Ractopamine (RAC) is fed to an estimated 80% of all beef, swine and turkey raised in the United States. It promotes muscle mass development, limits fat deposition and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral‐facial movements and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC's physiological actions begin with its stimulation of β1 and β2 adrenergic receptor‐mediated signaling in skeletal muscle and adipose tissue, however the molecular pharmacology of RAC's psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for intracellular cAMP we found that RAC and p-Tyramine (TYR) produced concentration‐dependent increases in chloride conductance in oocytes co-expressing hCFTR and mouse trace amine associated receptor 1 (mTAAR1), which was completely reversed by the TAAR1-selective antagonist EPPTB. Oocytes co‐expressing hCFTR and the human β2 adrenergic receptor (hβ2AR) showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human β2AR but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea this novel mechanism of action influences the physiology and behavior of pigs and other species, as well. These findings should stimulate future studies to characterize the pharmacological, physiological and behavioral actions of RAC in humans and other species exposed to this drug.
- The American Society for Pharmacology and Experimental Therapeutics