Hippocampal-Dependent Antidepressant Action of the H sub(3) Receptor Antagonist Clobenpropit in a Rat Model of Depression

• Published in: The international journal of neuropsychopharmacology 2015-07, Vol.18 (9), p.1-11
• Main Authors: Femenia, Teresa, Magara, Salvatore, Dupont, Caitlin M, Lindskog, Maria
• Format: Article
• Language: English
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyv032

Background: Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H sub(3) receptor (H sub(3)R) 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 H sub(3)R 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 CAI 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. H sub(1)R and H sub(2)R 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 H sub(1)R and H sub(2)R 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.