Neurochemical and behavioral factors in the development of tolerance to anorectics.

Tolerance and cross-tolerance among several anorectic drugs were investigated in four separate tests. The same animals served as subjects in all four tests. In the first test, animals given milk shortly after injection of 3 mg/kg amphetamine (Cont group) developed tolerance to amphetamine anorexia, but animals given milk when amphetamine's anorectic effects had worn off (Noncon group) did not develop tolerance in spite of equal drug exposure. In the second test, Cont animals were tolerant to 2 mg/kg apomorphine, a drug with a neurochemical action related to amphetamine. No tolerance to 2 mg/kg apomorphine was shown by the Noncon animals. Next, it was found that both Cont and Noncon groups were tolerant to a smaller dose of 1.25 mg/kg apomorphine. The final test replicated part of the first test; that is, the Cont group was tolerant to amphetamine, but the Noncon group was not. In addition, animals in neither group were tolerant to anorexia produced by 5 mg/kg fenfluramine, a drug whose action is neurochemically different from amphetamine and apomorphine. From these experiments it appears that both learning and specific neurochemical mechanisms are involved in the development of tolerance to anorectic drugs.