What role does histamine play in post-SSRI sexual dysfunction (PSSD)

Histamine plays an important role in the sexual response and many post-SSRI sexual dysfunction (PSSD) sufferers experience relief of anhedonia as well as a libido boost during periods of illness (cold and flu). During these states, there's a significant increase in histamine release in a bid to fight the infection.

Histamine release modulates sexual function generally speaking. There are 4 histamine receptors (H1, H2, H3, and H4), some are anti-sexual while others are pro-sexual.

H1 receptors:

H1 receptor activation promotes nitric oxide (NO) synthesis, but receptors present on the corpus cavernosum promote contraction, so it's overall anti-erectile [1][2][3]. However, H1 receptors are very important for sexual arousal at least in females, this is mediated by estrogen via upregulation of hypothalamic (VMN) H1 receptor expression. H1 receptors in that area promotes sexual arousal [4].

H1 receptor activation stimulates tyrosine hydroxylase (TH), which leads to increased dopamine and norepinephrine synthesis in the brain. This is mediated through protein kinases (PKA and PKC) [5]. PKC activation also induces corpus cavernosum contraction, making H1 receptors more anti-erectile [6].

H1R antagonism directly promotes dopamine release in the neostriatum and nucleus accumbens, increasing the hedonistic 'pleasure' response [7]. This can explain why some people combine antihistamine with their drugs of abuse to potentiate their reinforcing effects. H1R activation also promotes prolactin release through inhibiting dopamine, which is very bad for us [8].

H1R activation induces microglia activation and dopaminergic neuronal toxicity in the presence of neuroinflammation. So, it's very bad for people who suffer from Parkinson's disease or neuroinflammation in general, which could be relevant to our condition [9].

It's not all bad with this receptor though, as activation leads to enhancement of NMDA receptors, leading to facilitation of synaptic excitation and long-term potentiation (LTP) [10]. NMDA receptor function is very important for supporting testosterone synthesis.

H2 receptors:

These have the opposite effects of H1 receptors, in a sense that activation directly increases dopamine release and enhance penile erection [11][12]. They also enhance nitric oxide release [13]. This receptor subtype most likely mediates the enhanced sexual response during colds and flu.

H3 receptors:

This receptor subtype is an autoreceptor for histamine and also inhibits release of several neurotransmitters (Acetylcholine, dopamine, norpinephrine, serotonin, glutamate and GABA) [14].

However, it's much more complex than that. H3 receptors form heterodimers with both D1 and D2 receptors in the dorsal and ventral striatum, where the vast majority of H3 receptors are located postsynaptically. This mediates enhancement of dopamine activation [15]. H3 also form a heteroreceptor complexes with NMDA receptors, mediating NMDA potentiation and enhancing LTP [16]. However, due to inhibition of several neurotransmitters, including glutamate, inhibition of H3 receptors have memory promoting and nootropic effects [17]. H3 receptors could also promote penile erection [11].

H4 receptors:

This subtype is relatively newly discovered, as such there isn't much research on its function. However, I did find that H4 histamine receptors inhibit steroidogenesis and proliferation in Leydig cells [url=https://www.ncbi.nlm.nih.gov/pubmed/25253872][18][/url]. That being said, it's been found to be present in the mammalian neurons, so it must have a CNS effect as well [url=https://www.ncbi.nlm.nih.gov/pubmed/19413571][19][/url].

Antidepressants effect on DAO and HNMT expression:

In mammals, histamine is mainly metabolised by diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT). TCAs induced enzyme mRNA synthesis and increased enzyme activity, and consequently lowered tissue histamine concentration. Sertraline increased DAO activity, but had no effect on HNMT activity [20].

Furthermore, antidepressants require the histamine system to exert their effects [21], so it makes sense that PSSD is closely linked to the histaminergic system. SSRIs, or at least Citalopram, induces genome-wide DNA methylation alteration, which reduces oxytocin and dopamine functioning, but also sex hormones and histamine [22].

As a conclusion, I think both extremes of low and high histamine and increased methylation are closely implicated in PSSD pathophysiology.