Differences among 'serotonergic' anorectics in a cross-tolerance paradigm: do they all act on serotonin systems?

Rats on a 4 hr/day feeding schedule showed anorexia after i.p. injections of several 'serotonergic' agents. Tolerance developed within a few days of daily administration of all drugs except fluoxetine. The tolerant animals were then given a cross-tolerance test with a different agent, either the next day or after a drug free washout period. Rats which were tolerant to quipazine or MK 212 showed no cross-tolerance to fenfluramine or norfenfluramine. In contrast, rats which were tolerant to fenfluramine showed good cross-tolerance to quipazine or MK 212. However, after a washout period between the end of the chronic fenfluramine regimen and the cross-tolerance test, quipazine regained its full anorectic potency. The development of tolerance to fenfluramine was dependent upon the number of injections, not on their spacing. Fenfluramine-tolerant animals showed a partial decay of tolerance after a 3 day washout, but still retained some tolerance after 12 days. These findings imply that the mechanisms underlying the development of tolerance may differ from those which mediate its maintenance. Our data further suggest that not all of the agents act on the same neural system(s), and raise the possibility that non-serotonergic and/or non-cerebral systems may be involved in the mode of action of these agents.