[en] Ethanol administration induces both locomotor stimulant and sedative effects depending upon blood ethanol concentrations. Recent studies in rats and mice suggest that acetaldehyde, the first product of ethanol metabolism, might be involved in the expression of both the stimulant and the sedative effects of ethanol. A number of studies have used the drug cyanamide in an attempt to clarify the role of acetaldehyde in the behavioral effects of ethanol. The results of such studies are, however, difficult to interpret because cyanamide is an inhibitor of the enzymes catalase and aldehyde dehydrogenase, two enzymes with opposite effects on brain acetaldehyde concentrations. This study was aimed at clarifying the effects of cyanamide on ethanol-induced locomotor stimulant and sedative effects in Swiss mice. The locomotor stimulant effects of ethanol were measured in standard activity boxes, whereas the sedative effects of ethanol were quantified using the loss of righting reflex procedure. Cyanamide prevented the locomotor stimulant effects of 2 g/kg ethanol, although this was mainly due to a potentiation of the inhibitory effects of ethanol as evidenced by a prolongation of ethanol-induced loss of righting reflex. Additionally, 4-methylpyrazole, an inhibitor of the enzyme alcohol dehydrogenase, prevented these effects of cyanamide. It is concluded that in vivo the effects of cyanamide are predominantly due to the inhibition of the enzyme aldehyde dehydrogenase, rather than to its effects on catalase.
Research center :
Centre de Neurosciences Cognitives et Comportementales - ULiège
Arizzi-LaFrance MN, Correa M, Aragon CMG, Salamone JD (2006). Motor stimulant effects of ethanol injected into the substantia nigra pars reticulata: importance of catalase-mediated metabolism and the role of acetaldehyde. Neuropsychopharmacology 31:997-1008.
Correa M, Miquel M, Sanchis-Segura C, Aragon CMG (1999). Acute lead acetate administration potentiates ethanol-induced locomotor activity in mice: the role of brain catalase. Alcohol Clin Exp Res 23:799-805.
Correa M, Arizzi MN, Betz A, Mingote S, Salamone JD (2003). Open field locomotor effects in rats after intraventricular injections of ethanol and the ethanol metabolites acetaldehyde and acetate. Brain Res Bull 62: 197-202.
DeMaster EG, Shirota FN, Nagasawa HT (1985). Catalase mediated conversion of cyanamide to an inhibitor of aldehyde dehydrogenase. Alcohol 2:117-121.
Dudek BC, Phillips TJ, Hahn ME (1991). Genetic analysis of the biphasic nature of the alcohol dose response curve. Alcohol Clin Exp Res 15: 262-269.
Escarabajal MD, Aragon CMG (2002). The effect of cyanamide and 4-methylpyrazole on the ethanol-induced locomotor activity in mice. Pharmacol Biochem Behav 72:389-395.
Escarabajal MD, Aragon CMG (2003). DDTC, a metabolite of disulfiram, reduces the stimulating effect on ethanol's locomotor activity in mice. Psychopharmacol Bull 37:113-119.
Escarabajal MD, 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.
Hillbom ME, Sarviharju MS, Lindros KO (1983). Potentiation of ethanol toxicity by cyanamide in relation to acetaldehyde accumulation. Toxicol Appl Pharmacol 70:133-139.
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 Analyt Technol Biomed Life Sci 798:155-158.
Jamal M, Ameno K, Uekita I, Kumihashi M, Wang W, Ijiri I (2007). Catalase mediates acetaldehyde formation in the striatum of free-moving rats. Neurotoxicology (in press).
Kupari M, Lindros K, Hillbom M, Heikkila J, Ylikahri R (1983). Cardiovascular effects of acetaldehyde accumulation after ethanol ingestion: their modification by beta-adrenergic blockade and alcohol dehydrogenase inhibition. Alcohol Clin Exp Res 7:283-288.
Pastor R, Sanchis-Segura C, Aragon CMG (2002). Ethanol-stimulated behaviour in mice is modulated by brain catalase activity and H 2O2 rate of production. Psychopharmacology 165:51-59.
Phillips TJ, Shen EH (1996). Neurochemical bases of locomotion and ethanol stimulant effects. Int Rev Neurobiol 39:243-282.
Quertemont E, Tambour S (2004). Is ethanol a pro-drug? The role of acetaldehyde in the central effects of ethanol. Trends Pharmacol Sci 25:130-135.
Quertemont E, Tambour S, Bernaerts P, Zimatkin SM, Tirelli E (2004). Behavioral characterization of acetaldehyde in C57BL/6J mice: locomotor, hypnotic, anxiolytic and amnesic effects. Psychopharmacology 177:84-92.
Quertemont E, Tambour S, Tirelli E (2005). The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies. Prog Neurobiol 75:247-274.
Riveros-Rosas H, Julian-Sanchez A, Pina E (1997). Enzymology of ethanol and acetaldehyde metabolism in mammals. Arch Med Res 28:453-471.
Sanchis-Segura C, Miquel M, Correa M, Aragon CMG (1999). Cyanamide reduces brain catalase and ethanol-induced locomotor activity: is there a functional link? Psychopharmacology 144:83-89.
Tambour S, Didone V, Tirelli E, Quertemont E (2006). Locomotor effects of ethanol and acetaldehyde after peripheral and intraventricular injections in Swiss and C57BL/6J mice. Behav Brain Res 172:145-154.
Zimatkin SM (1991). Histochemical study of aldehyde dehydrogenase in the rat CNS. J Neurochem 56:1-11.
Zimatkin SM, Pronko SP, Vasiliou V, Gonzales FJ, Deitrich RA (2006). Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500-1505.