Cyanamide, an aldehyde dehydrogenase inhibitor, has been shown to suppress voluntary ethanol consumption in animals. Studies were carried out to compare the effect of cyanamide on ethanol, saccharin-quinine and water intake in a restricted (10 min) access and in a free-choice nonrestricted access paradigm. An immediate and constant increase in fluid consumption was observed in the restricted access schedule paradigm independent of the fluid tested as cyanamide affected the consumption of all fluids including water. In the nonrestricted access study, cyanamide significantly increased total fluid intake. However, while saccharin-quinine-drinking animals treated with cyanamide demonstrated no change in intake preference, ethanol consumption was suppressed with a concomitant decrease in preference for ethanol. The present findings suggested that cyanamide may possess at least two, paradigm-specific, independent properties. It may enhance the consumption of fluid in general; however, it may also have a specific effect on ethanol intake when animals have continuous ethanol availability.

In studies designed to further examine the previously reported involvement of catalase in ethanol-induced effects, we attempted to confirm earlier observations by using normal (C3H-N) and acatalasemic (C3H-A) mice. These mice are identical in every respect and differ only in their catalase activity. Data suggested that the application of 3-amino-1,2,4-triazole (AT), a catalase inhibitor, to both substrains of mice resulted in a proportional decrease in motor activity, thus supporting our earlier observations. We also showed that this effect was specific to ethanol because AT did not have any effect on cocaine-induced motor activity in both substrains. Contrary to the effects of ethanol, these substrains did not differ in motor activity in response to cocaine. In an additional study, we observed that acatalasemic mice differed from the normals in their pattern of voluntary ethanol consumption. Acatalasemic mice consumed more ethanol but only when it was presented in the range of concentrations between 12 and 18%. Finally, we also obtained data suggesting that acatalasemic mice have longer duration of sleep time following ethanol administration compared to normals. Catalase activity was measured in both substrains. Results, once again, confirmed earlier data that the substrains differ in this activity and that AT further decreases brain catalase activity in both mice. Finally, when brain homogenates derived from both substrains were incubated with ethanol significant differences in the amount of generated acetaldehyde were found between the two mice strains. Together, these results provide strong support for the involvement of brain catalase in a variety of ethanol-induced behavioral effects.

It has been reported that acute, simultaneous injections of taurine and ethanol were effective in reducing ethanol-induced locomotor activity and sleep time. The possible involvement of taurine administration in ethanol-induced conditioned taste aversion (CTA) was investigated. The results obtained in the present study following simultaneous administration of taurine (45 mg/kg) and ethanol (0.8, 1.2, and 1.6 g/kg) demonstrate a significant interaction between taurine and ethanol in their effect on ethanol-induced CTA in rats. This interaction was biphasic in nature and dependent upon the specific dose of ethanol. At the lowest ethanol dose (0.8 g/kg), which in itself resulted in a marginal CTA, taurine significantly enhanced the CTA induced by this dose. The intermediate ethanol dose of 1.2 g/kg produced a significant CTA. This CTA was blocked by administration of taurine. Finally, the CTA produced by the high dose of ethanol (1.6 g/kg) was not affected by administration of taurine. Taurine by itself does not produce a CTA. Peripheral levels of ethanol were ethanol dose dependent and the same in all animals regardless of treatment, indicating taurine had no effects on plasma ethanol levels. These data are similar to those obtained by earlier studies on the effects of taurine on ethanol-induced motor activity in mice. The present results support the findings reported by other investigators that taurine administration exerts a significant effect on ethanol-induced behaviors.

Homogenates of perfused rat brains incubated in the presence of ethanol (50-100 mM) and glucose (10 mM) were found to oxidize ethanol to acetaldehyde. The addition of glucose oxidase, a known hydrogen peroxide generator, to the incubation medium, significantly (P less than 0.05) increased the generation of acetaldehyde. The presence in the incubation medium of metyrapone, an inhibitor of cytochrome P450, or pyrazole, an alcohol dehydrogenase inhibitor, did not affect the levels of acetaldehyde obtained. Conversely, the presence of 3-amino-1,2,4-triazole, a known catalase inhibitor, induced a concentration-dependent reduction of the amount of acetaldehyde generated after incubation, even in the presence of glucose oxidase. Homogenates of perfused brains of rats treated with 3-amino-1,2,4-triazole or cyanamide (another H2O2-dependent catalase blocker) also showed a dose-dependent reduction of the acetaldehyde obtained. These findings support the notion that a catalase-mediated oxidation of ethanol is present in rat brain homogenates. It is suggested that this local oxidation of ethanol may have important biological implications. The data of both studies increase support for the notion that acetaldehyde is produced directly in the brain and that it may be the agent mediating some of the psychopharmacological properties of ethanol and be one of the factors determining the propensity of an animal to voluntarily consume ethanol.

