Aldehyde Dehydrogenase Inhibitors and Voluntary Ethanol Drinking by Rats
Aldehyde dehydrogenase (ALDH) inhibitors, cyanamide (200 mg or 40 mg/kg food) and coprine (N5-(hydroxycyclopropyl)-L-glutamine, 500 mg/kg food), strongly suppressed, with similar time courses, the free-choice consumption of 10% v/v ethanol. The suppression occurred with both continual and alternate access to alcohol. The presence of the inhibitors (plus 4-methylpyrazole to prevent acetaldehyde accumulation) did not affect ethanol-induced (1.5 g/kg i.p.) motor impairment on the tilting plane, but the rats on alternate-day access, which consumed more alcohol on days of access, were significantly less impaired.
The results show that the suppression of drinking is a general phenomenon for the ALDH inhibitors, not mediated by a modification of acute ethanol intoxication. As shown by us previously, the suppression by the ALDH inhibitors does not seem to be mediated by an accumulation of acetaldehyde or by its condensation product with the bigenic amines, but rather may be caused by a shift in the metabolism of consumption-regulating biogenic amines as a consequence of reduced brain ALDH capacity.
One of the most effective and reliable ways of suppressing alcohol drinking by rats is with inhibitors of aldehyde dehydrogenase (ALDH), such as disulfiram, ethylenglycol dinitrate and calcium cyanamide (see Lindros, 1978). The widely accepted general explanation for this effect is that reduced ALDH activity causes acetaldehyde to accumulate when alcohol is drunk and metabolized and that the acetaldehyde is aversive and in this way reduces the alcohol consumption, Problems with this interpretation have been pointed out: acetaldehyde alone does not produce all the chracteristics seen after ethanol plus ALDH inhibitors (see Waligren and Barry, 1970), acetaldehyde, at least at lower concentrations, may not be aversive but rather positively reinforcing (Amit et al., 1980), and, since rather high blood acetaldehyde levels must be reached before acetaldehyde is found in the brain (Sippel, 1974), it is unlikely that in rats drinking alcohol voluntarily there would be enough acetaldehyde reaching their central neurons to affect behaviour (see Lindros, 1978).
None of these arguments is particularly strong and all can be countered. Recently, however, we have shown that preventing the accumulation of acetaldehyde does not prevent the suppression of alcohol drinking caused by cyanamide (200 mg/kg food) (Lindros and Sinclair, 1979). This was done by adding a small amount of the alcohol dehydrogenase inhibitor, 4-methylpyrazole (4MP, 1 mM) to both drinking fluids of rats having a choice between water and 10% v/v ethanol solution. The 4MP reduces ethanol metabolism by only 15–20%, but the dose is sufficient to completely prevent acetaldehyde accumulation by cyanamide in the blood. 4MP also did not affect the normal (i.e., without cyanamide) voluntary ethanol consumption of Long-Evans rats, nor the voluntary or forced consumption by the ANA strain developed for low levels of ethanol drinking and known to have elevated concentrations of acetaldehyde during ethanol metabolism under normal circumstances (Eriksson, 1973).
These results indicated that the suppression of alcohol drinking by ALDH inhibitors and also the correlation between endogenous liver ALDH activity and the levels of voluntary alcohol consumption in various strains of mice and rats (see Lindros, 1978) may not have been caused by acetaldehyde accumulation. Since a change in liver ALDH activity could hardly affect behaviour except through acetaldehyde, it is more likely that changes in brain ALDH activity, which usually are correlated with liver ALDH activity (Amir, 1978) and thus to acetaldehyde levels, are significant, especially considering their important role in the metabolism of certain neural transmitters, which might influence alcohol drinking behaviour.
We have found (Sinclair, in press) that lithium, which affects these transmitters, suppresses the alcohol drinking of rats having continual access to alcohol, but not that of rats having periodic access, i.e. alcohol available only every second day. Would cyanamide be effective also with only periodic alcohol access?
Would a lower dose of cyanamide suppress alcohol drinking equally much?
If brain ALDH inhibition is responsible for the suppression, all of its inhibitors should be effective; if, however, these inhibitors would act by another mechanism, it might be possible to find an ALDH inhibitor that would not suppress alcohol drinking. Would coprine (N5-(1-hydroxycyclopropyl)-L-glutamine) a known ALDH inhibitor (Marchner and Tottmar, 1978) also suppress ethanol consumption?
In several cases (e.g. with lithium (Sinclair, in press) the level of alcohol drinking has been found to be positively correlated to the tolerance to ethanol intoxication. Do ALDH inhibitors also suppress alcohol drinking by decreasing ethanol tolerance?
KeywordsAlcohol Drinking ALDH Activity Blood Alcohol Level Periodic Access Ethanol Intoxication
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