ethanol; acetaldehyde; locomotion; loss of righting reflex; elevated plus-maze; passive avoidance
Abstract :
[en] Rationale: Acetaldehyde, the first metabolite of ethanol, was recently suggested to contribute to many behavioral effects of ethanol, although few studies have directly investigated the behavioral effects of acetaldehyde itself. Objectives: The aim of the present study was to characterize the locomotor, hypnotic, anxiolytic-like and amnesic effects of acetaldehyde in C57BL/6J mice. Methods: Increasing doses of acetaldehyde (0 - 300 mg/kg) were injected intraperitoneally and their effects on a series of representative behaviors were investigated. The locomotor effects of acetaldehyde were measured in activity boxes. The duration of the loss of righting reflex was used as an index of the hypnotic effects of acetaldehyde. The anxiolytic-like effects of acetaldehyde were tested with an elevated plus-maze and the amnesic effects with the one-trial passive avoidance test. Finally, brain and blood acetaldehyde concentrations were assessed. Results: Acetaldehyde induced a significant hypolocomotor effect at 170 mg/kg and higher doses. In addition, the hypnotic effects of acetaldehyde were demonstrated by a loss of righting reflex after the administration of 170 and 300 mg/kg acetaldehyde. The elevated plus-maze showed that acetaldehyde does not possess anxiolytic-like properties. Finally, acetaldehyde ( 100 - 300 mg/kg) dose-dependently altered memory consolidation as shown by a reduced performance in the passive avoidance test. Conclusions: The present results show that acetaldehyde induces sedative, hypnotic and amnesic effects, whereas it is devoid of stimulant and anxiolytic-like properties in C57BL/6J mice. However, the behavioral effects of acetaldehyde after intraperitoneal administration were apparent at very high brain concentrations. The present results also indicate that acetaldehyde is unlikely to be involved in the anxiolytic properties of ethanol in mice.
Research center :
Centre de Neurosciences Cognitives et Comportementales - ULiège
Aragon CMG, Spivak K, Amit Z (1985) Blockade of ethanol-induced conditioned taste aversion by 3-amino-1,2,4-triazole: evidence for catalase mediated synthesis of acetaldehyde in rat brain. Life Sci 37:2077-2084
Aragon CMG, Abitbol M, Amit Z (1986) Acetaldehyde may mediate reinforcement and aversion produced by ethanol. Neuropharmacology 25:79-83
Aragon CMG, Spivak K, Amit Z (1991) Effect of 3-amino-1,2,4-triazole on ethanol-induced narcosis, lethality and hypothermia in rats. Pharmacol Biochem Behav 39:55-59
Aversano M, Ciamei A, Cestari V, Passino E, Middei S, Castellano C (2002) Effects of MK-801 and ethanol combinations on memory consolidation in CD1 mice: involvement of GABAergic mechanisms. Neurobiol Learn Mem 77:327-337
Bernaerts P, Tirelli E (2003) Facilitatory effect of the dopamine D 4 receptor agonist PD 168,077 on memory consolidation of an inhibitory avoidance learned response in C57BL/6J mice. Behav Brain Res 142:41-52
Castellano C, Populin R (1990) Effect of ethanol on memory consolidation in mice: antagonism by the imidazobenzodiazepine Ro 15-4513 and decrement by familiarization with the environment. Behav Brain Res 40:67-72
Correa M, Sanchis-Segura C, Aragon CMG (2001a) Brain catalase activity is highly correlated with ethanol-induced locomotor activity in mice. Physiol Behav 73:641-647
Correa M, Sanchis-Segura C, Aragon CMG (2001b) Influence of brain catalase on ethanol-induced loss of righting reflex in mice. Drug Alcohol Depend 65:9-15
Crabbe JC, Johnson NA, Gray DK, Kosobud A, Young ER (1982) Biphasic effects of ethanol on open-field activity: sensitivity and tolerance in c57BL/6N and DBA/2N mice. J Comp Physiol Psychol 96:440-451
Durcan MJ, Lister RG (1988) Time course of ethanol's effects on locomotor activity, exploration and anxiety in mice. Psychopharmacology 96:67-72
Eriksson CJP, Sippel HW (1977) The distribution and metabolism of acetaldehyde in rats during ethanol oxidation. I. The distribution of acetaldehyde in liver, brain, blood and breath. Biochem Pharmacol 26:241-247
Eriksson CJ, Sippel HW, Forsander OA (1977) The determination of acetaldehyde in biological samples by head-space gas chromatography. Anal Biochem 80:116-124
