Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function.
The striatum contains a high density of histamine H(3) receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H(3) and dopamine D(1) receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H(3) and dopamine D(2) receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H(3) and D(1) and also between H(3) and dopamine D(2) receptors. The selective H(3) receptor agonist imetit inhibited, while the H(3) receptor antagonist thioperamide potentiated locomotor activation induced by either the D(1) receptor agonist SKF 38393 or the D(2) receptor agonist quinpirole. High scores of locomotor activity were obtained with H(3) receptor blockade plus D(1) and D(2) receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H(3)-D(2) receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H(3) receptors with several H(3) receptor agonists significantly decreased the affinity of D(2) receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H(3) (but not H(4)) receptors were found to form heteromers with D(2) receptors. This study demonstrates an important role of postsynaptic H(3) receptors in the modulation of dopaminergic transmission by means of a negative modulation of D(2) receptor function.
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, University of Barcelona, 08028 Barcelona, Spain.
Carla
C
Ferrada
Sergi
S
Ferré
Vicent
V
Casadó
Antonio
A
Cortés
Zuzana
Z
Justinova
Chanel
C
Barnes
Enric I
EI
Canela
Steven R
SR
Goldberg
Rob
R
Leurs
Carme
C
Lluis
Rafael
R
Franco
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004735:Energy Transfer / Q000502:physiology; D018494:Histamine Agents / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D018100:Receptors, Histamine H3 / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D014162:Transfection
D018759:Adrenergic Uptake Inhibitors; D015259:Dopamine Agents; D018494:Histamine Agents; D017448:Receptors, Dopamine D2; D018100:Receptors, Histamine H3; D012110:Reserpine; D000242:Cyclic AMP