title: Dopamine D4 receptor-induced postsynaptic inhibition of GABAergic currents in mouse globus pallidus neurons.
abstract: Dopamine D4 receptors (D4R) are localized in the globus pallidus (GP), but their function remains unknown. In contrast, dopamine D2 receptor activation hyperpolarizes medium spiny neurons projecting from the striatum to the GP and inhibits GABA release. However, using slice preparations from D2R-deficient [D2 knock-out (D2KO)] mice, we found that dopamine inhibited GABA(A)-receptor-mediated currents in GP neurons. The paired-pulse ratio was statistically unchanged after dopamine application but was significantly elevated in D2KO wild-type littermates (WT). Furthermore, in D2KO mice, outward currents elicited by iontophoretically applied GABA were suppressed by dopamine. Dopamine (30 microm) decreased the amplitude of miniature IPSCs in both WT and D2KO mice, but the decrease in the frequency was observed only in the former but not significantly in the latter. Dopamine-induced suppression of IPSCs was blocked by selective D4R antagonists (clozapine or 3-[4-(4-iodophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride), and a D4R-selective agonist N-[[4-(2-cyanophenyl)-1-piperazinyl]methyl]-3-methyl-benzamide reversibly and dose-dependently suppressed IPSCs, whereas agonists [SKF38,393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride) or (+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol] or antagonists [SCH23,390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) or sulpiride] of other receptor subtypes had little effect. In GP neurons from D4R-deficient mice, dopamine-induced inhibition of GABAergic outward currents was undetectable. D4R activation suppressed the activity of protein kinase A in GP neurons, resulting in a decrease in the amplitude of GABAergic IPSCs. These findings showed that postsynaptic activation of D4R on the GP neurons reduces GABAergic currents through the suppression of PKA activity.
authors.affiliation: Neural Circuits Dynamics Research Group, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Ryong-Moon
authors.initials: RM
authors.lastname: Shin
authors.forename: Masao
authors.initials: M
authors.lastname: Masuda
authors.forename: Masami
authors.initials: M
authors.lastname: Miura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sano
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Song
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Aosaki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D004553:Electric Conductivity; D018756:GABA Antagonists / Q000494:pharmacology*; D005917:Globus Pallidus / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology*; D050638:Receptors, Dopamine D4; D011963:Receptors, GABA-A / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C493600:Drd4 protein, mouse; D018756:GABA Antagonists; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D050638:Receptors, Dopamine D4; D005680:gamma-Aminobutyric Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine