Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

Abstract

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.Correspondence to: James H. Woods. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl) Methods-The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-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 as well as 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.

Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys

“…*P , 0.05 versus drugnaive controls. consistent with predominant D2R-mediated signal associated with [ 11 C]PHNO binding potential and pharmacological studies suggesting that the descending limb of the quinpirole-elicited yawning dose-response curve is D2R-mediated (Collins et al, 2005(Collins et al, , 2007. Recent PET studies of chronic cocaine (Payer et al, 2014) and polydrug MA (Boileau et al, 2012) users reported that both drugs were associated with elevated levels of D3R availability in the substantia nigra.…”

“…In contrast, only 20% of the signal in the ventral striatum was attributed to D3R, whereas 100% of the signal in the caudate nucleus was a result of D2R binding (Tziortzi et al, 2011). Because the ascending limb of the quinpirole-elicited yawning dose-response curve is thought to be D3R-mediated (Collins et al., 2005(Collins et al., , 2007, the results of the mixed model, which showed approximately five greater yawns for every 1-unit increase in binding potential in the globus pallidus, support this conclusion. Furthermore, in the present study, yawning was negatively correlated with binding in the caudate nucleus and putamen, Fig.…”

“…A behavioral assay that has been frequently used to characterize D3R agonists is the unconditioned behavior of drug-elicited yawning using the D 3 /D 2 receptor agonist quinpirole in rodents (e.g., Collins et al, 2005Collins et al, , 2007Baladi and France, 2009) and nonhuman primates (Martelle et al, 2007;Hamilton et al, 2010;Blaylock et al, 2011). The quinpirole-induced yawning doseresponse curve is an inverted U-shaped function of dose.…”

“…The quinpirole-induced yawning doseresponse curve is an inverted U-shaped function of dose. Collins et al (2005Collins et al ( , 2007 concluded that the ascending limb of the quinpirole dose-response curve is mediated by D3R, whereas the descending limb is primarily D 2 receptor (D2R)-mediated and coincides with an onset of hypothermia. Despite the differences noted in D2-like and D3R availability after cocaine exposure, quinpirole-elicited yawning was not different in cocaine-naive versus cocaine-experienced monkeys (Blaylock et al, 2011).…”

Grateful DREADDs: Engineered Receptors Reveal How Neural Circuits Regulate Behavior

“…The rationale for developing D 3 receptor-selective treatment candidates has been strengthened by evidence suggesting a history of cocaine use dynamically impacts D 3 receptor expression and activity. The recent development of highaffinity D 3 receptor-selective compounds and the validation of agonistelicited yawning as a D 3 -specific unconditioned behavior (Collins et al, 2007) have provided an experimental framework for the examination of the relationship between cocaine exposure and D 3 receptor function. One strategy for drug development is the use of partial agonistsFcompounds with less functional activity than full agonists in vitro.…”