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

Abstract

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.

Tolerance to amphetamine: Contingent suppression of stereotypy mediates recovery of feeding.

“…It has recently been suggested that contingent tolerance to amphetamine involves a specific neurochemical change rather than a more general behavioral adaptation (Streather & Hinson, 1985). This conclusion is based on the finding that cross-tolerance occurs among anorexigenic drugs that interact with catecholamine systems (e.g., amphetamine and apomorphine, methylphenidate, or cocaine; Emmett-Oglesby & Taylor, 1981; Streather & Hinson, 1985; Woolverton & Schuster, 1978) but not between catecholaminergic (amphetamine) and serotonergic (fenfluramine) anorexigens (e.g., Kandel, Doyle, & Fischman, 1975; Streather & Hinson, 1985). The present data suggest an alternative explanation for these findings in terms of the behavioral effects of these drugs.…”

Procedures affecting maintenance and loss of tolerance to amphetamine-induced anorexia and cross-tolerance to haloperidol-induced catalepsy

“…Anorexia may be expected to occur 20 min after a dose of 3 mg/kg amphetamine and to last for at least a further 30 min (e.g. Carlton and Wolgin, 1971;Streather and Hinson, 1985). Haloperidol (in the form of Haldol) was administered at a dose of 1.25 mg/kg of body wt.…”

“…Only rats acutely anorexic to this dose of amphetamine were needed, thus animals that drank >40% of their baseline milk intake were discarded from the experiment (see Streather and Hinson, 1985). Forty animals failed to meet this criterion.…”

“…Carlton and Wolgin, 1971;Poulos, Wilkinson and Cappell, 1981; Goudie, 1982, 1983;Streather and Hinson, 1985;Wolgin and Salisbury, 1985;Wolgin, Thompson and Oslan, 1987). Carlton and Wolgin (1971) found that animals given amphetamine chronically developed tolerance to anorexia only if milk was available shortly after each amphetamine injection.…”