title: Hippocampal-Dependent Antidepressant Action of the H3 Receptor Antagonist Clobenpropit in a Rat Model of Depression.
abstract: BACKGROUND
  Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model of depression with impaired memory and altered glutamatergic transmission.
  
  
  METHODS
  Behavioral tests included the forced swim test, memory tasks (passive avoidance, novel object recognition tests), and anxiety-related paradigms (novelty suppressed feeding, social interaction, light/dark box tests). Hippocampal protein levels were detected by Western blot. Hippocampal plasticity was studied by in slice field recording of CA3-CA1 long-term synaptic potentiation (LTP), and glutamatergic transmission by whole-cell patch clamp recording of excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons.
  
  
  RESULTS
  Clobenpropit, administered systemically or directly into the hippocampus, decreased immobility during the forced swim test; systemic injections reversed memory deficits and increased hippocampal GluN2A protein levels. FSL rats displayed anxiety-related behaviors not affected by clobenpropit treatment. Clobenpropit enhanced hippocampal plasticity, but did not affect EPSCs. H1R and H2R antagonists prevented the clobenpropit-induced increase in LTP and, injected locally into the hippocampus, blocked clobenpropit's effect in the forced swim test.
  
  
  CONCLUSIONS
  Clobenpropit's antidepressant effects and the enhanced synaptic plasticity require hippocampal H1R and H2R activation, suggesting that clobenpropit acts through disinhibition of histamine release. Clobenpropit reverses memory deficits and increases hippocampal GluN2A expression without modifying anxiety-related phenotypes or EPSCs in CA1 pyramidal neurons.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Femenía, Magara, and Lindskog, and Ms DuPont).
authors.forename: Teresa
authors.initials: T
authors.lastname: Femenía
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Femenía, Magara, and Lindskog, and Ms DuPont).
authors.forename: Salvatore
authors.initials: S
authors.lastname: Magara
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Femenía, Magara, and Lindskog, and Ms DuPont).
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: DuPont
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (Drs Femenía, Magara, and Lindskog, and Ms DuPont). mia.lindskog@ki.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Lindskog
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects*; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D018698:Glutamic Acid; D013890:Thiourea; C086108:clobenpropit
keywords: Anxiety; FSL; glutamate; memory; plasticity