Modulation of mesolimbic dopamine release by the selective dopamine D3 receptor antagonist, (+)-S 14297.
In Chinese hamster ovary cells stably transfected with recombinant rat dopamine D2 or D3 receptors, the naphthofurane antagonist, (+)-S 14297 [(+)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro- naphtho(2,3b)dihydro,2,3-furane]], displayed a pronounced preference for dopamine D3 versus D2 receptors: Ki values = 13 and 365 nM, respectively. In contrast, its distomer, (-)-S 17777, showed low affinity (296 versus 3403 nM). The aminotetralin agonist, (+)-7-OH-DPAT (7-hydroxy-2-(di-n-propylamino)tetralin), also showed high affinity at dopamine D3 (1.8 nM) versus D2 (96 nM) receptors while its (-)-isomer showed low affinity (71 and 1461 nM). In freely moving rats, (+)-7-OH-DPAT (0.16 mg/kg s.c.)-but not (-)-7-OH-DPAT-decreased dialysate levels of dopamine in the nucleus accumbens. (+)-S 14297 (1.25 mg/kg s.c.) markedly inhibited the action of (+)-7-OH-DPAT without influencing dopamine levels alone. Further, this action was stereospecific in that (-)-S 17777 (20.0 mg/kg s.c.) was inactive. In conclusion, data obtained with the novel, selective dopamine D3 receptor antagonist, (+)-S 14297 suggest that dopamine D3 autoreceptors modulate the release of dopamine from mesolimbic dopaminergic neurones.
Rivet
J M
JM
Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, France.
Audinot
V
V
Gobert
A
A
Peglion
J L
JL
Millan
M J
MJ
D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005663:Furans / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D017660:Autoreceptors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D005663:Furans; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; C090812:7-(N,N-dipropylamino)-5,6,7,8-tetrahydronaphtho(2,3-b)dihydro-2,3-furan; D015081:2-Naphthylamine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D004298:Dopamine