The effects of the catalase inhibitor, 3-amino-1,2,4-triazole (AT), on maintenance of voluntary consumption of ethanol was tested in male Long-Evans rats. AT produced a dose-dependent reduction in ethanol intake but did not affect total fluid consumption. AT also produced a dose-dependent inhibition of brain catalase lasting throughout the drinking period. These results suggest a role for brain catalase in determining the level of ethanol intake in rats.

The role of brain catalase in modulating the psychopharmacological effects of ethanol was investigated by examining ethanol induced motor activity in normal, C3H-N, and a corresponding group of acatalasemic C3H-A, mice. Following administration of one of three doses of ethanol (0.8, 1.6, and 3.2 g/kg) or saline, mice were placed in open field chambers and locomotor and rearing activity was measured during a 10-min testing period. A significant increase in locomotor activity was recorded in both groups of mice at lower doses of ethanol, while the higher dose produced a marked depression. Normal mice demonstrated more locomotor activity than acatalasemic mice at all ethanol doses. No differences between both groups of mice were observed in rearing activity. Also, no differences in blood ethanol levels were observed between the two substrains. Brain and liver residual catalase activity in the acatalasemic mice was found to be 40% and 50%, respectively, of normal mice. Furthermore, evidence for possible involvement of the peroxidatic activity in ethanol-induced motor activity is presented. These results suggest a role for centrally formed acetaldehyde as a factor mediating some of ethanol's psychopharmacological effects.

In the present investigation we questioned whether taurine antagonized the effects of ethanol on motor activity measured in the open field. Ten minutes following simultaneous administration (IP) of ethanol (1.0, 1.5, 2.0 and 2.5 g/kg) or saline and taurine (30, 45 and 60 mg/kg) or saline, mice were placed in open field chambers and locomotor activity was measured during a 10 min testing period. A significant interaction was found between taurine and ethanol. Taurine-treated mice displayed lower motor excitation with the 1.0 g/kg dose of ethanol than the saline group treated with the same dose of ethanol. However at the 2.0 g/kg ethanol dose, taurine-treated mice demonstrated higher motor activity than the saline treated mice, once again, treated with the same dose of ethanol. No differences in blood ethanol levels were observed between the two groups. In a second study, taurine administration (30, 45 and 60 mg/kg) did not show any effect on d-amphetamine-induced enhancement of locomotor activity (1, 2, and 3 mg/kg). Data from this study demonstrated an interaction between taurine and ethanol in their effect on locomotor activity in the open field.

The results presented in this study demonstrate a progressive inhibition of rat brain catalase activity by AT in vivo. Furthermore, the inhibition of brain catalase by AT demonstrates the presence of hydrogen peroxide in brain, since AT inhibits catalase in the presence of this compound. The rate of inhibition of catalase seems to be dependent upon the rate by which H2O2 is generated. A time course study showed slower onset of the inhibition of brain as compared to liver catalase, possibly reflecting tissue hydrogen peroxide levels or, alternatively, a rate-limiting penetration of AT into brain and into the catalase compartment. The presence of AT in brain was confirmed over the time period of the observed inhibition of brain catalase. Catalase inhibitors are of particular interest in the study of the physiological role of catalase. This study further supports the use of AT in investigations designed to further understand the role of brain catalase.

It has been proposed that ethanol can be oxidized in brain via the peroxidatic activity of catalase and that centrally formed acetaldehyde may mediate several of the psychopharmacological actions of ethanol. The present study was designed to investigate the role of brain catalase in the mediation of ethanol-induced narcosis, hypothermia and lethality in rats. Rats were pretreated with the catalase inhibitor 3-amino-1,2,4-triazole (AT) or saline. Five hours later, animals in each pretreatment group received IP injections of ethanol (3 or 4 g/kg). Ethanol-induced narcosis was significantly attenuated in AT-pretreated rats compared to the saline control group. As well, AT pretreatments reduced significantly the lethal effect of these ethanol doses. However, AT-pretreated ethanol-injected animals significantly reduce their body temperature as compared to the saline-ethanol animals. Blood ethanol determinations revealed that AT did interfere with ethanol metabolism. AT inhibits significantly brain catalase activity at all doses used in this study. The results indicate a role for brain catalase in ethanol effects. Furthermore, they suggest that catalase may be involved in the oxidation of ethanol in brain and that centrally formed acetaldehyde may play a role in ethanol-induced narcosis and lethality, but not hypothermia.

