title: Histamine impairs midbrain dopaminergic development in vivo by activating histamine type 1 receptors.
abstract: BACKGROUND
  Histamine (HA) regulates the sleep-wake cycle, synaptic plasticity and memory in adult mammals. Dopaminergic specification in the embryonic ventral midbrain (VM) coincides with increased HA brain levels. To study the effect of HA receptor stimulation on dopamine neuron generation, we administered HA to dopamine progenitors, both in vitro and in vivo.
  
  
  RESULTS
  Cultured embryonic day 12 (E12) VM neural stem/progenitor cells expressed transcripts for HA receptors H1R, H2R and H3R. These undifferentiated progenitors increased intracellular calcium upon HA addition. In HA-treated cultures, dopamine neurons significantly decreased after activation of H1R. We performed intrauterine injections in the developing VM to investigate HA effects in vivo. HA administration to E12 rat embryos notably reduced VM Tyrosine Hydroxylase (TH) staining 2 days later, without affecting GABA neurons in the midbrain, or serotonin neurons in the mid-hindbrain boundary. qRT-PCR and Western blot analyses confirmed that several markers important for the generation and maintenance of dopaminergic lineage such as TH, Lmx1a and Lmx1b were significantly diminished. To identify the cell type susceptible to HA action, we injected embryos of different developmental stages, and found that neural progenitors (E10 and E12) were responsive, whereas differentiated dopaminergic neurons (E14 and E16) were not susceptible to HA actions. Proliferation was significantly diminished, whereas neuronal death was not increased in the VM after HA administration. We injected H1R or H2R antagonists to identify the receptor responsible for the detrimental effect of HA on dopaminergic lineage and found that activation of H1R was required.
  
  
  CONCLUSIONS
  These results reveal a novel action of HA affecting dopaminergic lineage during VM development.
authors.forename: Itzel
authors.initials: I
authors.lastname: Escobedo-Avila
authors.forename: Fernanda
authors.initials: F
authors.lastname: Vargas-Romero
authors.forename: Anayansi
authors.initials: A
authors.lastname: Molina-Hernández
authors.forename: Rodrigo
authors.initials: R
authors.lastname: López-González
authors.forename: Daniel
authors.initials: D
authors.lastname: Cortés
authors.forename: Juan A
authors.initials: JA
authors.lastname: De Carlos
authors.affiliation: Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, México D,F,-04510, Mexico. ivelasco@ifc.unam.mx.
authors.forename: Iván
authors.initials: I
authors.lastname: Velasco
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D002744:Chlorpheniramine / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology*; D042541:Intracellular Space / Q000378:metabolism; D008636:Mesencephalon / Q000196:embryology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism
chemical_list: D011969:Receptors, Histamine H1; D002744:Chlorpheniramine; D002927:Cimetidine; D006632:Histamine; D002118:Calcium
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