Outlined briefly in Ghost 2016a and 5-HT1A Autoreceptor Desensitization Video (Ghost, 2016).
This page is still under construction. Please excuse its incompleteness.
When I first joined the PSSD forum in 2014, the prevailing theory on PSSD went like this:
What is the main thing causing this problem?
It is inhibition of dopamine receptors in general, particularly in and around the Raphe nucleus. Which is a small cluster of nuclei found in the brain stem. It’s main function is to release serotonin to the rest of the brain. SSSRI antidepressants are believed to act in these nuclei. They are not damaged, they are not desensitized, there is nothing wrong with dopamine binding, and it is more complicated than there just not being enough dopamine release into the synapse.
The autoreceptor is releasing too much serotonin into the synapse. So we have to figure out why that is. The autoreceptor is regulated by the same neurotransmitter, in this case serotonin. So the amount of serotonin which binds to it, controls how much serotonin it releases.
The main cause of PSSD is the receiving part of the autoreceptor being desensitized. So the normal amount of serotonin that was the right amount to do the job, now causes LESS activation of the receptor, and therefore it’s inhibitory effect on serotonin release is INSUFFICIENT.
Our autoreceptors didn’t go back to normal. They are stuck in that desensitized state. So the normal amount of serotonin which has always been there is not enough to do the job.
So in order to get the same amount of activation you had before, you must have MORE serotonin there than is normal. You have to compensate for that lack of sensitivity.
It’s kind of like when a button on a remote wears out. The normal amount of pressure won’t send the signal. You have to press harder to get it to work. In the same way, we have to press harder on the autoreceptor.
– Sonny (2014)
Sonny, the founder of the original PSSD forum, was off to a good start. While most of the PSSD community had been hiding in the shadows of pseudoscience and misquoted Pubmed articles for over a decade, Sonny had slowly been building a theory that got to the heart of PSSD. Much of the scientific community had come to these conclusions for patients currently on SSRI treatment, but Sonny made the assumption that PSSD was the continued version of the SSRI state. The power of this assumption is often underestimated, but it’s still something that is missed by some sufferers and researchers alike. While many people considered PSSD “brain damage” or “nerve destruction”, Sonny claimed that the problem in PSSD was much more specific. Additionally, it had the power to be treated scientifically.
Sonny’s forum, and the research-minded quest that it started, was nothing short of a breakthrough.
Once people started looking at the things that were working for PSSD, they all seemed to tie back to serotonin.
Ginkgo Biloba, Forskolin, Yohimbine, Tumeric, etc…
It was also noticed that Dopamine agonists such as Ropinirole were improving symptoms.
It seemed that Sonny was on to something after all.
Fast forward to 2015, and I had begun trying to pull the PSSD community closer to this connection between these observations.
(Terms in the following section might be confusing for new readers. My video explains each in detail)
In the Raphe Nuclei (RN), the 5HT1A receptor acts as a presynaptic somatodendritic autoreceptor. At the ends of its projections in the in the hippocampus, frontal cortex, and hypothalamus, it functions a presysnaptic autoreceptor and a postsynaptic heteroreceptor (Sotelo et al., 1990; Burnet et al., 1995; Riad et al., 2000). When more Serotonin (5-HT) is found in the synapses in the RN, binding of autoreceptors inhibits for the release of 5-HT in the projections of RN neurons (Koek et al., 1998; Gobbi et al., 2001). In this manner, 5-HT1A autoreceptors work as an effective regulator of 5-HT levels in the brain (Bang et al., 2012). Decreased 5-HT transmission has long been associated with MDD (Van Praag et al. 1970) and it is thought that the RN is where SSRI antidepressants exhibit their therapeutic effects. It then comes as little surprise that the 5-HT1A has been heavily implicated in effective clinical treatment of depression and anxiety. SSRIs are believed to block 5-HT reuptake by binding to SERT (5-HTT) and reducing its reuptake abilities (Murphy et al., 2004). If this was the only result, increased somatodendritic and terminal autoreceptor binding would inhibit release of 5-HT into the synapse: Resulting in no increased 5-HT levels. Through a process that is still unknown, serotonin transmission is eventually enhanced by “desensitization” of both the somatodendritic and terminal autoreceptors (Chaput et al., 1985), allowing synaptic 5-HT to accumulate in the synapse. This accounts for the characteristic 4-8 week delay between treatment origins and therapeutic relief (Gartside et al., 1995; Blier, 2010; Richardson-Jones et al., 2010). 5-HT and 5-HT1A agonist binding on the presynaptic autoreceptor inhibits 5-HT activity by hyperpolarizing the neuronal membrane (Penington and Fox, 1994). Presynaptic 5-HT1A receptors are preferentially desensitized by chronic SSRI treatment while postsynaptic receptors are not (Pineyro and Blier, 1999). This preferential presynaptic desensitization is also seen after chronic administration of 5-HT1A agonists (Blier and de Montigny, 1994). 5-HT1B/1D autoreceptor agonists have shown less inhibitory action in cells treated chronically with low dose Fluvoxamine (Blier and de Montigny, 1983).
