Drug-induced
vomiting (
emesis) is a major concern in patient care and a significant hurdle in the development of novel
therapeutics. With respect to the latter, rodents, such as the rat and mouse, are typically used in efficacy and safety studies; however,
drug-induced
emesis cannot be readily observed in these species due to the lack of an
emetic reflex. It is known that
emesis can be triggered by neural activity in brain regions including area postrema (AP) and nucleus tractus solitarius (NTS). In this study, using pharmacological magnetic resonance imaging (phMRI) and a blood-pool
contrast agent, we imaged the hemodynamic consequences of brain activity in awake rats initiated by the administration of compounds (
apomorphine 0.1, 0.3 micromol/kg i.v. and
ABT-594 0.03, 0.1, 0.3 micromol/kg i.v.) that elicit
emesis in other species. Regional
drug-induced relative cerebral blood volume (rCBV) changes and percent activated area within the AP and NTS were calculated, in which a dose-dependent relationship was evident for both
apomorphine and
ABT-594. Additionally, to correlate with behavioral readouts, it was found that the activation of AP and NTS was observed at plasma concentrations consistent with those that induced
emesis in ferrets for both drugs. Our data thus suggest that phMRI in awake rats may be a useful tool for predicting
emetic liability of CNS-acting drugs and may provide insights into depicting the underlying
emetic neural pathways in vivo.