The purpose of the present investigation was to further study the relationship between ethanol and brain catalase in vivo. Rats were pretreated intraperitoneally (ip) with varying doses of ethanol or saline 30 min prior to administration of cyanamide (0.68 mmol/kg; ip), 4-hydroxypyrazole (1 mmol/kg; ip) or saline. Rat tissues were perfused in situ under ether anaesthesia. Brain catalase activity was measured using the Clark electrode. Results confirmed inhibition of brain catalase activity by cyanamide and 4-hydroxypyrazole. Ethanol protected catalase from cyanamide and 4-hydroxypyrazole inactivation in a dose-related manner. In a second study, homogenates from perfused brains were incubated in the presence of glucose and glucose oxidase with ethanol or saline and cyanamide or saline. Cyanamide was shown to inhibit the catalase activity in vitro in a dose-related manner. Ethanol prevented this inhibition of catalase when added to the incubation medium prior to cyanamide. These data suggest a competition between ethanol and inhibitors for the H2O2-catalase compound. They also confirm the presence and generation of H2O2 in the rat brain in vivo, and overall seem to support the notion that centrally formed acetaldehyde via brain catalase may be responsible for some of the psychopharmacological actions of ethanol.

The involvement of endogenous opioid mechanisms in the interaction between stress and ethanol was investigated in the rat. Animals were pretreated with naltrexone (10 mg/kg) or saline 3 h before a second injection consisting of ethanol (1.0 g/kg) or saline. They were then restrained for 15 or 60 min or left in home cages for an equivalent amount of time. After restraint, animals were either subjected to an open-field test or decapitated to collect blood for corticosterone determinations. Locomotor depression was found to be induced by 15 but not 60 min restraint. In naltrexone-treated animals, however, 60 min restraint was also found to induce locomotor depression. Ethanol pretreatment was found to block the locomotor depression induced by 15 min restraint. Such an interaction was in turn antagonized by naltrexone. In the 15 min condition, stress and ethanol were also found to interact in their effects on plasma levels of corticosterone. Naltrexone did not alter any effects of the stressors on corticosterone levels. These results provide support for the involvement of endogenous opioid mechanisms in the interaction of stress and ethanol at a behavioural level.

The possible involvement of catecholamines (CA) in the mediation of acetaldehyde's conditioned taste aversion (CTA) was examined by testing the effects of alpha-methyl-para-tyrosine (AMPT, a tyrosine hydroxylase inhibitor) on the CTAs produced by acetaldehyde. AMPT blocked the acquisition of the CTA normally produced by a low dose of acetaldehyde (0.2 g/kg), but had no significant effect on CTA produced by a high dose of acetaldehyde (0.3 g/kg). In a second study, acetaldehyde's role in the CTA produced by ethanol was investigated using the pre-exposure conditioned taste aversion paradigm. Pre-exposure to acetaldehyde (both doses) blocked the ethanol CTAs but when pre-exposure with acetaldehyde was coupled with AMPT, only the larger dose of acetaldehyde blocked the ethanol aversion. These results suggest that while the CTA to the low dose of acetaldehyde may be primarily central and catecholamine-mediated, the mechanism underlying the high dose CTA is probably peripheral and emetic in nature. These findings support the conclusion that acetaldehyde may be mediating many of the actions of ethanol.

Stress effects vary with different environmental situations or stress intensities. The effects of restraint stress on locomotion and or corticosterone were examined. Rats were restrained for 0, 15, 30, 60, 90 or 120 min, subsequent locomotion was measured for 10 min. Rats were also sacrificed for corticosterone determinations. Restraint stress affects both variables. Locomotion was recorded in rats pretreated with naltrexone or vehicle prior to restraint of 15 or 60 min. Naltrexone influenced the effects of stress differentially. It did not affect the results following 15 min of restraint but suppressed locomotion after 60-min restraint to a level comparable to that found after 15 min. Treatment with ethanol (1.0, 1.5, 2.0 g/kg) prior to 15 or 60 min of restraint resulted in the prevention of hypomotility induced by 15-min stress. It also interacted nonadditively with 15-min stress on corticosterone release. No such interaction occurred with 60 min stress. Also, naltrexone made it possible to block the effect of ethanol on restraint-induced hypomotility. Results describe stress as a nonunitary concept. Its effects tend to vary with its duration. The differential interaction of stress with naltrexone and ethanol depending on its duration supports the above notion. Results further suggest recruitment of opioid systems in long duration stress (60 min).

