Proerectile Effects of Dopamine D2-Like Agonists Are Mediated by the D3 Receptor in Rats and Mice
- Gregory T. Collins,
- Andrew Truccone,
- Faiza Haji-Abdi,
- Amy Hauck Newman,
- Peter Grundt,
- Kenner C. Rice,
- Stephen M. Husbands,
- Benjamin M. Greedy,
- Cecile Enguehard-Gueiffier,
- Alain Gueiffier,
- Jianyong Chen,
- Shaomeng Wang,
- Jonathan L. Katz,
- David K. Grandy,
- Roger K. Sunahara and
- James H. Woods
- Departments of Pharmacology (G.T.C., A.T., F.H.-A., S.W., R.K.S., J.H.W.) and Internal Medicine and Medicinal Chemistry (J.C., S.W.), University of Michigan Medical School, Ann Arbor, Michigan; Medicinal Chemistry (A.H.N., P.G.) and Psychobiology (J.L.K.) Sections, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, Maryland; Chemical Biology Research Branch (K.C.R.), National Institute on Drug Abuse-Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (S.M.H., B.M.G.); Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Université de Tours, Tours, France (C.E.-G., A.G.); and Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon (D.K.G.)
- Address correspondence to:
Gregory T. Collins, Department of Pharmacology, 1301 MSRB III, 1150 W. Medical Center Dr., University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: collinsg{at}umich.edu
Abstract
Dopamine D2-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D4 and D3 receptors, respectively. The current studies were aimed at characterizing a series of D2, D3, and D4 agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D4 receptor (R) knockout (KO) mice. All D3 agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D4 agonists. Likewise, D2, D3, and D4 antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N′-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D3 antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D2 antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D4 antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D3 receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D4RKO mice, effects that were inhibited by the D3 antagonist, PG01037, in both wild-type and D4R KO mice. Together, these studies provide strong support that D2-like agonist-induced PE and yawning are differentially mediated by the D3 (induction) and D2 (inhibition) receptors. These studies fail to support a role for the D4 receptor in the regulation of PE or yawning by D2-like agonists.
Footnotes
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This work was supported in part by the National Institutes of Health [Grants DA020669, F013771, GM068603, MH67497]; by the Intramural Research program of the National Institutes of Health National Institute on Drug Abuse and National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; and by the University of Michigan Biological Sciences Scholars Program.
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doi:10.1124/jpet.108.144048.
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ABBREVIATIONS: PE, penile erection; apomorphine, (R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol hydrochloride; pramipexole, N′-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride; quinpirole, trans-(-)-(4aR)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride; haloperidol, 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone hydrochloride; ABT-724, 2-[[4-pyridin-2-yl)piperazin-1-yl]methyl]-1H-benzimidazole; PD-168,077, N-(methyl-4-(2-cyanophenyl)piperazinyl-3-methylbenzamide maleate; PIP3EA, 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]imidazo[1,2-a]pyridine; L-745,870, 3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride; R, receptor; WT, wild type; KO, knockout; PG01037, N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride; 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 hydrochloride; sumanirole, (5R)-5,6-dihydro-5-(methylamino) 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (2Z)-2-butenedioate; L-741,626, 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole; SB-277011A, trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclo-hexyl]-4-quinolinecarboxamide; raclopride, 3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide tartrate salt; Ro 61-6270, 2-amino-benzoic acid-1-benzyl-piperidin-4-yl-ester; ANOVA, analysis of variance; 7-OH-DPAT, (±)-7-hydroxy-2-dipropylaminotetralin; CP226269, 5-fluoro-2-[[4-(2-pyridinyl)-1-piperazinly]methyl]-1H-indole; (+)3-PPP, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine.
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- Received July 25, 2008.
- Accepted December 16, 2008.
- U.S. Government work not protected by U.S. copyright
