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Proc Natl Acad Sci U S A. 2016 May 10;113(19):E2714-20. doi: 10.1073/pnas.1604841113. Epub 2016 Apr 26.

Memory retrieval of inhibitory avoidance requires histamine H1 receptor activation in the hippocampus.

Author information

1
Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, 90610-000 Porto Alegre, RS, Brazil; Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, 50139 Florence, Italy;
2
Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, 90610-000 Porto Alegre, RS, Brazil;
3
Dipartimento di Scienze della Salute, Sezione di Farmacologia e Chemioterapia, Universitá di Firenze, 50139 Florence, Italy;
4
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, 50139 Florence, Italy;
5
Dipartimento di Medicina Sperimentale e Clinica, Universitá di Firenze, 50134 Florence, Italy.
6
Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, 90610-000 Porto Alegre, RS, Brazil; izquier@terra.com.br jociane_carvalho@hotmail.com patrizio.blandina@unifi.it.
7
Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmacologia e Tossicologia, Universitá di Firenze, 50139 Florence, Italy; izquier@terra.com.br jociane_carvalho@hotmail.com patrizio.blandina@unifi.it.

Abstract

Retrieval represents a dynamic process that may require neuromodulatory signaling. Here, we report that the integrity of the brain histaminergic system is necessary for retrieval of inhibitory avoidance (IA) memory, because rats depleted of histamine through lateral ventricle injections of α-fluoromethylhistidine (a-FMHis), a suicide inhibitor of histidine decarboxylase, displayed impaired IA memory when tested 2 d after training. a-FMHis was administered 24 h after training, when IA memory trace was already formed. Infusion of histamine in hippocampal CA1 of brain histamine-depleted rats (hence, amnesic) 10 min before the retention test restored IA memory but was ineffective when given in the basolateral amygdala (BLA) or the ventral medial prefrontal cortex (vmPFC). Intra-CA1 injections of selective H1 and H2 receptor agonists showed that histamine exerted its effect by activating the H1 receptor. Noteworthy, the H1 receptor antagonist pyrilamine disrupted IA memory retrieval in rats, thus strongly supporting an active involvement of endogenous histamine; 90 min after the retention test, c-Fos-positive neurons were significantly fewer in the CA1s of a-FMHis-treated rats that displayed amnesia compared with in the control group. We also found reduced levels of phosphorylated cAMP-responsive element binding protein (pCREB) in the CA1s of a-FMHis-treated animals compared with in controls. Increases in pCREB levels are associated with retrieval of associated memories. Targeting the histaminergic system may modify the retrieval of emotional memory; hence, histaminergic ligands might reduce dysfunctional aversive memories and improve the efficacy of exposure psychotherapies.

KEYWORDS:

H1 receptor; histamine; inhibitory avoidance; memory; retrieval

PMID:
27118833
PMCID:
PMC4868453
DOI:
10.1073/pnas.1604841113
[Indexed for MEDLINE]
Free PMC Article

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