The histamine H₃ receptor: an attractive target for the treatment of cognitive disorders

Abstract

The histamine H 3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H 3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H 3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H 3 receptors by selective H 3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H 3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H 3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H 3 receptor antagonist has been reported to date. The discovery of effective H 3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H 3 receptor.

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

“…Nevertheless, the H3 receptor has been recently implicated in learning and memory processes. Blockade of presynaptic H3 autoreceptors would enhance the release of histamine and other transmitter systems involved in cognitive processes and, indirectly, ameliorate cognitive performances (Esbenshade et al, 2008). Present results suggest a beneficial activity induced by neuronal H4 receptor stimulation on memory impairments, extending and further clarifying the role of the histaminergic system in the modulation of cognitive functions.…”

“…The administration of histamine or L-histidine induces an anxiogenic-like effect (Kumar et al, 2007) whereas the destruction of the rat tuberomammillary rostroventral E-2 subregion, from which histaminergic neuron fibers arise, can induce anxiolytic-like effects (Frisch et al, 1998). Furthermore, clinically effective anxiolytic drugs, such as diazepam and buspirone, have been found to decrease the turnover rate of brain histamine in mice and rats (Oishi et al, 1992;Chikai et al, 1993).…”

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT‐288, in healthy young adults and elderly volunteers

“…For parts 1 and 2 of study 1, blood samples were collected within 10 min prior to dosing (0 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9,12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h after dosing in each study period. For part 3 of study 1, blood samples were collected (i) prior to dosing (0 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after dosing on days 1 and 7; (ii) prior to dosing (0 h) on days 5, 6, 12 and 13; and (iii) prior to dosing (0 h) and at 0.5, 1, 1.5, 2, 3,4,6,9,12,16,24,36,48,60,72,96,120,144,168,192,216 and 240 h after dosing on day 14. For study 2, blood samples were collected (i) prior to dosing (0 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 h after dosing on day 1; (ii) prior to dosing (0 h) on days 4, 7, 10 and 11; and (iii) prior to dosing (0 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 96, 168 and 240 h after dosing on day 12.…”

“…Accordingly, in multiple non-human experimental paradigms, selective H3 receptor antagonists have shown the potential to improve wakefulness, attention and performance in different cognitive domains [14,15]. It was thus hypothesized that H3 receptor antagonists might provide a new pharmacological approach to improve cognitive impairment associated with AD [16][17][18].…”

Polypharmacology of dopamine D1-like receptor antagonists

“…Pathophysiology of schizophrenia and related diseases is mainly based on dysfunctions in dopamine, serotonin, and glutamate, [33,53,54]. However, selective D 1 antagonism alone is not accepted as effective antipsychotic principle [55,56].…”