Agents that activate the
dopamine D2-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 D2-like receptor subtype(s) contributes to the
emetic response. In this study, stable cell lines expressing the ferret
dopamine D2-long (D2L) and D4 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 D1-like and D4 receptors had no
emetic effect in ferrets. Conversely, stimulation of
dopamine D2 and/or D3 receptors resulted in a robust
emetic response characterized by a relatively short latency (<15 min) and multiple
emetic events. Competitive antagonists of
dopamine D2-like receptors (
domperidone,
haloperidol) dose-dependently blocked the
emetic response to PNU95666E, a
dopamine D2 receptor selective agonist. Thus,
dopamine D2 and/or D3 receptor agonists elicit
emesis, while
dopamine D1/D5 or D4 receptor-selective agonists are devoid of
emetic properties.