The interaction between restraint-stress and ethanol was investigated in the rat. The effects of ethanol pretreatment (0.0, 1.0, 1.5, 2.0 g/kg, 20% v/v) on locomotor depression and corticosterone release induced by restraint-stress (15, 60 min) were measured. Restraint durations of 15, 30, 90 and 120 min were found to decrease locomotor activity while animals restrained for 60 min did not differ from home cage controls. All restraint durations induced a significant increase in plasma levels of corticosterone. Locomotor activity counts of ethanol-pretreated (1.0, 1.5, 2.0 g/kg; 20% v/v) animals restrained for 15 min were not found to be lower than those of ethanol-pretreated animals remaining in home cages. Ethanol pretreatment did not differentially affect the locomotor activity of restrained or home cage animals in the 60-min condition. Plasma corticosterone levels of ethanol-pretreated animals restrained for 15 min were identical to those of ethanol-pretreated home cage controls. However, ethanol-pretreated animals restrained for 60 min demonstrated plasma corticosterone levels higher than those obtained by ethanol pretreatment or 60-min restraint alone. Blood ethanol levels were not found to be different between ethanol-control and ethanol-stress animals. These results provide support for a stress-ethanol interaction. They also suggest a differential interaction of ethanol with different intensities of stress.

The adverse use of alcohol is a serious global public health problem. Maternal alcohol consumption during pregnancy usually causes prenatal alcohol exposure (PAE) in the developing fetus, leading to a spectrum of disorders known as fetal alcohol spectrum disorders (FASD) and even fetal alcohol syndrome (FAS) throughout the lifelong sufferers. The prevalence of FASD is approximately 7.7 per 1,000 worldwide, and is even higher in developed regions. Generally, Ethanol in alcoholic beverages can impair embryonic neurological development through multiple pathways leading to FASD. Among them, the leading mechanism of FASDs is attributed to ethanol-induced neuroinflammatory damage to the central nervous system (CNS). Although the underlying molecular mechanisms remain unclear, the remaining multiple pathological mechanisms is likely due to the neurotoxic damage of ethanol and the resultant neuronal loss. Regardless of the molecular pathway, the ultimate outcome of the developing CNS exposed to ethanol is almost always the destruction and apoptosis of neurons, which leads to the reduction of neurons and further the development of FASD. In this review, we systematically summarize the current research progress on the pathogenesis of FASD, which hopefully provides new insights into differential early diagnosis, treatment and prevention for patents with FASD. [ABSTRACT FROM AUTHOR]

Rationale: Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. Objectives: The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. Methods: Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75 mg, sc), estradiol (0.0005 or 0.005 mg, sc), progesterone, (0.0125 or 0.125 mg, sc), or their vehicles. After 14 days of chronic treatment, a dose–effect curve was determined for heroin (0.0003—0.03 mg/kg/infusion) over the course of one week. Results: Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125 mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. Conclusions: These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder. [ABSTRACT FROM AUTHOR]

Ethanol metabolism plays an essential role in how the body perceives and experiences alcohol consumption, and evidence suggests that modulation of ethanol metabolism can alter the risk for alcohol use disorder (AUD). In this review, we explore how ethanol metabolism, mainly via alcohol dehydrogenase and aldehyde dehydrogenase 2 (ALDH2), contributes to drinking behaviors by integrating preclinical and clinical findings. We discuss how alcohol dehydrogenase and ALDH2 polymorphisms change the risk for AUD, and whether we can harness that knowledge to design interventions for AUD that alter ethanol metabolism. We detail the use of disulfiram, RNAi strategies, and kudzu/isoflavones to inhibit ALDH2 and increase acetaldehyde, ideally leading to decreases in drinking behavior. In addition, we cover recent preclinical evidence suggesting that strategies other than increasing acetaldehyde-mediated aversion can decrease ethanol consumption, providing other potential metabolism-centric therapeutic targets. However, modulating ethanol metabolism has inherent risks, and we point out some of the key areas in which more data are needed to mitigate these potential adverse effects. Finally, we present our opinions on the future of treating AUD by the modulation of ethanol metabolism. [ABSTRACT FROM AUTHOR]

