A method for determining cumulative behavioral toxicity after chronic oral administration of 1-α-acetylmethadol to female rats

A behavioral method is described in which fixed-ratio 15 (FR 15) responding for food is measured before and after daily oral administration of l-α-acetylmethadol (LAAM) by schedule-induced polydipsia. We hypothesized that if the interval between doses of drug was too great, and the subjects experienced episodes of withdrawal between doses, this would be manifest as diminished responding before drug which improved following drug administration. On the other hand, if the doses of drug given were too high or spaced too closely, any decrement in responding seen prior to drug would worsen following drug administration. Using this method, we have shown that daily oral administration of 0.5-2.0 mg LAAM/kg to female rats resulted in apparent cumulative toxicity in 6 of 10 subjects tested in the above manner. Further behavioral testing revealed that those subjects not showing signs of toxicity were both dependent upon LAAM and cross-tolerant to the behavioral suppressant action of morphine.