Development of cellular tolerance to lethality and analgesia concurrent with physical dependence following repeated oral administration of LAAM.

Following the repeated oral administration of l-alpha-acetylmethadol (LAAM) employing a dose (28 mg/kg per day) shown to induce its own metabolism by three- to four-fold, mice exhibited a rapid development of cellular tolerance and physical dependence which correlated on a temporal basis with this self-induction of LAAM metabolism. Evidence of cellular tolerance included significant elevations in the LAAM oral LD50, LAAM ICV (intracerebroventricular) LD50, LAAM oral AD50 and the LAAM ICV AD50 following repeated administration of this narcotic. Since the ICV parameters and the morphine AD50 were elevated over water control values, cellular tolerance appeared to play an important role in explaining the elevations noted for the oral parameters because the former were not influenced by changes in the rate of LAAM metabolism. Moreover, SKF-525A, a microsomal enzyme inhibitor, had little effect on the LAAM oral LD50 and the LAAM oral AD50, further indicating a minor role for dispositional tolerance. It is concluded that the induction noted for repeated oral LAAM administration most likely is responsible for generating more potent metabolites which in turn act to produce the cellular tolerance and physical dependence in these mice through constant exposure of the CNS.