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 [(S)-(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], PD-128,908 [(R)-(-)-(4aS,10bS)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol HCl], quinelorane [(5aR-trans)-5,5a,6,7,8, 9,9a,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-(-)-(4aR)-4,4a,5,6,7,8, 8a,9-octahydro-5-propyl-1H-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)-(-)-5,6,6a,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 L-741,626 (3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-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-1H-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 (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 receptor-mediated activities.

Fig. 1

Dose-dependent induction of yawning by dopamine D3-preferring agonists: A, PD-128,907 (0.0032–0.32 mg/kg), quinelorane (0.0001–0.032 mg/kg), and pramipexole (0.00032–1.0 mg/kg); B, PD-128,907 (0.0032–0.32 mg/kg), 7-OH-DPAT (0.0032–0.1 mg/kg), and quinpirole (0.0032–0.32 mg/kg); and C, PD-128,907 (0.0032–0.32 mg/kg), bromocriptine (0.32–10.0 mg/kg), apomorphine (0.001–0.32 mg/kg), and PD-128,908 (0.01–1.0 mg/kg). Data are presented as mean (± S.E.M.), n = 8, number of yawns during a 20-min observation period.

Fig. 2

Effects of the D2-selective antagonist L-741,626 (0.32 and 1.0 mg/kg) on PD-128,907 (0.0032–1.0 mg/kg)-induced yawning (A) and quinelorane (0.0001–0.032 mg/kg)-induced yawning (B). Effects of the nonselective dopamine receptor antagonist haloperidol (0.01 and 0.032 mg/kg) on PD-128,907 (0.0032–1.0 mg/kg)-induced yawning (C) and quinelorane (0.0001–0.1 mg/kg)-induced yawning (D). Data are presented as mean (± S.E.M.), n = 8, number of yawns during a 20-min observation period.*,p < 0.05;**, p < 0.01;***, p < 0.001. Significant difference from vehicle-treated animals was determined by unbalanced, two-way ANOVA with post hoc Bonferroni tests.

Fig. 3

Effects of D3-preferring antagonists on PD-128,907 (0.0032–0.32 mg/kg)-induced yawning in rats. A, nafadotride at doses of 0, 0.001, 0.1, and 0.32 mg/kg; B, U99194 at doses of 0, 1.0, 3.2, and 10.0 mg/kg; C, SB-277011A at doses of 0, 3.2, 32.0, and 56.0 mg/kg; and D, PG01037 at doses of 0, 10.0, 32.0, and 56.0 mg/kg. Data are presented as mean (±S.E.M.), n = 8, number of yawns during a 20-min observation period.*, p < 0.05; **, p < 0.01; ***, p < 0.001. Significant difference from vehicle-treated animals was determined by unbalanced, two-way ANOVA with post hoc Bonferroni tests.

Fig. 4

A, dose-response curves for PD-128,907 (0.0032–0.32 mg/kg)-, physostigmine (0.01–1.0 mg/kg i.p.)-, and TFMPP (0.32–10.0 mg/kg)-induced yawning in rats. B, effects of scopolamine (0, 0.0001, 0.001, and 0.01 mg/kg) on yawning induced by PD-128,907 (0.1 mg/kg), physostigmine (0.1 mg/kg i.p.), and TFMPP (3.2 mg/kg). C, effects of mianserin (0, 0.0032, 0.032, and 0.32 mg/kg) on yawning induced by PD-128,907 (0.1 mg/kg), physostigmine (0.1 mg/kg i.p.), and TFMPP (3.2 mg/kg). Data are presented as mean (± S.E.M.), n = 8, number of yawns during a 20-min observation period. *, p < 0.05; **, p < 0.01; ***, p < 0.001. Significant difference from vehicle-treated rats was determined by one-way repeated-measures ANOVAs with post hoc Dunnett’s tests.

Fig. 5

Effects of D3-preferring antagonists on yawning induced by PD-128,907 (0.1 mg/kg), physostigmine (0.1 mg/kg i.p.), and TFMPP (3.2 mg/kg). A, nafadotride at doses of 0, 0.01, 0.1, and 1.0 mg/kg; B, U99194 at doses of 0, 1.0, 3.2, and 10.0 mg/kg; C, SB-277011A at doses of 0, 3.2, 32.0, and 56.0 mg/kg; and D, PG01037 at doses of 0, 10.0, 3.2, and 56.0 mg/kg. Data are presented as mean (±S.E.M.), n = 8, number of yawns during a 20-min observation period. *, p < 0.05; **, p < 0.01; ***, p < 0.001. Significant difference from vehicle-treated rats was determined by one-way repeated-measures ANOVAs with post hoc Dunnett’s tests.