Concurrent administration of diethyldithiocarbamate and 4-methylpyrazole enhances ethanol-induced locomotor activity: the role of brain ALDH.
BACKGROUND
It has been proposed that brain aldehyde dehydrogenase (ALDH) plays a role in the modulation of some psychopharmacological effects of ethanol. Diethyldithiocarbamate (DDTC), an ALDH inhibitor, elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole (4-MP), an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by DDTC.


OBJECTIVE
To investigate the effects of concurrent DDTC and 4-MP administration on ethanol-induced locomotor activity in mice.


METHODS
Mice were pretreated IP with saline (S+S) or 4-MP (10 mg/kg) (S+4-MP), then received IP injections of ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg) prior to testing in the open field.


RESULTS
Pretreatment with 4-MP does not modify the spontaneous or ethanol-induced locomotor activity. In the second experiment, the DDTC (114, 228 and 456 mg/kg) and 4-MP (DDTC+4-MP) were administered 8 h prior to testing locomotor activity in the open field. Animals were then treated with ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg), and placed in open field chambers. The locomotor activity of animals pretreated with DDTC and 4-MP was significantly enhanced here compared to groups S+S and S+4-MP. These effects cannot be attributed to elevated blood acetaldehyde levels, as pretreatment with 4-MP prevented peripheral accumulation of acetaldehyde.


CONCLUSIONS
These data suggest that brain ALDH may contribute to the effects of ethanol on locomotor activity. This role of the enzyme ALDH in some of the psychopharmacological effects of ethanol may be a result of its ability to regulate levels of acetaldehyde in brain.
Escarabajal
M Dolores
MD
Area de Psicobiología, Departamento de Psicología, Facultad de Humanidades, Universidad de Jaén, Paraje Las Lagunillas s/n, 23071 Edificio D-2, Spain. descara@ujaen.es
Aragon
Carlos M G
CM
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004050:Ditiocarb / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D000431:Ethanol / Q000494:pharmacology*; D000077604:Fomepizole; D007274:Injections, Intraperitoneal; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage*
D002492:Central Nervous System Depressants; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D000431:Ethanol; D000077604:Fomepizole; D004050:Ditiocarb; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase