An investigation of tolerance to the actions of leptogenic and anorexigenic drugs in mice.

Abstract This study compared the effects of chronic administration of anorexigenic drugs on weight loss in mice. Tolerance to the effects of peripheral anorexigenic peptides, viz. cholecystokinin-octapeptide and bombesin, developed rapidly. Morphine, cocaine and dehydroepiandrosterone-sulfate caused weight loss and appeared similar to d-amphetamine in mechanisms of action. A high dose of fluoxetine (25 mg/kg) proved to be a potent leptogenic agent but was also associated with death in some animals. A lower dose of fluoxetine (5 mg/kg) was associated with the development of tolerance. Calcitonin, a potent anorexigenic agent, did not produce weight loss and tolerance to its anorectic effect had developed by 10 days. Animals varied widely in their individual responsiveness to a given drug. Peripheral administration of peptide YY caused weight loss. We conclude that acute or chronic effects of agents on food intake do not necessarily predict effects on body weight. However, neurotransmitters that enhance feeding centrally appear to cause weight loss when administered peripherally. Since the first reports by Ehrich and Krumbhaar (1) in 1937 that amphetamine reduced food intake, numerous anorectic agents have been investigated as possible anti-obesity agents. As the purpose of these studies was to find compounds that would produce weight loss, the most appropriate term for these compounds would be leptogenic (from Greek leptos = lean) agents (2). This also recognizes that weight loss may be secondary to effects other than those on food intake such as malabsorption, increased activity or increased metabolism. A major problem in the development of adequate leptogenic agents has been the fact that tolerance develops to the initial anorectic effect of amphetamine and other appetite suppressants (3). The mechanism of action of amphetamine appears to involve catecholaminergic and/or dopaminergic systems, while other agents, e.g., fenfluramine, predominantly act on serotonergic systems (4,5). It is believed that they produce their effects by acting on feeding systems within the central nervous system (6). Recently a number of gastrointestinal peptides have been shown to have short-term anorectic effects though only a few studies of their long-term leptogenic effects have been undertaken (7). These agents appear to form part of a peripheral satiety system producing their effects, either by vagal-dependent or non-vagal mechanisms (8,9). Tolerance to the leptogenic effect of cholecystokinin octapeptide (CCK-8S) appears to develop very rapidly (10,11). The purpose of the studies reported here was to directly compare the effects of chronic administration of a number of agents that are recognized to be anorectic or leptogenic on body weight and food intake. This should allow an investigation of the patterns of tolerance displayed by the different agents and also whether their leptogenic effects are due to effects on food intake or through alternative mechanisms. The anorectic agents studied included d- and 1-amphetamine, fluoxetine (an agent thought to produce its effects through serotonergic pathways), nalmefene (a long-acting opioid antagonist), cocaine, dehydroepiandrosteronesulfate (DHEA-S), and the peptides, calcitonin, CCK-8S and bombesin. In addition, we studied the effects of morphine, which increases feeding through a central nervous system mediated mechanism (12) and peptide YY (PYY), which is a potent orexigenic agent when administered into the cerebroventricles (13).