Memory retrieval of inhibitory avoidance requires histamine H 1 receptor activation in the hippocampus

Several neurotransmitters contribute to memory formation by modulating selectively acquisition, consolidation, and/or retrieval. Integrity of the brain histamine system is necessary for the consolidation of inhibitory avoidance (IA) memory. Here, we report that cerebral histamine depletion also impairs retrieval of IA in rats and blunts retrieval-induced c-Fos activation and cAMP-responsive element binding protein phosphorylation in the CA1 region of the hippocampus. Histamine infusion into the CA1 restores IA retrieval in histamine-depleted rats by targeting brain histamine H 1 receptors. Our study uncovers previously unidentified mechanisms involved in memory retrieval and may offer possible targets for eventual pharmacotherapies to treat dysfunctional aversive memories, including phobias, panic attacks, and posttraumatic stress disorders, as well as improve the efficacy of exposure psychotherapies. 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 H 1 and H 2 receptor agonists showed that histamine exerted its effect by activating the H 1 receptor. Noteworthy, the H 1 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, hi