TABLE 2.
The role of histamine in the aetiology of neurodevelopmental disorders.
| Role of histamine | References | |
| Tourette’s syndrome | A rare nonsense mutation in the gene encoding Histidine decarboxylase (Hdc), the rate-limiting enzyme in histamine synthesis, has been implicated in a two-generation pedigree | Ercan-Sencicek et al., 2010 |
| There is a gene-dose dependent decrease in histamine concentration in the hypothalamus, striatum and cortex, in mice that were heterozygous or knock out for Hdc compared to wild type mice. | Baldan et al., 2014 | |
| Hdc KO mice exhibit repetitive movements in response to acute stress and psychostimulant challenge that were mitigated with pre-treatment with the dopamine 2 receptor antagonist, haloperidol. | Baldan et al., 2014 | |
| Dopamine levels and D2/D3 receptor expression are increased in Hdc KO mice, suggesting that there may be an interaction between histaminergic and dopaminergic signaling in mediating the symptoms of Tourette syndrome. | Baldan et al., 2014 | |
| H3 receptors are upregulated in Hdc KO mice, and chemogenetic activation of these receptors in the dorsal striatum can precipitate stereotypies. | Rapanelli et al., 2017 | |
| Histamine infusion may reduce the concentration of dopamine in the striatum by agonizing H3 heteroreceptors on dopaminergic afferents. | Schlicker et al., 1993 | |
| Autism spectrum disorders | Histamine dysregulation may have a role in mediating autism spectrum disorder phenotype with altered expression of key histamine signaling genes HNMT, HRH1, HRH2, and HRH3 in post-mortem brains of patients with ASD. | Wright et al., 2017 |
| H3 receptor has been implicated in repetitive behavior-like pathology including stereotypies that may be a feature of ASDs. | Rapanelli et al., 2017 | |
| Attention deficit hyperactivity disorder | Methylphenidate, and atomoxetine may stimulate cortical histamine through enhanced dopamine and noradrenaline transmission. | Horner et al., 2007 |
| Polymorphisms of the HNMT gene have been seen in those with ADHD. | Stevenson et al., 2010 | |
| Schizophrenia | Elevated levels of the histamine metabolite tele-methylhistamine have been implicated in schizophrenia, suggesting greater histamine release and turnover. | Prell et al., 1995, 1996 |
| Adjunct use of the H2 receptor antagonist, ranitidine, led to a significant but non-sustained reduction in negative symptoms in people with schizophrenia. | Mehta and Ram, 2014 | |
| H3 receptors are upregulated in the prefrontal cortex of people with schizophrenia. | Jin et al., 2009a | |
| H3 receptor antagonists improved symptoms of cognitive impairment in animal studies but this has so far not been translated to human studies. | Pre-clinical studies: Southam et al., 2009; Bardgett et al., 2010; Brown et al., 2013. Clinical trials: Haig et al., 2014; Jarskog et al., 2015 |
D2, dopamine 2; D3, dopamine 3; H1, histamine 1; H2, histamine 2; H3, histamine 3; H4, histamine 4; Hdc KO, histamine decarboxylase knock out; HRH1, histamine receptor H1; HRH2, histamine receptor H2; HRH3, histamine receptor H3; HNMT, histamine N-methyltransferase.