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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 314; no. 1; pp. 310 - 319
• Main Authors: Collins, Gregory T., Witkin, Jeffrey M., Newman, Amy H., Svensson, Kjell A., Grundt, Peter, Cao, Jianjing, Woods, James H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2005; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Adrenergic alpha-Antagonists - pharmacology; Animals; Cholinergic Agents - pharmacology; Dopamine Agonists - pharmacology; Dose-Response Relationship, Drug; Ligands; Male; Muscarinic Agonists - pharmacology; Parasympathomimetics - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1 - agonists; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D3; Receptors, Dopamine D4; Receptors, Dopamine D5; Serotonin Agents - pharmacology; Yawning - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.085472

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 [(S)-(+)-(4 aR, 10 bR)-3,4,4 a,10 b-tetrahydro-4-propyl-2 H,5 H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], PD-128,908 [(R)-(-)-(4 aS,10 bS)-3,4,4 a,10 b-tetrahydro-4-propyl-2 H,5 H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], quinelorane [(5 aR-trans)-5,5 a,6,7,8, 9,9 a,10-octahydro-6-propylpyrido[2,3-g]quinazolin-2-amine dihydrochloride], pramipexole (N′-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine), 7-OH-DPAT [(±)-7-hydroxy-2-dipropylaminotetralin HBr], quinpirole [trans-(-)-(4 aR)-4,4 a,5,6,7,8, 8 a,9-octahydro-5-propyl-1 H-pyrazolo[3,4-g]quinoline HCl], bromocriptine [(+)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl) ergotaman-3′,6′-18-trione methanesulfonate], and apomorphine [(R)-(-)-5,6,6 a,7-tetrahydro-6-methyl-4 H-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 L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1 H-indole), haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone HCl), nafadotride (N-[(1-butyl-2-pyrrolidinyl)methyl]-4-cyano-1-methoxy-2-naphtha-lenecarboxamide), U99194 (2,3-dihydro-5,6-dimethoxy-N,N-dipropyl-1 H-inden-2-amine maleate), SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide), 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 dose-response 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 (1 a,2 b,4 b, 5 a,7 b)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]-non7-yl ester hydrobromide], mianserin (1,2,3,4,10,14 b-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 [(3 aS)-cis-1,2,3,3 a,8,8 a-hexahydro-1,3 a,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 receptor-mediated activities.