This model explains the widespread negative sexual and emotional changes that many people with PSSD report. Increased synaptic levels of Serotonin at RN projections would lead to more post-synaptic 5-HT receptor binding. Activation of post-synaptic 5-HT receptors inhibits the release of dopamine (DA) (Montgomery et al., 1991). Synaptic DA levels have been shown to have their activity and firing rate reduced after the administration of Escitalopram (a common SSRI antidepressant) for as little as two days (Dremencov et al., 2009). This suggests that there are several 5-HT receptors and autoreceptors that play a role in PSSD. With each SSRI likely affecting specific receptors differently. Dr. Dremencov observed that administration of a 5-HT2C antagonist completely reversed this DA inhibition in the VTA (Fig. 1). It is well known that Dopamine plays a critical role in pleasure and reward: Especially in the sexual response. A decrease in DA activity and firing rate could explain many of the symptoms associated with PSSD. Further, DA D2 binding has been shown to inhibit the secretion of Prolactin by the pituitory gland (Ben-Jonathan et al., 2001). Increased Prolactin levels are shown to negatively impact male sexual drive and ability, and play a role in the refractory period (Haake et al., 2003) (This can be seen as Hyperprolactinemia in some patients on D2 antagonists for the treatment of Schizophrenia). Because of these downstream implications of desensitization of the 5-HT1A Autoreceptor, it is very common to see sexual dysfunction in SSRI patients. However, this dysfunction is relieved in nearly all cases after the cessation of medication. Why then, do we see thousands of antidotal reports of sexual dysfunction after treatment has ceased? Even in the absence of residual mental illness? Male mice who had mothers on SSRIs showed a permanent decrease in sexual drive (Gouvêa et al., 2008) Recently there have been new studies that are reiterating what people suffering from PSSD already know (Sheetrit et al., 2015) (Farnsworth et al., 2009) (Stinson, 2009) (Waldinger et al., 2015) (Leiblum et al., 2008) (Bolton et al., 2006) (Csoka et al., 2006), sexual side effects can remain after treatment.
– Ghost (2015)
Once the PSSD community had closed in on a mechanism that explained a plausible mechanism for PSSD symptoms, there was debate on what was causing 5-HT1A autoreceptor desensitization.
I spent a lot of time thinking about this in 2015.
What could be happening downstream of the receptor?
A Deeper Look at the 5-HT1A Autoreceptor
Could lowering the density of autoreceptors be causing our symptoms?
5-HT1A/Gene Coding related research
I was focusing on any part of the 5-HT1A autoreceptor pathway that could explain the lack of responsively that we knew was seen in SSRI treatment, and whose activity we expected to be present in PSSD.
In 2016 I spent a considerable amount of time looking at G-Protein Inwardly-Rectifying K+ (GIRK) channels.
The seven 5-HT receptor families (5-HT1-7) can be divided into three major subgroups depending on which G protein signaling pathway they activate. 5-HT1 receptors (Ex: 5-HT1A) couple mainly to the Gi/o pathway, 5-HT4–7 receptors couple to the Gs pathway, and 5-HT2 receptors activate the Gq pathway. 5HT3 receptors are inotropic ligand-gated ion channels, and therefore aren’t G-Coupled Protein Receptors (GPCRs).
