Dopamine D 2, but not D 4, receptor agonists are emetogenic in ferrets

Abstract

Agents that activate the dopamine D 2-like family of receptors elicit emesis in humans and other species with a vomiting/emetic reflex; however, the lack of dopamine receptor subtype selective agonists has hampered an understanding of which dopamine D 2-like receptor subtype(s) contributes to the emetic response. In this study, stable cell lines expressing the ferret dopamine D 2-long (D 2L) and D 4 receptors were used to characterize known dopamine agonists via radioligand binding and calcium ion flux assays, while emetic activity of these dopamine receptor agonists was determined in male ferrets. Latencies to first emetic event, average number of emetic episodes, and stereotypical behaviors which may be indicative of nausea were also determined. Agonists at dopamine D 1-like and D 4 receptors had no emetic effect in ferrets. Conversely, stimulation of dopamine D 2 and/or D 3 receptors resulted in a robust emetic response characterized by a relatively short latency (< 15 min) and multiple emetic events. Competitive antagonists of dopamine D 2-like receptors (domperidone, haloperidol) dose-dependently blocked the emetic response to PNU95666E, a dopamine D 2 receptor selective agonist. Thus, dopamine D 2 and/or D 3 receptor agonists elicit emesis, while dopamine D 1/D 5 or D 4 receptor-selective agonists are devoid of emetic properties.