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Previous studies have shown that both 3-amino-1,2,4-triazole (AT), which inhibits metabolism of ethanol (EtOH) to acetaldehyde by inhibiting catalase, and D-penicillamine (D-P), an acetaldehyde-sequestering agent, modulate EtOH-conditioned place preference (CPP) in male albino Swiss (IOPS Orl) mice. These studies followed a reference-dose-like procedure, which involves comparing cues that have both been paired with EtOH. However, the role of EtOH-derived acetaldehyde has not been examined using a standard CPP method, and efficacy of these treatments could be different under the two circumstances. In the present investigation, we manipulated the strength of CPP across five separate studies and evaluated the effect of D-P and AT on EtOH-induced CPP following a standard unbiased CPP procedure. Mice received pairings with vehicle-saline injections with one cue and, alternatively, with AT- and D-P-EtOH with another cue. Our studies indicate that AT and D-P only disrupt CPP induced by EtOH in mice when the number of conditioning sessions and the dose of EtOH are low. These findings suggest that acquisition of EtOH-induced CPP may depend on the levels of acetaldehyde available during memory acquisition and the strength of the memory. Therefore, we propose that, at least when the memory processes are labile, brain acetaldehyde could participate in the formation of Pavlovian learning elicited by EtOH.

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.

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 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.

Intracerebroventricular (icv) injection of hydrogen peroxide (H 2 O 2 ) or the increase of endogenous H 2 O 2 centrally produced by catalase inhibition with 3-amino-1,2,4-triazole (ATZ) injected icv reduces the pressor responses to central angiotensin II (ANG II) in normotensive rats. In the present study, we investigated the changes in the arterial pressure and in the pressor responses to ANG II icv in spontaneously hypertensive rats (SHRs) and 2-kidney, 1-clip (2K1C) hypertensive rats treated with H 2 O 2 injected icv or ATZ injected icv or intravenously (iv). Adult male SHRs or Holtzman rats (n = 5-10/group) with stainless steel cannulas implanted in the lateral ventricle were used. In freely moving rats, H 2 O 2 (5 μmol/1 μl) or ATZ (5 nmol/1 μl) icv reduced the pressor responses to ANG II (50 ng/1 µl) icv in SHRs (11 ± 3 and 17 ± 4 mmHg, respectively, vs. 35 ± 6 mmHg) and 2K1C hypertensive rats (3 ± 1 and 16 ± 3 mmHg, respectively, vs. 26 ± 2 mmHg). ATZ (3.6 mmol/kg of body weight) iv alone or combined with H 2 O 2 icv also reduced icv ANG II-induced pressor response in SHRs and 2K1C hypertensive rats. Baseline arterial pressure was also reduced (-10 to -15 mmHg) in 2K1C hypertensive rats treated with H 2 O 2 icv and ATZ iv alone or combined and in SHRs treated with H 2 O 2 icv alone or combined with ATZ iv. The results suggest that exogenous or endogenous H 2 O 2 acting centrally produces anti-hypertensive effects impairing central pressor mechanisms activated by ANG II in SHRs or 2K1C hypertensive rats.

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.

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.