5-HT induces hyperpolarization by activating 5-HT1A autroreceptors whose Gi/o alpha subunit activates GIRK channels located within the presynaptic membrane (Innis and Aghajian, 1987) (Bayliss, 1997) (Katayama, 1997). In the DRN, GABAB receptors use the same intracellular G-protein pathway as 5-HT1A autroreceptors: though coupling to pertussis-toxin-sensitive G-Proteins (Innis and Aghajian, 1987). Chronic treatment with the SSRI fluvoxamine reduces both 5-HT1A autoreceptor and GABAB receptor-mediated GIRK currents (Cornelisse et al., 2007). This suggests that desensitization of 5-HT1A autoreceptors by SSRI treatment occurs downstream of the receptor, and with a mechanism shared with GABAB receptors.
In this literature review, I propose a G-Protein model of 5-HT1A autoreceptor desensitization occurring downstream of the receptor through GIRK channels that explains this autoreceptor desensitization. The clinical implications of understanding 5-HT1A autoreceptor desensitization are very important in creating new-age antidepressant treatments that quickly and effectively raise 5-HT levels in patients who either cannot wait for treatments to work, or who are treatment resistant to current SSRI medications. Additionally, persistant sexual changes occasionally occur in both animals and humans treated with SSRI antidepressants. Male mice that had mothers on SSRIs showed a permanent decrease in sexual drive (Gouvêa et al., 2008). Recent studies suggest that these lingering side effects are also seen in humans (Sheetrit et al., 2015) (Farnsworth et al., 2009) (Stinson, 2009) (Waldinger et al., 2015) (Leiblum et al., 2008) (Bolton et al., 2006) (Csoka et al., 2006). The implications of this persistent Post-SSRI Sexual Dysfunction (PSSD) have widespread emotional, social, and sexual implications in patients, and often lead to them feeling alienated from their peers and loved ones (Stinson, 2013). It has been hypothesized that PSSD is a result of persistent 5-HT1A desensitization after SSRI treatment has been stopped (Ghost, 2016). Therefore, understanding 5-HT1A autoreceptor desensitization could help develop treatment plans for patients with PSSD.
GIRK Channels
Under physiological conditions the resting membrane potential of a typical neuron is positive to EK, and the small outward K+ current through GIRK channels decreases the excitability of a neuron. Different types of neurotransmitters, such as acetylcholine, dopamine, opioids, serotonin, somatostatin, adenosine and GABA, activate these channels by stimulating their cognate G protein coupled receptors (GPCRs), which in turn couple specifically to pertussis toxin (PTX) sensitive heterotrimeric G proteins that activate GIRK channels (4). Strong evidence supports the conclusion that Gβγ dimers released from PTX-sensitive (Gαi/Gαo) G proteins bind directly to GIRK channels causing them to open (5-9). Conformational changes induced by binding of Gi/o Gβγ dimers control the opening of GIRK channels (CITE). Mammals express four types of GIRK channel subunits (GIRK1-4) (Lüscher and Slesinger, 2010). However, only GIRK1-3 are common within the brain (Wickman et al., 2000). These subunits assemble into tetrameric channels (3,19-23). GIRK2 plays the largest role in generation of GIRK current in neurons (TABLE 1). GIRK1/2 heterotetramers are the predominant form of GIRK channels in the brain (19). GIRK3 may play a regulatory role in GIRK signaling in the brain (Wickman et al., 2000). Several GIRK channel modulators are known to alter their activity. Na+(44-45) and Ethanol (46-48) appear to stimulate GIRK channels through specific binding sites on the channels. Additionally, phosphorylation by PKA and PKC kinases modulate GIRK channel function (49-57). PKC-dependent phosphorylation decreases while PKA-dependent phosphorylation enhances channel activity. Finally, levels of the membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2), can regulate the activity of GIRK channels (58-60).– Ghost (2016)
2 years of research had shown me that the 5-HT1A autoreceptor was playing an essential role in PSSD, but I didn’t know why it was stuck in this desensitized state.
While I believe this model is at the heart of why PSSD symptoms are so devastating for sexual dysfunction, as well as how changes could cause theses symptoms, I knew that there was more to the story. Somewhere upstream of the 5HT1A autoreceptor there was something causing this persistent desensitization.
Answering the initial questions opened up substantially more for the PSSD community as we moved forward.
