title: Histamine facilitates consolidation of fear extinction.
abstract: Non-reinforced retrieval induces memory extinction, a phenomenon characterized by a decrease in the intensity of the learned response. This attribute has been used to develop extinction-based therapies to treat anxiety and post-traumatic stress disorders. Histamine modulates memory and anxiety but its role on fear extinction has not yet been evaluated. Therefore, using male Wistar rats, we determined the effect of the intra-hippocampal administration of different histaminergic agents on the extinction of step-down inhibitory avoidance (IA), a form of aversive learning. We found that intra-CA1 infusion of histamine immediately after non-reinforced retrieval facilitated consolidation of IA extinction in a dose-dependent manner. This facilitation was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrilamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-2-pyridylethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction while the H3 receptor agonist imetit hampered it. Extinction induced the phosphorylation of ERK1 in dorsal CA1 while intra-CA1 infusion of the MEK inhibitor U0126 blocked extinction of the avoidance response. The extinction-induced phosphorylation of ERK1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, our data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of ERK signalling.
authors.affiliation: Centro de Memória, Instituto do Cérebro, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brasil.
authors.forename: Juliana Sartori
authors.initials: JS
authors.lastname: Bonini
authors.forename: Weber Cláudio
authors.initials: WC
authors.lastname: Da Silva
authors.forename: Clarice Kras Borges
authors.initials: CK
authors.lastname: Da Silveira
authors.forename: Cristiano André
authors.initials: CA
authors.lastname: Köhler
authors.forename: Iván
authors.initials: I
authors.lastname: Izquierdo
authors.forename: Martín
authors.initials: M
authors.lastname: Cammarota
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005239:Fear / Q000187:drug effects; D006632:Histamine / Q000008:administration & dosage / Q000502:physiology*; D017442:Histamine Agonists / Q000008:administration & dosage / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors; D057967:Infusions, Intraventricular; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011970:Receptors, Histamine H2 / Q000737:chemistry / Q000502:physiology*; D018100:Receptors, Histamine H3 / Q000737:chemistry / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D017442:Histamine Agonists; D006635:Histamine H2 Antagonists; D009419:Nerve Tissue Proteins; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D006632:Histamine; D006637:Histamine N-Methyltransferase; D048052:Mitogen-Activated Protein Kinase 3