title: Thromboxane receptor activation enhances striatal dopamine release, leading to suppression of GABAergic transmission and enhanced sugar intake.
abstract: The extracellular dopamine level is regulated not only by synaptic inputs to dopamine neurons but also by local mechanisms surrounding dopaminergic terminals. However, much remains to be investigated for the latter mechanism. Thromboxane A(2) is one of the cyclooxygenase products derived from arachidonic acid, and acts on its cognate G protein-coupled receptor [thromboxane receptor (TP)]. We show here that TP in the striatum locally facilitates dopamine overflow. Intrastriatal injection of a TP agonist increased extracellular dopamine levels in the striatum as measured by in vivo microdialysis. TP stimulation also augmented electrically evoked dopamine overflow from striatal slices. Conversely, TP deficiency reduced dopamine overflow evoked by N-methyl-d-aspartic acid (NMDA) and acetylcholine in striatal slices. TP immunostaining showed that TP is enriched in vascular endothelial cells. Pharmacological blockade of nitric oxide (NO) synthesis and genetic deletion of endothelial NO synthase (eNOS) suppressed NMDA/acetylcholine-induced dopamine overflow. This involvement of NO was abolished in TP-deficient slices, suggesting a role for eNOS-derived NO synthesis in TP-mediated dopamine overflow. As a functional consequence of TP-mediated dopamine increase, a TP agonist suppressed GABAergic inhibitory postsynaptic currents in medium spiny neurons through a D2-like receptor-dependent mechanism. Finally, TP is involved in sucrose intake, a dopamine-dependent motivational behavior. These data suggest that TP stimulation in the striatum locally facilitates dopamine overflow evoked by synaptic inputs via NO synthesis in endothelial cells.
authors.affiliation: Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mitsumori
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Furuyashiki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Momiyama
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.forename: Takahide
authors.initials: T
authors.lastname: Shuto
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ushikubi
authors.forename: Shiho
authors.initials: S
authors.lastname: Kitaoka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Aoki
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Inoue
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009569:Nitric Oxide / Q000096:biosynthesis; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017482:Receptors, Thromboxane / Q000378:metabolism*; D013395:Sucrose; D009435:Synaptic Transmission / Q000502:physiology*; D013928:Thromboxane A2 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D017482:Receptors, Thromboxane; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D013395:Sucrose; D013928:Thromboxane A2; D004298:Dopamine