[en] Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested whether acetaldehyde injected directly into the brain of mice has stimulant properties. Recently, it was also shown in rats that both ethanol and acetaldehyde can induce opposite locomotor effects according to the route of administration. Whereas peripheral administrations of ethanol and acetaldehyde induced locomotor depressant effects, their infusions directly into the brain produced locomotor stimulation. The aim of the present study was to characterize in mice the locomotor effects of ethanol and acetaldehyde injected either peripherally by the intraperitoneal route or centrally into the brain ventricles. Additionally, the effects of ethanol and acetaldehyde were compared in two strains of mice known for their differential sensitivity to the locomotor effects of ethanol, namely Swiss and C57BL/6J mice. Ethanol induced a biphasic effect on locomotor activity in Swiss mice, with stimulant effects at low to moderate doses and depressant effects at higher doses. Such a profile of effects was observed whatever the route of administration, peripheral or central. In C57BL/6J mice, ethanol only induced monophasic depressant effects. In this mouse strain, no evidence of the stimulant effects of ethanol was found after either an i.p. or an i.c.v. administration of ethanol. In contrast to ethanol, acetaldehyde yielded only depressant effects in both strains of mice after both peripheral and central administrations. These results indicate that the route of administration does not alter the locomotor effects of ethanol and acetaldehyde in mice. Additionally, the present study shows that the stimulant properties of acetaldehyde, even after direct infusion into the brain, are not as obvious as previously speculated.
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Aragon C.M.G., Rogan F., and Amit Z. Ethanol metabolism in rat brain homogenates by a catalase-H2O2 system. Biochem Pharm 44 (1992) 93-98
Arizzi M.N., Correa M., Betz A.J., Wisniecki A., and Salamone J.D. Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats: studies with low and high rate operant schedules. Behav Brain Res 147 (2003) 203-210
Arizzi-LaFrance M.N., Correa M., Aragon C.M.G., and Salamone J.D. Motor stimulant effect of ethanol injected into substantia nigra pars reticulata: importance of catalase-mediated metabolism and the role of acetaldehyde. Neuropsychopharmacology 31 (2006) 997-1008
Babbini M., Gaiardi M., and Bartoletti M. Dose-time motility effects of morphine and methadone in naive or morphinized rats. Pharmacol Res Commun 11 (1979) 809-813
Bell R.L., Rodd-Henricks Z.A., Webster A.A., Lumeng L., Li T.-K., McBride W.J., et al. Heart rate and motor-activating effects of orally self-administered ethanol in alcohol-preferring (P) rats. Alcohol Clin Exp Res 26 (2002) 1162-1170
Besheer J., Lepoutre V., and Hodge C.W. GABAB receptor agonist reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice. Psychopharmacology 174 (2004) 358-366
Brown Z.W., Amit Z., and Rockman G.E. Intraventricular self-administration of acetaldehyde, but not ethanol, in naive laboratory rats. Psychopharmacology 64 (1979) 271-276
Campisi P., Carmichael F.J., Crawford M., Orrego H., and Khanna J.M. Role of adenosine in the ethanol-induced potentiation of the effects of general anesthetics in rats. Eur J Pharmacol 325 (1997) 165-172
Chuck T.L., McLaughlin P.J., Arizzi-LaFrance M.N., Salamone J.D., and Correa M. Comparison between multiple behavioral effects of peripheral ethanol administration in rats: sedation, ataxia and bradykinesia. Life Sci 79 (2006) 154-161
