Prostaglandin E receptor EP1 enhances GABA-mediated inhibition of dopaminergic neurons in the substantia nigra pars compacta and regulates dopamine level in the dorsal striatum.
Dopamine (DA) is a neuromodulator that is critical for sensory-motor, cognitive and emotional functions. We previously found that mice lacking prostaglandin E receptor EP1 showed impulsive emotional behaviors accompanied by enhanced DA turnover in the frontal cortex and striatum. Given that these behavioral phenotypes were corrected by DA receptor antagonists, we hypothesized that EP1 deficiency causes a hyperdopaminergic state for its behavioral phenotype. Here we tested this hypothesis by examining the EP1 action in the nigrostriatal dopaminergic system. We first used microdialysis and found an elevated extracellular DA level in the dorsal striatum of EP1-deficient mice compared with wild-type mice. Despite the EP1 expression in the striatum, neither deficiency nor activation of EP1 altered the intrastriatal control for DA release, uptake or degradation. Immunohistochemistry revealed punctate EP1 signals apposed with dopaminergic neurons in the substantia nigra pars compacta (SNc). Many EP1 signals were colocalized with a marker for GABAergic synapses. Further, an EP1 agonist enhanced GABA(A)-mediated inhibitory inputs to SNc dopaminergic neurons in midbrain slices. Therefore, the prostaglandin E(2)-EP1 signaling directly enhances GABAergic inputs to SNc dopaminergic neurons. The lack of this EP1 action may lead to a hyperdopaminergic state of EP1-deficient mice.
Tanaka
Yasuhiro
Y
Department of Pharmacology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Furuyashiki
Tomoyuki
T
Momiyama
Toshihiko
T
Namba
Hisaaki
H
Mizoguchi
Akira
A
Mitsumori
Tomoyuki
T
Kayahara
Tetsuro
T
Shichi
Hitoshi
H
Kimura
Kazushi
K
Matsuoka
Toshiyuki
T
Nawa
Hiroyuki
H
Narumiya
Shuh
S
D000818:Animals; D001921:Brain / Q000502:physiology*; D003342:Corpus Striatum / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013378:Substantia Nigra / Q000502:physiology; D013569:Synapses / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C545636:Ptger1 protein, mouse; D011963:Receptors, GABA-A; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D005680:gamma-Aminobutyric Acid; D004298:Dopamine