Paraquat-induced, dose-dependent conditioned taste aversions and weight loss mediated by the area postrema

Abstract

Paraquat's (PQ) effect on feeding behavior in the rat was examined using a conditioned taste aversion (CTA) paradigm. CTA is a learned avoidance of tastes closely associated with prior illness. Male Sprague-Dawley rats trained to drink an instant breakfast solution were subsequently offered a novel-flavored solution and consumption was measured over 30 min. Following consumption of the novel solution, PQ (0.48–48.0 μmol/kg) was injected subcutaneously. Peak blood PQ concnetrations were measured by serially sampling blood (0.15 ml) from an indwelling jugular cannula between 10 and 35 min after injection. Two days later, the rats were offered the same novel-flavored solution. Paraquat produced dose-dependent avoidance of the novel solution when injected subcutaneously. A PQ dosage of 2.7 μmol/kg or less did not alter consumption. The ED50 for CTA production of 13.0 μmol/kg was determined by log-probit analysis. The minimum effective dosage was 4.2 μm/kg. The doses examined did not produce overt clinical or histological signs of toxicity. Peak blood paraquat concentration was linearly related ( r = 0.995) to dosage. Additionally when administered by gavage CTAs occurred only with a much larger PQ dosage (480 μmol/kg). Thermal lesions of a hindbrain circum ventricular organ, the area postrema (AP), prevented PQ-induced CTAs despite repeated PQ injections. Additionally, weight loss following PQ exposure was also attenuated by AP lesions. CTAs were induced in these same AP-lesioned rats by oral administration of copper sulfate. This substance conditions taste aversions by activating vagal afferent neurons. The fact that copper sulfate-induced aversions were not blocked by lesions of the area posterema indicates that the lesioned rats are capable of forming CTAs when treated with a toxicant which does not act via the AP. These data indicate that PQ produces CTAs in a dose-dependent manner. Furthermore, PQ-induced CTAs and weight loss are mediated by the AP. The AP may contain receptors which detect xenobiotics, enabling animals to avoid future contact with these compounds.