title: The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons.
abstract: The basal ganglia have a central role in motor patterning, habits, motivated behaviors, and cognition as well as in numerous neuropsychiatric disorders. Receptors for histamine, especially the H3 receptor (H3R), are highly expressed in the striatum, the primary input nucleus of the basal ganglia, but their effects on this circuitry have been little explored. H3R interacts with dopamine (DA) receptors ex vivo; the nature and functional importance of these interactions in vivo remain obscure. We found H3R activation with the agonist R-(-)-α-methylhistamine to produce a unique time- and cell type-dependent profile of molecular signaling events in the striatum. H3 agonist treatment did not detectably alter extracellular DA levels or signaling through the cAMP/DARPP-32 signaling pathway in either D1- or D2-expressing striatal medium spiny neurons (MSNs). In D1-MSNs, H3 agonist treatment transiently activated MAPK signaling and phosphorylation of rpS6 and led to phosphorylation of GSK3β-Ser9, a novel effect. Consequences of H3 activation in D2-MSNs were completely different. MAPK signaling was unchanged, and GSK3β-Ser9phosphorylation was reduced. At the behavioral level, two H3 agonists had no significant effect on locomotion or stereotypy, but they dramatically attenuated the locomotor activation produced by the D1 agonist SKF82958. H3 agonist co-administration blocked the activation of MAPK signaling and the phosphorylation of rpS6 produced by D1 activation in D1-MSNs, paralleling behavioral effects. In contrast, GSK3β-Ser9phosphorylation was seen only after H3 agonist treatment, with no interactive effects. H3R signaling has been neglected in models of basal ganglia function and has implications for a range of pathophysiologies.
authors: From the Departments Psychiatry and.
authors: Maximiliano
authors: http://orcid.org/0000-0001-7329-2364
authors: M
authors: Rapanelli
authors: From the Departments Psychiatry and.
authors: Luciana R
authors: http://orcid.org/0000-0001-5595-8636
authors: LR
authors: Frick
authors: Interdepartmental Neuroscience Program, and.
authors: Kyla D
authors: http://orcid.org/0000-0001-8340-3654
authors: KD
authors: Horn
authors: Graduate Program in Cell Biology, Yale University, New Haven, Connecticut 06519.
authors: Rivka C
authors: RC
authors: Schwarcz
authors: From the Departments Psychiatry and.
authors: Vladimir
authors: V
authors: Pogorelov
authors: From the Departments Psychiatry and angus.nairn@yale.edu.
authors: Angus C
authors: http://orcid.org/0000-0002-7075-0195
authors: AC
authors: Nairn
authors: From the Departments Psychiatry and Interdepartmental Neuroscience Program, and Psychology, Child Study Center, christopher.pittenger@yale.edu.
authors: Christopher
authors: http://orcid.org/0000-0003-2117-9321
authors: C
authors: Pittenger
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D008124:Locomotion / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism
chemical_list: D001552:Benzazepines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018100:Receptors, Histamine H3; D038601:Ribosomal Protein S6; C448579:ribosomal protein S6, mouse; C071262:SK&F 82958; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Akt PKB; H3R; MAPK; dopamine; dopamine receptor; histamine; medium spiny neuron; striatum