Drinking Patterns in Genetic Low-Alcohol-Drinking (LAD) Rats After Systemic Cyanamide and Cerebral Injections of THP or 6-OHDA

Abstract

A key question related to the role of acetaldehyde and aldehyde adducts in alcoholism concerns their relationship to the genetic mechanisms underlying drinking. Experimentally, the low-alcohol-drinking (LAD) rat represents a standard rodent model having a strong aversion to alcohol. In these experiments, preferences for water vs. alcohol, offered in concentrations from 3% to 30%, were determined over 10 days in adult LAD rats ( N = 6 per group). Then a saline vehicle or either 10 or 20 mg/kg of the aldehyde dehydrogenase (AlDH) inhibitor, cyanamide, was injected SC twice daily for 3 days. Secondly, either 0.5 or 1.0 μg of tetrahydropapaveroline (THP) was infused ICV twice daily for 3 days in LAD rats ( N = 8) and, as a genetic control, THP also was infused identically in Sprague–Dawley (SD) rats ( N = 8). The results showed that the lower and higher doses of cyanamide augmented alcohol intakes in 33% and 50% of the LAD rats, respectively, with the patterns of drinking resembling that of genetic high-alcohol-drinking HAD or P rats. Although ICV infusions of THP had little effect on alcohol preference of LAD rats, alcohol drinking was enhanced significantly in the SD rats. In a supplementary study, 200 μg of 6-hydroxydopamine (6-OHDA) also was infused ICV in LAD rats ( N = 7) on two consecutive days; no change occurred in the characteristic aversion to alcohol. These findings suggest that in certain individuals, a perturbation in the synthesis of AlDH can modify the genetically based aversion to alcohol, thus precipitating the liability for alcoholism. In that neither THP nor 6-OHDA lesioning exerted any effect on the genetic nondrinking LAD animal suggests that an unknown endogenous factor in the brain must underlie the cyanamide-induced shift to alcohol preference. We conclude that the genetic elements that normally prevent the progression to addictive drinking in most individuals appear to be invariant and irreversible.