Phycomyces strain C5, carrying mutation carB10, accumulates phytoene instead of beta-carotene. Heterokaryons containing C5 nuclei and different other nuclei carrying the wild type carB allele accumulate significant amounts of phytofluene, zota-carotene and neurosporene. From quantitative analyses of carotenes and nuclear proportions in the heterokaryons we conclude that four copies of the carB gene product, assembled in an enzyme complex, act sequentially in the conversion of phytoene to lycopene.

Lycopene cyclization to gamma-carotene and then to beta-carotene is partially blocked in Phycomyces by the presence of car R mutations in heterokaryosis or by the addition of 2-(4-chlorophenyl)thiotriethylamine . HCl to the medium. We have quantitatively determined the carotenes synthesized by Phycomyces under conditions of partially blocked cyclization and in the presence of either car A mutations in heterokaryosis or polyoxyethylenesorbitan monooleate (Tween-80) in the medium. We conclude that transfer of intermediate substrates between the enzyme aggregates involved in carotenogenesis does occur in the wild type but not in heterokaryons for car A mutations, and is facilitated by Tween-80.

The role of brain aldehyde dehydrogenase (ALDH) and acetaldehyde in mediating ethanol-induced locomotor activity was investigated using several enzyme inhibitors. Cyanamide, an ALDH inhibitor elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole, an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by cyanamide. Two hr prior to testing locomotor activity in open field boxes, 111 male Long Evans rats were pretreated with i.p. injections of saline (S+S), 4-methylpyrazole (4MP+S), cyanamide (S+C) or 4-methylpyrazole + cyanamide (4MP+C). Subjects then received i.p. injections of one of three doses of ethanol (0.4, 0.8 or 1.2 gm/kg) or saline vehicle one minute prior to testing in the open field and locomotor activity was recorded for a 10 min period. Locomotor activity of animals pretreated with cyanamide (S+C and 4MP+C) was significantly depressed compared to groups S+S and 4MP+S particularly at the two lower doses tested. These effects cannot be attributed to elevated blood acetaldehyde levels since pretreatment with 4MP+C prevented peripheral accumulation of acetaldehyde. A characteristic common to both cyanamide-treated groups was the inhibition of brain ALDH. It is therefore suggested that brain ALDH may play a role in the mediation of locomotor effects produced by ethanol. It is conceivable that ALDH plays this role by regulating the levels of acetaldehyde in brain.

The effect of a centrally acting noradrenergic agonist on voluntary ethanol intake was investigated in the laboratory rat. Doses of 1.5, 7.5, 15 and 25 mg/kg of FLA-136 were administered to animals chronically exposed to ethanol on a free choice basis. Administration of the highest dose of the drug brought about a 40% reduction in voluntary ethanol intake with no significant effect on total fluid consumption. These results would seem to indicate a possible functional relationship between rate of norepinephrine turnover and amounts of ethanol voluntarily consumed by the laboratory rat.

The role of peripherally and centrally acting acetaldehyde in ethanol-induced conditioned taste aversion (CTA) was investigated using various enzyme manipulations. Cyanamide, an aldehyde dehydrogenase inhibitor (ALDH) elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole (4MP), an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by cyanamide. Under both treatment conditions brain and liver ALDH activity is inhibited. Water-deprived rats were pretreated 4 hr prior to fluid presentation with intraperitoneal injections of saline (S+S), 4-methylpyrazole (4MP+S), cyanamide (S+C), or 4-methylpyrazole + cyanamide (4MP+C). Subsequently, animals were presented with a novel saccharin solution followed immediately by intraperitoneal injection of one of three doses of ethanol (0.4, 0.8, or 1.2 g/kg) or saline vehicle on four occasions. Results suggested that animals pretreated with cyanamide (groups S+C and 4MP+C) drank significantly less saccharin after conditioning with a subthreshold dose of ethanol (0.4 g/kg) in comparison to groups S+S and 4MP+S. Moreover, at the conditioning dose of 1.2 g/kg, cyanamide-treated animals demonstrated an attenuation of CTA compared to the other two groups. These effects cannot be attributed to elevated blood acetaldehyde levels since pretreatment with 4MP+C prevented peripheral acetaldehyde accumulation. A characteristic common to both cyanamide-treated groups was the inhibition of brain ALDH. It is therefore suggested that brain ALDH may play a role in the mediation of ethanol-induced CTAs. It is conceivable that ALDH plays this role by regulating the levels of acetaldehyde in brain.

