Rationale: Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases. Objectives: These studies were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia. Materials and methods: The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-selective and D2-selective antagonists to inhibit the induction of yawning and hypothermia were assessed and a series of D2/D3 antagonists were characterized with respect to their ability to alter yawning induced by a low and high dose of PD-128,907 and sumanirole-induced hypothermia. Results: D3-preferring agonists induced yawning at lower doses than those required to induce hypothermia and the D2-preferring agonist, sumanirole, induced hypothermia at lower doses than were necessary to induce yawning. The rank order of D3 selectivity was pramipexole > PD-128,907 = 7-OH-DPAT = quinpirole = quinelorane > apomorphine = U91356A. Sumanirole had only D2 agonist effects. PG01037, SB-277011A, and U99194 were all D3-selective antagonists, whereas haloperidol and L-741,626 were D2-selective antagonists and nafadotride's profile of action was more similar to the D2 antagonists than to the D3 antagonists. Conclusions: D3 and D2 receptors have specific roles in the mediation of yawning and hypothermia, respectively, and the analysis of these effects allow inferences to be made regarding the selectivity of D2/D3 agonists and antagonists with respect to their actions at D2 and D3 receptors.
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Acknowledgement This research was supported by the USPHS NIDA grants DA 020669, DA 019322, F013771 and the NIDA-IRP. We acknowledge with appreciation the technical assistance of Davina Barron and the editorial assistance of Roger Sunahara and Gail Winger.
- D2 receptors
- D3 receptors