Symposium 26 Tuesday Sept. 25th 1.30 pm–3.00 pm; Room: Lecture Hall 2
Acetaldehyde, alcohol-induced behaviours and alcoholism: clinical and experimental perspectives: Chairpersons: Quertemont E (Belgium), Yin SJ (Taiwan)
 |
Abstract |
|---|
Presentation S26-1
Pharmacokinetic and pharmacodynamic effects of acetaldehyde in ALDH2*2 alcoholics
Yin S-J (Taiwan)
Aims. It has been well documented that homozygosity of the variant aldehyde dehydrogenase-2 (ALDH2) gene allele, ALDH2*2, in Asians almost fully protects against developing alcohol dependence and that the heterozygosity only affords a partial protection to varying degrees.
Methods. To explore physiological basis for the full versus the partial protection against alcoholism by ALDH2 polymorphism, direct correlations of blood ethanol/acetaldehyde/acetate concentrations, cardiac and extracranial/intracranial arterial hemodynamic parameters, as well as subjective reactions have been investigated in alcohol-dependent patients and control subjects with different ALDH2 allelotypes following a low (0.2 g/kg) to a moderate (0.5 g/kg) dose of alcohol for a period of 130 min.
Results. The pharmacokinetic consequences and pharmacodynamic effects indicate that acetaldehyde, rather than ethanol or acetate, is primarily responsible for the observed alcohol sensitivity reactions and suggest that the full protection by ALDH2*2/*2 can be ascribed to the intense unpleasant physiological/psychological reactions caused by persistently elevated blood acetaldehyde after ingesting a small amount of alcohol and that the partial protection by ALDH2*1/*2 can be attributed to a faster elimination of acetaldehyde and accordingly the lower accumulation in circulation.
Conclusions. Physiological tolerance or innate insensitivity to acetaldehyde appears to be crucial for developing alcohol dependence in the heterozygous alcoholics.
Presentation S26-2
Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system
Diana M, Enrico P, Peana A-T, Melis M (Italy)
Aims. To elucidate the role of acetaldehyde on ethanol-induced motivational effects and its activation of the mesolimbic dopamine system.
Methods. Conditioned place preference, microdialysis of dopamine in vivo, patch-clamp studies of DA neurons in vitro.
Results. We show that Etoh-derived ACD is necessary for Etoh-induced place preference, a preclinical test with high predictive validity for reward liability. We also found that ACD is essential for Etoh-increased microdialysate dopamine (DA) levels in the nucleus accumbens (NAcc), and that this effect is mimicked by intra-Ventral tegmental area (VTA) ACD administration. Furthermore, in vitro, ACD enhances VTA DA neuronal firing through action on two ionic currents: reduction of IA and activation of Ih. Coherently, Etoh-stimulating properties on DA neurons are prevented by pharmacological blockade of local catalase: the main metabolic step for biotransformation of Etoh into ACD in the central nervous system.
Conclusions. These results provide in vivo and in vitro evidence for a key role of ACD in Etoh motivational properties and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD by increasing VTA DA neuronal activity, would oppose its well-known peripherally originating aversive properties. Careful consideration of these findings could help in devising new effective pharmacological therapies aimed at reducing Etoh intake in alcoholics.
Presentation S26-3
Aldh2 transgenic knockout mouse dislike alcohol drinking and receive more sever acetaldehyde toxicity
Isse T, Kitagawa K, Matsuno K, Matsuda T, Matsumoto A, Oyama T, Kawamoto T (Japan)
Aims. Acetaldehyde is metabolized by aldehyde dehydrogenase 2 (ALDH2). Half of Japanese are inactive aldehyde dehydrogenase genotype (ALDH2*2/*2 and ALDH2*1/*2). ALDH2-inactive individuals were estimated to be at a higher risk of toxicity due to a higher internal exposure to acetaldehyde. However, toxicity of acetaldehyde has not been evaluated in these populations. In order to directly elucidate the toxicity differences between these populations, we generated Aldh2 transgenic knockout mice and use them for the evaluation.
Methods. We compared the ethanol preference, ethanol and acetaldehyde clearance after drinking, acetaldehyde inhalation toxicity difference, and acetaldehyde DNA adducts between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2–/–) mice.