The present experiment demonstrated that acute administration of ethanol appeared to have a biphasic effect on the accumulation of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4) in rat brain. The magnitude of these alterations in MHPG-SO4 levels was also observed to be highly correlated with peripheral blood ethanol levels. Since levels of MHPG-SO4 are considered to be an index of noradrenergic activity, the findings suggest that ethanol may affect norepinephrine activity in a specific dose- and time-dependent manner. These results are discussed in reference to previous reports describing apparent divergent effects on norepinephrine. Possible mechanisms for the biphasic actions are also suggested.

Voluntary ethanol consumption and high Km (mM range) brain and liver aldehyde dehydrogenase (ALDH) activity were measured in male rats of the Long-Evans, Wistar and Sprague-Dawley strains. The total amounts of ethanol consumed by the three strains did not differ significantly, nor did the levels of cerebral ALDH activity. Levels of brain ALDH did not differ as a function of ethanol exposure and across strains. Levels of ethanol consumption correlated better with levels of brain than liver aldehyde-oxidizing capacity, which were tested separately for each strain and also combining all the animals. Inherent variation in brain ALDH may be a biochemical counterpart of observed differences in voluntary ethanol intake within strains.

Groups of water-deprived rats were exposed to acetaldehyde, ethanol or vehicle control. On the conditioning day, the animals were first presented with a solution of saccharin after which the animals that were exposed to acetaldehyde received ethanol and those exposed to ethanol received acetaldehyde. Saccharin was again presented on three more occasions (testing days) without injection of drug. Using the percentage change in saccharin consumed from the first presentation as a measure of aversion, it was found that exposure to acetaldehyde blocked the taste aversion conditioned by ethanol. Animals exposed to ethanol showed no aversion to the saccharin which was paired with a small dose of acetaldehyde, indicating a symmetrical relationship between ethanol and acetaldehyde at this dose. However, exposure with ethanol did not block the aversion produced by conditioning with larger doses of acetaldehyde. These results suggest that the mechanism underlying the smaller dose of the taste aversion conditioned with acetaldehyde may be central while the mechanism underlying the larger dose is probably peripheral.

This investigation seeks to present evidence for the oxidation of ethanol in the brain via the peroxidatic activity of catalase and simultaneously provide evidence for the role of central acetaldehyde (ACH) in the mediation of an ethanol-induced conditioned taste aversion (CTA). Ethanol is capable of inducing a conditioned taste aversion. Pretreatment with the catalase inhibitor, 3-amino-1,2,4-triazole (AT), shows an attenuation of this ethanol-induced CTA. Animals receiving ethanol injections showed a CTA to a novel solution paired with a drug administration, while ethanol injected animals pretreated with AT did not show a CTA to ethanol administration. This effect of AT appears to be specific to the effects of ethanol as CTA's to morphine and lithium chloride were not affected by AT pretreatment. Peripheral levels of ethanol were the same in all animals regardless of pretreatment indicating that AT had no effect on peripheral levels of ethanol. These data increase support for the notion that acetaldehyde is produced directly in the brain and that it may be the agent mediating some of the psychopharmacological properties of ethanol.

Catalase activity in blood collected from young rats naive to ethanol (65 days) was significantly and positively correlated with later voluntary consumption of ethanol. Catalase activity levels were also correlated with catalase activity in brain and blood sampled after exposure to ethanol. The results obtained in the present study extend and confirm earlier findings (Aragon et al. 1985c) that brain catalase activity and voluntary ethanol intake are unidirectionally and causally related. The results also suggest that brain catalase activity may be part of an enzymatic system controlling the production and elimination of acetaldehyde in brain. This system may be a biological marker system mediating the affinity of organisms to ingest ethanol.

The relationship between voluntary ethanol intake and brain aldehyde dehydrogenase (ALDH) activity was investigated in the laboratory rat. Voluntary ethanol intake was compared to subcellular forms of brain ALDH. Mitochondrial, microsomal and cytosolic fractions were prepared and recovered ALDH activity of each form was compared to voluntary ethanol intake in Long Evans rats. Strong correlations were found between both mitochondrial and microsomal ALDH fractions and ethanol intake. No activity was observed in cytosolic fraction as measured with aromatic or aliphatic aldehydes. In addition, microsomal activity was detected with aromatic aldehydes only, whereas the mitochondrial form would oxidize both aromatic and aliphatic aldehydes.

