ABSTRACT
Recent studies suggest that the brain histaminergic system and especially the H3 receptors are involved in the regulation of alcohol consumption and alcohol-induced behaviors. Part of this effect might be due to a modulation of ethanol-induced sedation by central histamine. The aim of the present study was to investigate the effects of several histaminergic drugs on ethanol-induced sedation using the loss of righting reflex experimental protocol in female Swiss mice. A pretreatment with L-histidine, the histamine precursor, significantly reduced ethanol-induced sedation, suggesting that brain histamine protects against the sedative effects of ethanol. In a second set of experiments, several H3 receptor agonists (immepip or imetit) and inverse agonists/antagonists (thioperamide, A331440, or BF2.649) were tested. Surprisingly, both H3 receptor agonists and antagonists potentiated the sedative effects of ethanol. This paradoxical effect might be due to the subtle regulatory actions related to the H3 heteroreceptor function.
Subject(s)
Brain/drug effects , Ethanol/pharmacology , Histidine/pharmacology , Hypnotics and Sedatives/pharmacology , Receptors, Histamine H3/physiology , Reflex, Righting/drug effects , Animals , Biphenyl Compounds/pharmacology , Female , Imidazoles/pharmacology , Mice , Nitriles/pharmacology , Piperidines/pharmacology , Pyrrolidines/pharmacology , Thiourea/analogs & derivatives , Thiourea/pharmacologyABSTRACT
BACKGROUND: Acetaldehyde, the first metabolite of ethanol, has been suggested to be involved in many behavioral effects of ethanol. However, few studies have investigated the hypothermic effects of acetaldehyde or the contribution of acetaldehyde to ethanol-induced hypothermia. The aim of the present study is to better understand the hypothermic effects of acetaldehyde and the possible contribution of acetaldehyde in ethanol-induced hypothermia, especially under conditions leading to acetaldehyde accumulation. METHODS: Female Swiss mice were injected intraperitoneally with ethanol and acetaldehyde and their rectal temperatures were measured with a digital thermometer at various time points after the injections. Experiment 1 compared the hypothermic effects of various acetaldehyde doses (0 to 300 mg/kg) with a reference dose of ethanol (3 g/kg). Experiment 2 tested the effects of a pretreatment with the aldehyde dehydrogenase (ALDH) inhibitor cyanamide (25 mg/kg) on ethanol- and acetaldehyde-induced hypothermia. In experiments 3 and 4, mice received a combined pretreatment with cyanamide and the alcohol dehydrogenase (ADH) inhibitor 4-Methylpyrazole (10 mg/kg) before the injection of ethanol or acetaldehyde. RESULTS: Acetaldehyde at doses between 100 and 300 mg/kg induced significant hypothermic effects, but of shorter duration than ethanol-induced hypothermia. The inhibition of ALDH enzymes by cyanamide induced a strong potentiation of both ethanol- and acetaldehyde-induced hypothermia. The pretreatment with 4-MP prevented the potentiation of ethanol-induced hypothermia by cyanamide, but slightly increased the potentiation of acetaldehyde-induced hypothermia by cyanamide. CONCLUSIONS: The results of the present study clearly show that acetaldehyde has hypothermic properties in mice at least at relatively high concentrations. Furthermore, the accumulation of acetaldehyde following ALDH inhibition strongly enhanced the hypothermic effects of ethanol. These latter results confirm the hypothermic properties of acetaldehyde and show that acetate, the next step in ethanol metabolism, is not involved in these hypothermic effects. Finally, the experiment with 4-MP indicates that the potentiating effects of cyanamide are mediated by the peripheral accumulation of acetaldehyde, which then reaches the brain to induce a severe hypothermia.
Subject(s)
Acetaldehyde/toxicity , Central Nervous System Depressants/toxicity , Ethanol/toxicity , Hypothermia/chemically induced , Acetaldehyde/metabolism , Aldehyde Dehydrogenase/antagonists & inhibitors , Animals , Body Temperature/drug effects , Central Nervous System Depressants/metabolism , Cyanamide/toxicity , Drug Synergism , Enzyme Inhibitors/pharmacology , Ethanol/metabolism , Female , Fomepizole , Liver/metabolism , Mice , Pyrazoles/pharmacologyABSTRACT
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.