Cohen C., Perrault G., and Sanger D.J. Evidence for the involvement of dopamine receptors in ethanol-induced hyperactivity in mice. Neuropharmacology 36 (1997) 1099-1108
Colombo G., Agabio R., Lobina C., Reali R., Vacca G., and Gessa G.L. Stimulation of locomotor activity by voluntarily consumed ethanol in Sardinian alcohol-preferring rats. Eur J Pharmacol 357 (1998) 109-113
Correa M., Arizzi M.N., Betz A., Mingote S., and Salamone J.D. Open field locomotor effects in rats after intraventricular injections of ethanol and the ethanol metabolites acetaldehyde and acetate. Brain Res Bull 63 (2003) 197-202
Correa M., Arizzi M.N., Betz A., Mingote S., and Salamone J.D. Locomotor stimulant effects of intraventricular injections of low doses of ethanol in rats: acute and repeated administration. Psychopharmacology 170 (2003) 368-375
Correa M., Miquel M., and Aragon C.M.G. Lead acetate potentiates brain catalase activity and enhances ethanol-induced locomotion in mice. Pharmacol Biochem Behav 66 (2000) 137-142
Correa M., Miquel M., Sanchis-Segura C., and Aragon C.M.G. Acute lead acetate administration potentiates ethanol-induced locomotor activity in mice: the role of brain catalase. Alcohol Clin Exp Res 23 (1999) 799-805
Correa M., Sanchis-segura C., and Aragon C.M.G. Brain catalase activity is highly correlated with ethanol-induced locomotor activity in mice. Physiol Behav 73 (2001) 641-647
Correa M., Sanchis-Segura C., Pastor R., and Aragon C.M.G. Ethanol intake and motor sensitization: the role of brain catalase activity in mice with different genotypes. Physiol Behav 82 (2004) 231-240
Crabbe J.C., Gallaher E.S., Phillips T.J., and Belknap J.K. Genetic determinants of sensitivity to ethanol in inbred mice. Behav Neurosci 108 (1994) 186-195
Crabbe Jr. J.C., Johnson N.A., Gray D.K., Kosobud A., and Young E.R. Biphasic effects of ethanol on open-field activity: sensitivity and tolerance in C57BL/6N and DBA/2N mice. J Comp Physiol Psychol 96 (1982) 440-451
Deitrich R.A. Acetaldehyde: deja vu du jour. J Stud Alcohol 65 (2004) 557-572
Dyr W., and Kostowski W. Preliminary phenotypic characterization of the Warsaw high preferring (WHP) and Warsaw low preferring (WLP) lines of rats selectively bred for high and low ethanol consumption. Pol J Pharmacol 56 (2004) 359-365
Engel J.A. Influence of age and hormones on the stimulatory and sedative effects of ethanol. In: Rydberg U. (Ed). Alcohol and the developing brain (1985), Raven Press, New York 57-67
Eriksson C.J., and Sippel H.W. 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 (1977) 241-247
Escarabajal D., Miquel M., and Aragon C.M.G. A psychopharmacological study of the relationship between brain catalase activity and ethanol-induced locomotor activity in mice. J Stud Alcohol 61 (2000) 493-498
Filip M., Papla I., Nowak E., and Przegalinski E. Blocking impact of clozapine on cocaine locomotor and sensitizing effects in rats. Pol J Pharmacol 55 (2003) 1125-1130
Frye G.D., and Breese G.R. An evaluation of the locomotor stimulating action of ethanol in rats and mice. Psychopharmacology 75 (1981) 372-379
Gill K., Menez J.F., Lucas D., and Deitrich R.A. Enzymatic production of acetaldehyde from ethanol in rat brain tissue. Alcohol Clin Exp Res 16 (1992) 910-915
King T.S., and Chinchilli V.M. Robust estimators of the concordance correlation coefficient. J Biopharm Stat 11 (2001) 83-105
Liljequist S., and Ossowska K. Genotypic differences in locomotor stimulation and dopaminergic activity following acute ethanol administration. Eur Neuropsychopharmacol 4 (1994) 31-38
Lopez M., Simpson D., White N., and Randall C. Age- and sex-related differences in alcohol and nicotine effects in C57BL/6J mice. Addict Biol 8 (2003) 419-427
Masur J., and Dos Santos H.M. Response variability of ethanol-induced locomotor activation in mice. Psychopharmacology 96 (1988) 547-550
Masur J., Oliveira de Souza M.L., and Zwicker A.P. The excitatory effect of ethanol: absence in rats, no tolerance and increased sensitivity in mice. Pharmacol Biochem Behav 24 (1986) 1225-1228
Middaugh L.D., Boggan W.O., and Randall C.L. Stimulatory effects of ethanol in C57BL/6 mice. Pharmacol Biochem Behav 27 (1987) 421-424
Ostrowski N.L., and Caggiula A.R. Correlation between locomotor stimulation and the electrophysiological effects of low doses of morphine on substantia nigra dopamine neurons. I. Acute drug administration. J Pharmacol Exp Ther 257 (1991) 72-81
Paivarinta P., and Korpi E.R. Voluntary ethanol drinking increases locomotor activity in alcohol-preferring AA rats. Pharmacol Biochem Behav 44 (1993) 127-132
Pastor R., Sanchis-Segura C., and Aragon C.M.G. Ethanol-stimulated behaviour in mice is modulated by brain catalase activity and H2O2 rate of production. Psychopharmacology 165 (2002) 51-59
Paxinos G., and Franklin K.B.J. The mouse brain in stereotaxic coordinates (2001), Academic Press, New York
Phillips T.J., Dickinson S., and Burkhart-Kasch S. Behavioral sensitization to drug stimulant effects in C57BL/6J and DBA/2J inbred mice. Behav Neurosci 108 (1994) 789-803
Ponomarev I., and Crabbe J.C. Characterization of acute functional tolerance to the hypnotic effects of ethanol in mice. Alcohol Clin Exp Res 28 (2004) 991-997
Quertemont E. Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism. Mol Psychiatry 9 (2004) 570-581
Quertemont E., and De Witte P. Conditioned stimulus preference after acetaldehyde but not ethanol injections. Pharmacol Biochem Behav 68 (2001) 449-454
Quertemont E., and Grant K.A. Role of acetaldehyde in the discriminative stimulus effects of ethanol. Alcohol Clin Exp Res 26 (2002) 812-817
Quertemont E., and Tambour S. Is ethanol a pro-drug? Role of acetaldehyde in the central effects of ethanol. Trends Pharmacol Sci 25 (2004) 130-134
Quertemont E., Tambour S., Bernaerts P., Zimatkin S.M., and Tirelli E. Behavioral characterization of acetaldehyde in C57BL/6J mice: locomotor, hypnotic, anxiolytic and amnesic effects. Psychopharmacology 177 (2004) 84-92
Quertemont E., Tambour S., and Tirelli E. The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies. Prog Neurobiol 75 (2005) 247-274
Rodd Z.A., Bell R.L., Zhang Y., Murphy J.M., Goldstein A., Zaffaroni A., et al. Regional heterogeneity for the intracranial self-administration of ethanol and acetaldehyde within the ventral tegmental area of alcohol-preferring (P) rats: involvement of dopamine and serotonin. Neuropsychopharmacology 30 (2005) 330-338
Sanchis-Segura C., Miquel M., Correa M., and Aragon C.M.G. Daily injections of cyanamide enhance both ethanol-induced locomotion and brain catalase activity. Behav Pharmacol 10 (1999) 459-465
Sanchis-Segura C., Miquel M., Correa M., and Aragon C.M.G. The catalase inhibitor sodium Azide reduces ethanol-induced locomotor activity. Alcohol 19 (1999) 37-42
Waller M.B., Murphy J.M., McBride W.J., Lumeng L., and Li T.K. Effect of low dose ethanol on spontaneous motor activity in alcohol-preferring and -nonpreferring lines of rats. Pharmacol Biochem Behav 24 (1986) 617-623
White J.M., and Smith A.M. Modification of the behavioural effects of ethanol by nifedipine. Alcohol Alcohol 27 (1992) 137-141
Wise R.A., and Bozarth M.A. A psychomotor stimulant theory of addiction. Psychol Rev 94 (1987) 469-492