The role of brain catalase in the mediation of ethanol's effects on motor activity was investigated. Male Long-Evans rats were pretreated with i.p. injections of the catalase inhibitor, 3-amino-1,2,4-triazole (AT) (1 g/kg) or saline (S). Four hours later, animals in each group received i.p. injections of one of two doses of ethanol (ETOH) [1.0 g/kg (E1) or 2.0 g/kg (E2)] or one of two volumes of distilled water (W1 or W2). Ten minutes after the administration of these agents, animals were placed in open-field chambers and motor activity was recorded during a 10-min testing period. Results indicated that the motor depression produced by 2.0 g/kg of ETOH was significantly attenuated in AT pretreated rats (group AT-E2). AT pretreatment, however, had no effect on motor activity for subjects injected with 1.0 g/kg ethanol or water. Total brain catalase activity in AT-pretreated animals was 15% of control animals. No differences in blood ethanol levels were observed between AT- and S-pretreated animals. An interaction between ethanol and AT at the level of the central nervous system is suggested. The results of the present study suggest that brain catalase activity may be involved in ethanol's effects. They also provide further support for the notion that acetaldehyde may be produced directly in the brain via catalase and that it may be a factor mediating some of ethanol's central effects.

The corticosterone response to an acute dose of ethanol (2 g/Kg, i.p.) was measured in the same rats in three different occasions: prior to, immediately following exposure to ethanol in a free choice self-administration paradigm and after a 15 day period of abstinence following exposure. Corticosterone was measured fluorometrically from tail blood samples collected 30 minutes following the ethanol injection. Blood ethanol levels were determined by gas chromatography. Mean plasma corticosterone and ethanol levels following the acute ethanol challenge were not significantly different in the three tested periods. A significant negative correlation between plasma corticosterone levels in the naive state and subsequent levels of individual voluntary ethanol intake was obtained. No apparent relationship was observed, however, between the same levels of ethanol consumption and the corticosterone response in these animals after ethanol exposure or exposure with abstinence. These data suggest that levels of ethanol intake may be related to the initial response to acute ethanol of the adrenal-pituitary axis. If so, this acute response to ethanol may be used to predict subsequent levels of ethanol intake.

The possible existence of a biological marker system mediating voluntary consumption of ethanol in rats has been examined in a series of studies. The working hypothesis underlying this research was that acetaldehyde, the primary metabolite of ethanol, mediates the positive reinforcing properties of ethanol and thus underlies the voluntary consumption of ethanol in both animals and humans. We further hypothesized that brain catalase and aldehyde dehydrogenase, the enzymes controlling the production and elimination of acetaldehyde in the brain, may represent a biological marker system underlying the affinity of the animals to consume ethanol. Data demonstrating that the activity levels of these enzymes are positively correlated with alcohol ingestion seems to suggest that it is likely that the enzyme activity can serve as a predictor of the propensity to drink alcohol. A predictive model is proposed which describes the modulation of voluntary ethanol intake through the activity of these enzymes and their role in determining rates of formation and degradation of acetaldehyde in the brain.

The relationship between voluntary ethanol consumption and brain catalase activity was investigated in male Long Evans rats. In the first study, rats which were voluntarily consuming alcohol or water for 25 days were sacrificed by decapitation immediately (group A) or 15 days (group B) following withdrawal of alcohol and their brains analysed for catalase activity. Mean brain catalase activity did not differ among the two groups of rats exposed to ethanol and the ones exposed to water only. Furthermore, there were significant positive correlations between individual voluntary ethanol intake and catalase activity in both groups, (group A:r = .69, p less than or equal to 0.05; group B:r = .54, p less than or equal to 0.05). In the second study, rats were forced to drink high levels of ethanol presented as the only source of fluid for 25 days. Rats were sacrificed and brain, liver, muscle and heart tissue were extracted and analysed for catalase activity. There were no differences in mean brain catalase activity between water and forced ethanol drinking rats indicating that the enzyme was not inducible by high volume ethanol consumption. The results suggest that inherent differences in brain catalase activity may be one of the factors in determining an animal's propensity to voluntarily consume ethanol.