Results. The Aldh2–/– mice did not prefer ethanol drinking compared to Aldh2+/+ mice under the 2 bottle test. Area under the curve (AUC) of blood acetaldehyde level in Aldh2–/– mice was approximately 17 times higher than Aldh2+/+ mice after the 5.0 g/kg ethanol gavages. In the acetaldehyde inhalation test, the blood acetaldehyde concentration of Aldh2–/– mice was higher than that of Aldh2+/+ mice, and the levels of erosions in nose to respiratory tract of Aldh2–/– were more severe compared with that of Aldh2+/+ mice. The 1-compartment multiple dosing model figures out the risk factor of internal exposure for Aldh2–/– mice for the acetaldehyde inhalation is approximately 6 times higher than Aldh2+/+ mice. The Aldh2–/– mice show higher acetaldehyde DNA adduct level than Aldh2+/+ mice after 2 weeks ethanol drinking.
Conclusions. Based on the results of this study, acetaldehyde was inferred to pose a higher risk to ALDH2-inactive human subjects.
Presentation S26-4
Alcohol dehydrogenase (ADH), acetaldehyde burst and aversion to ethanol: conceptual and experimental examination
Quintanilla ME, Tampier L, Sapag A Israel Y (Chile)
Aims. The aim of this study was to determine the role of (i) a high ADH activity and (ii) the time-limited oxidizing state existent in the liver upon ethanol intake on (a) arterial acetaldehyde levels and (b) the development of an aversion to ethanol.
Methods. Male and female alcohol preferring (UChB) naïve rats were allowed access to 10% ethanol for 1 hour a day or were administered 1 g/kg ethanol intraperitoneally. Liver ADH activity, voluntary ethanol intake and arterial acetaldehyde levels were determined following the i.p. administration of ethanol.
Results. Females showed (i) a 70% higher hepatic ADH activity than males, (ii) a 60% lower voluntary ethanol intake and (iii) upon i.p. ethanol administration generated a transient arterial acetaldehyde elevation (‘burst’) with levels 2.5-fold (p< 0.02) greater than those in males. Castration of males led to (i) an increased ADH activity (+50%; p< 0.001), (ii) a reduction of voluntary ethanol intake to levels comparable to those in females and (iii) the appearance of an acetaldehyde burst (3–4 fold vs sham males). In females, the ADH inhibitor 4-methylpyrazole fully blocked the arterial acetaldehyde burst and increased ethanol intake. In males, administration of sodium pyruvate at the time of ethanol administration or access led to an abrupt acetaldehyde burst and to a marked aversion for ethanol.
Conclusions. Studies strongly suggest that the development of an ‘acetaldehyde burst’ constitutes an aversion mechanism by which a high ADH activity and high pre-steady levels of metabolites that oxidize NADH determine an aversion to ethanol. Supported: FONDECYT (1050480; 1040555), NIAAA (AA015421), ICM (P05-001F).
Presentation S26-5
Acute and chronic effects of acetaldehyde on learning and memory in mice
Quertemont E, Tambour S, Didone V (Belgium)
Acetaldehyde has been postulated to mediate several of the behavioral effects of ethanol, including its reinforcing properties. At the highest doses, alcohol disrupts the acquisition and performance of memory tasks, culminating with the blackout experience at high blood alcohol concentrations. However, it remains unknown whether acetaldehyde is involved in such memory impairments induced by acute ethanol. Additionally, chronic alcohol consumption in humans sometimes leads to persistent memory impairments, partly due to serious brain damages. The Wernicke-Korsakoff syndrome, characterized by severe anterograde amnesia, is the most serious memory disorder induced by chronic alcohol.
The aim of the present study was to show whether acute and chronic treatments with acetaldehyde, the first metabolite of ethanol, lead to similar memory impairments as ethanol in mice.
Methods. Memory performances of Swiss and C57BL/6J mice were tested in both the passive avoidance task and the fear conditioning procedure. In the first part of the experiments, mice were injected with acute acetaldehyde (50 to 300 mg/kg) immediately after the training phase. In the second part of the experiment, mice were tested for memory performance after 10 daily acetaldehyde injections.
Results. The first part of the experiments shows that acute acetaldehyde administrations produce a strong amnesic effect in both experimental paradigms. Additionally, the amnesic effects of acetaldehyde were more consistent than those observed after ethanol administration. In the second part of the studies, we show that 10 daily acetaldehyde injections to mice led to a severe and persistent anterograde amnesia in both the pavlovian and the operant learning tasks.
Conclusions. In conclusion, acute acetaldehyde produces strong amnesic effects through yet unknown pharmacological mechanisms. In addition, chronic acetaldehyde administration leads to persistent memory impairments. These results suggest that acetaldehyde might be involved in both the acute amnesic effects of high ethanol doses and the neurotoxic effects of chronic alcohol consumption.