Escarabajal D, Miquel M, Aragon CMG (2000) A psychopharmacological study of the relationship between brain catalase activity and ethanol-induced locomotor activity in mice. J Stud Alcohol 61:493-498
Escarabajal MD, De Witte P, Quertemont E (2003) Role of acetaldehyde in ethanol-induced conditioned taste aversion in rats. Psychopharmacology 167:130-136
Frye GD, Breese GR (1981) An evaluation of the locomotor stimulating action of ethanol in rats and mice. Psychopharmacology 75:372-379
Hunt WA (1996) Role of acetaldehyde in the actions of ethanol on the brain - a review. Alcohol 13:147-151
Jamal M, Ameno K, Kumihashi M, Ameno S, Kubota T, Wang W, Ijiri I (2003) Microdialysis for the determination of acetaldehyde and ethanol concentrations in the striatum of freely moving rats. J Chromatogr B 798:155-158
Liljequist S, Ossowska K (1994) Genotypic differences in locomotor stimulation and dopaminergic activity following acute ethanol administration. Eur Neuropsychopharmacol 4:31-38
Middaugh LD, Boggan WO, Randall CL (1987) Stimulatory effects of ethanol in C57BL/6 mice. Pharmacol Biochem Behav 27:421-424
Middaugh LD, Kelley BM, Bandy ALE, McGroarty KK (1999) Ethanol consumption by C57BL/6 mice: influence of gender and procedural variables. Alcohol 17:175-183
Nuutinen H, Lindros KO, Salaspuro M (1983) Determinants of blood acetaldehyde level during ethanol oxidation in chronic alcoholics. Alcohol Clin Exp Res 7:163-168
Peng GS, Wang MF, Chen CY, Luu SU, Chou HC, Li TK, Yin SJ (1999) Involvement of acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase gene in Asians. Pharmacogenetics 9:463-476
Prunell M, Escorihuela RM, Fernandez-Teruel A, Nunez JF, Tobena A (1994) Differential interactions between ethanol and RO 15-4513 on two anxiety tests in rats. Pharmacol Biochem Behav 47:147-151
Quertemont E (2003) Discriminative stimulus effects of ethanol with a conditioned taste aversion procedure: lack of acetaldehyde substitution. Behav Pharmacol 14:343-350
Quertemont E (2004) Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism. Mol Psychiatry (in press)
Quertemont E, De Witte P (2001) Conditioned stimulus preference after acetaldehyde but not ethanol injections. Pharmacol Biochem Behav 68:449-454
Quertemont E, Grant KA (2002) Role of acetaldehyde in the discriminative stimulus effects of ethanol. Alcohol Clin Exp Res 26:812-817
Quertemont E, Tambour S (2004) Is ethanol a pro-drug? Role of acetaldehyde in the central effects of ethanol. Trends Pharmacol Sci 25:130-134
Quertemont E, Escarabajal MD, De Witte P (2003) Role of catalase in ethanol-induced conditioned taste aversion: a study with 3-amino-1,2,4-triazole. Drug Alcohol Depend 70:77-83
Quintanilla ME, Callejas O, Tampier L (2002) Aversion to acetaldehyde: differences in low-alcohol-drinking (UchA) and high-alcohol-drinking (UchB) rats. Alcohol 26:69-74
Redila VA, Smith BR, Amit Z (2000) The effects of aminotriazole and acetaldehyde on an ethanol drug discrimination with a conditioned taste aversion procedure. Alcohol 21:279-285
Smith BR, Aragon CMG, Amit Z (1997) Catalase and the production of brain acetaldehyde: a possible mediator of the psychopharmacological effects of ethanol. Addict Biol 2:277-289
Tabakoff B, Kiianmaa K (1982) Does tolerance develop to the activating, as well as the depressant, effects of ethanol? Pharmacol Biochem Behav 17:1073-1076
White AM, Matthews DB, Best PJ (2000) Ethanol, memory, and hippocampal function: a review of recent findings. Hippocampus 10:88-93
Zimatkin SM, Deitrich RA (1997) Ethanol metabolism in the brain. Addict Biol 2:387-399
Zimatkin SM, Lindros KO (1996) Distribution of catalase in rat brain: aminergic neurons as possible targets for ethanol effects. Alcohol 31:167-174
Zimatkin SM, Liopo AV, Deitrich RA (1998) Distribution and kinetics of ethanol metabolism in the rat brain. Alcohol Clin Exp Res 22:1623-1627
Zimatkin SM, Liopo AV, Slychenkov VS, Deitrich RA (2001a) Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. I. Studies in outbred animals. Alcohol Clin Exp Res 25:976-981
Zimatkin SM, Liopo AV, Satanoversuskaya VI, Bardina LR, Deitrich RA (2001b) Relationship of brain ethanol metabolism to the hypnotic effect of ethanol. II. Studies in selectively bred rats and mice. Alcohol Clin Exp Res 25:982-988