Dopamine Agonist-Induced Yawning in Rats: A Dopamine D3 Receptor-Mediated Behavior

Abstract

A specific role for the dopamine D3 receptor in behavior has yet to be elucidated. We now report that dopamine D2/D3 agonists elicit dose-dependent yawning behavior in rats, resulting in an inverted U-shaped dose-response curve. A series of experiments was directed toward the hypothesis that the induction of yawning is a D3 receptor-mediated effect, whereas the inhibition of the yawning observed at higher doses is due to competing D2 receptor activity. We compared several dopaminergic agonists with a range of in vitro D3 selectivity, including PD-128,907 [(5aR-trans)-5,5a,6,7,8, 9,9a,10-octahydro-6-propylpyrido[2,3-g]quinazolin-2-amine dihydrochloride], pramipexole (NЈ-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(Ϯ)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [trans-(Ϫ)-(4aR)-4,4a,5,6,7,8, 8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline HCl], bromocriptine [(ϩ)-2-bromo-12Ј-hydroxy-2Ј-(1-methylethyl)-5Ј-(2-methylpropyl) ergotaman-3Ј,6Ј-18-trione methanesulfonate], and apomorphine [(R)-(Ϫ)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol HCl] with respect to their ability to induce yawning in rats. A series of D2/D3 antagonists differing in selectivity for D3 over D2 receptors were evaluated for their ability to alter the effects of the dopamine agonists. The antagonists, and PG01037 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl) were used to determine effects on doseresponse curves for D2/D3 agonist-induced yawning. In addition, the potential contribution of cholinergic and/or serotonergic mechanisms to the yawning response was investigated using a series of pharmacological tools including scopolamine [(a,S)-a-(hydroxymethyl)benzeneacetic acid (1a,2b,4b,5a,7b)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine HCl), and the D3-preferring antagonists nafadotride, U99194, SB-277011A, and PG01037 to differentially modulate yawning induced by PD-128,907, physostigmine [(3aS)-cis-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol methylcarbamate hemisulfate], and N- [3-(trifluoromethyl)phenyl]piperazine HCl. The results of these experiments provide convergent evidence that dopamine D2/D3 agonist-induced yawning is a D3 agonist-mediated behavior, with subsequent inhibition of yawning being driven by competing D2 agonist activity. Thus, dopamine agonist-induced yawning may represent an in vivo method for selectively identifying D3 and D2 receptormediated activities. Dopamine D3 receptors have received considerable interest since originally cloned (Sokoloff et al., 1990). The D3 receptor shares significant sequence homology with the dopamine D2 receptor but displays a much more restricted, limbic pattern of distribution compared with that of the D2 , trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)

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).…”

Pramipexole-Induced Increased Probabilistic Discounting: Comparison Between a Rodent Model of Parkinson's Disease and Controls

“…PPX is a direct-acting DA agonist with a preference for the D3R subtype of DA receptors. For example, in in vivo rat studies using presumed D2R-and D3R-selective behavioral assays (ie, hypothermia and yawning, respectively), PPX is B30-fold selective for D3R over D2R (Collins et al, 2007), and 1.0 mg/kg (À)PPX is sufficient to activate both D2R and D3R (Collins et al, 2005(Collins et al, , 2007(Collins et al, , 2009. Thus, it is likely that both subtypes were engaged by 2 mg/kg dose of (±)PPX used in the current study.…”