Neuronal histamine and the memory of emotionally salient events

Abstract

In this review, we describe the experimental paradigms used in preclinical studies to unravel the histaminergic brain circuits that modulate the formation and retrieval of memories associated with aversive events. Emotionally arousing events, especially bad ones, are remembered more accurately, clearly and for longer periods of time than neutral ones. Maladaptive elaborations of these memories may eventually constitute the basis of psychiatric disorders such as generalized anxiety, obsessive-compulsive disorders and post-traumatic stress disorder. A better understanding of the role of the histaminergic system in learning and memory has not only a theoretical significance but also a translational value. Ligands of histamine receptors are among the most used drugs worldwide; hence, understanding the impact of these compounds on learning and memory may help improve their pharmacological profile and unravel unexplored therapeutic applications.

Histamine pharmacology: from Sir Henry Dale to the 21st century

“…For example, the histamine‐containing neurons are ~4000 in the rat and ~64 000 in the human TMN (Nuutinen and Panula, 2010). The current knowledge of the histaminergic system and its interactions with other systems in the brain derives predominately from extensive studies in rodents, humans and the zebrafish, as summarized in a number of excellent reviews that are available in the literature (Haas and Panula, 2003; Haas et al ., 2008; Nuutinen and Panula, 2010; Sundvik and Panula, 2015; Nieto‐Alamilla et al ., 2016; Provensi et al ., 2018). In particular, the zebrafish has recently been shown to be a valuable tool for dissecting the role of histaminergic and histaminoceptive neurons in the brain by employing cutting‐edge methodologies, such as genome modification using the CRISPR/Cas9 editing tool (Haas, 2018).…”

“…EHRS Honorary Membership was awarded to Jean‐Charles Schwartz in 2014 (Figure 3). In later studies, evidence pointed to the presence of H 3 postsynaptic receptors or heteroreceptors in different neuronal populations, controlling the release of various neurotransmitters, including histamine, glutamate, γ‐aminobutyric acid (GABA), dopamine, noradrenaline and acetylcholine (Gbahou et al ., 2012), thus being implicated in various (patho)physiological conditions (Tiligada et al ., 2011; Sundvik and Panula, 2015; Nieto‐Alamilla et al ., 2016; Provensi et al ., 2018).…”

“…The continuing collaborative effort to develop H 3 ligands involving additional groups from academia and the pharmaceutical industry in Europe and in the USA did not manage to get a novel drug to the clinic at that point (Parsons and Ganellin, 2006; Schwartz, 2011). However, it contributed greatly to the current understanding of the role of histamine in the sleep–wake cycle and in neuropsychiatric (patho)physiology (Haas et al ., 2008; Nuutinen and Panula, 2010; Schwartz, 2011; Sundvik and Panula, 2015; Nieto‐Alamilla et al ., 2016; Provensi et al ., 2018) and laid the foundation for the prospective exploitation of the histamine H 3 receptor as a novel drug target (Kollb‐Sielecka et al ., 2017).…”

Challenges in the development and exploitation of new therapeutic options targeting the histaminergic system

“…Histamine and the H 4 receptor are commonly elevated in inflamed tissue, diabetic organs and cancer cells, offering wide clinical possibilities. These include common skin disorders, atopic dermatitis and psoriasis (H 4 receptor; Schaper‐Gerhardt, Rossbach, et al, 2020), diabetic nephropathies (H 1 , H 4 receptors; Grange et al, 2020), cancers (H 4 receptor as a target and marker; Massari, Nicoud, & Medina, 2018), neuropsychiatric and neurocognitive diseases (Provensi, Costa, et al, 2020; Provensi, Passani, et al, 2020), tic disorders (Pittenger, 2020) and chronic pain (Obara, et al, 2020). Sprinkled amongst the review articles, there are a series of original research papers which further highlight the potential of targeting the peripheral H 4 receptor for dermal (anti‐pruritic and anti‐inflammatory; Mommert, et al, 2020; Schaper‐Gerhardt, Wohlert, et al, 2020) and vestibular (Petremann, et al, 2020) disorders.…”

“…In terms of the CNS, histamine‐based maladaptive elaborations of fearful memories may eventually constitute the basis of psychiatric disorders such as generalized anxiety, obsessive–compulsive disorders and post‐traumatic stress disorder (Provensi, Costa, et al, 2020). The review also addresses histaminergic strategies that may help improve the treatment of impaired declarative memory, described in these affective and neuropsychiatric disorders, along with major neurocognitive disorders, such as ADHD and Alzheimer's disease (Provensi, Costa, et al, 2020; Provensi, Passani, et al, 2020). Alcohol use disorder (AUD) is a chronic relapsing CNS disease characterized by compulsive alcohol use, loss of control over alcohol intake and an emotional withdrawal state.…”