Apomorphine-induced emesis in dogs: Differential sensitivity to established and novel dopamine D 2/5-HT 1A antipsychotic compounds

Abstract

Small rodents (mice, rats) are the species of choice for evaluating the pharmacology of centrally acting compounds, such as antipsychotics, whereas toxicology data are routinely obtained from other species (rabbits, dogs, monkeys). Whilst there is a substantial number of “therapeutically relevant” pharmacological models for “antipsychotic-like” activity in small rodents, based on hyperdopaminergic or hypoglutamatergic/NMDA approaches, there is a remarkable paucity of such models in other species. Here, we compared the efficacy and potency of reference and new generation dopamine D 2/5-HT 1A putative antipsychotics, administered orally, against apomorphine-induced emesis in dogs, a model of central D 2 receptor activation that can be implemented with relative ease. Risperidone potently and fully (10 μg/kg) prevented emesis/retching induced by 0.1 mg/kg s.c. apomorphine. SLV313 and F15063 (D 2 receptor antagonists/5-HT 1A receptor agonists) also abolished emesis/retching, albeit less potently than risperidone (minimal effective dose, MEDs: 10 and 40 μg/kg, respectively). The D 2 receptor partial agonists/5-HT 1A receptor agonists aripiprazole and bifeprunox, (up to 80 μg/kg) only partially attenuated emesis, as did the peripheral D 2 receptor antagonist domperidone. Under the present experimental conditions, haloperidol was only efficacious at the highest dose tested (320 μg/kg). To summarize, dogs are very sensitive to the dopaminergic blocking effects of antipsychotics in this model of D 2 receptor activation. This model can thus be advantageously used to investigate the pharmacological activity of novel D 2 receptor antagonists/partial agonists in dogs.