http://link.springer.com/content/pdf/10.1007/978-1-4684-3450-7_27.pdf

A Critique of Animal Analogues of Alcoholism

Pharmacological aspects of physical dependence on ethanol.

The properties of 4-methylpyrazole (4-MP) as an inhibitor of ethanol metabolism were investigated in rats. No effect was seen on enzymatic determination of ethanol. 4-MP in doses of 0.0053–3.0 mmol/kg brought about a competitive inhibition of the metabolism of 32.6 mmol ethanol per kg body weight ranging from 20.8 to 80.5 %. A dose of 0.017 mmol 4-MP per kg gave an inhibition of 50 %. By varying the interval between the administration of 4-MP and ethanol from 15 min. to 48 hrs, it was found that the inhibitory effect disappeared after 12 hrs. The influence of 4-MP on ethanol-induced incoordination was measured by a modified tilting-plane technique. The mean maximal impairment was significant in all conditions, when compared to the controls. For ethanol alone the mean maximal impairment was 11.9 %, for 4-MP alone 7.2 % and for ethanol + 4-MP 14.9 %, the effect lasting for 8 hrs. Thus, 4-MP exerts significant central depressant effects per se, and produces an enhancement and a prolongation of ethanol-induced effects on coordination in the rat.

4-Methylpyrazole as an inhibitor of ethanol metabolism: differential metabolic and central nervous effects.

The involvement of sequential side-chain oxidation, sulphation and glutathione conjugation in the formation of mercapturic acids from toluene and xylenes was investigated. It was found that not only aralkanes but also aralkyl alcohols were excreted as mercapturic acids in the rat. The extent of mercapturic acid excretion varied over a more than 20-fold range. Inhibition of ADH caused an increase and inhibition of sulphotransferase a decrease in the urinary excretion of thio compounds after administration of toluene, benzyl alcohol, o-xylene and o-methylbenzyl alcohol to rats. The position of the methyl groups attached to the aromatic nucleus affects the metabolism of aromatic hydrocarbons considerably. Factors that are involved in the high yield of mercapturic acids after administration of o-xylene as compared to m- and p-xylene, include the relatively low apparent affinity of o-methylbenzyl alcohol for cytosolic ADH, the relatively high apparent affinity of o-methylbenzyl alcohol for cytosolic sulphotransferase, and the high electrophilic reactivity of the o-methylbenzyl sulphate.

Alcohol and sulphate intermediates in the metabolism of toluene and xylenes to mercapturic acids.

The influence of pyrazole on ethanol-induced incoordination was measured by a modified tilting-plane technique. Pyrazole (1–77 mmol/kg; 120 mg/kg) and/or ethanol (32.6 mmol/kg; 1.5 g/kg) was given intraperitoneally to rats. Impairment of coordination was related to blood ethanol concentrations. The mean maximal impairment was significant in all conditions. For ethanol alone the maximal impairment was 8.7%, for pyrazole alone 4.8% and for ethanol + pyrazole 16.5 %. Ethanol alone induced a total impairment, assessed planimetrically, of 530 units. Pyrazole alone induced an impairment gradually increasing with time (totally 1070 units). When pyrazole was combined with ethanol, the rate of ethanol elimination was reduced by 81%, and the time it remained in the blood was prolonged from 196 ± 11 to 850 ± 16 min. The rate of disappearance was reduced from 8.05 to 1.57 μg/ml per min. The total impairment increased to 5600 units, indicating a synergistic interaction between ethanol and pyrazole, which is contrary to the normalizing effects of pyrazole on ethanol-induced metabolic changes. A “post-drug” impairment was observed one week after pyrazole, while no such effects were found after repeated administration of saline or ethanol alone in control animals. Thus, pyrazole showed acute and long-term toxic eifects.

Synergistic action of pyrazole on ethanol incoordination: differential metabolic and central nervous system effects.

1. Interactions of pyrazole and ethanol were studied in three laboratory test procedures. They included sleeping time in mice, rotor rod balance in rats and lever pressing behaviour of rats.

2. Equimolar concentrations of pyrazole and 3-methylpyrazole were compared for effects on enhancement of ethanol's activity on rotor rod holding time of rats.

3. Minimally effective doses of pyrazole, the LADH inhibitor, and 3-methylpyrazole, a non-inhibitor of LADH, when administered before ethanol, resulted in an increased behavioural depression. These interaction effects are probably not caused by inhibition of LADH but rather by an increase in the direct depressant action of either one or both of the compounds.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1971.tb07157.x

J. E. Wallace

Papers

Interaction effects of ethanol and pyrazole in laboratory rodents