@Ghost what are your thoughts on this?
5HT1A autoreceptor desensitization is your theory right? I'm not sure how the rest of 5HT1A receptors are affected, but presumably they'd be downregulated too? Desensitized autoreceptors -> more serotonin released -> receptors overloaded -> more desensitization.
Yea that's been the theory for the past few years. I think that 5-HT1A is desensitized, but there needs to be something keeping it that way. I think that is SERT down-regulation, which I believe could be from Progesterone blocking Estrogen from protecting SERT density. This would be sufficient to desensitize 5-HT1A and cause dopamine (hence, sexual) problems. I posted this a few weeks ago, but I'll tag it along again in case it helps.
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SERT is essential becuase it is one of a few things that we know from the literature that SSRIs can decrease.
Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level.
Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. - PubMed - NCBI
Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT
Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT
" SERT density in the CA3 region of the hippocampus of the same rats, assessed by quantitative autoradiography with tritiated cyanoimipramine ([(3)H]CN-IMI), was decreased by 80-90% in SSRI-treated rats but not in those treated with phenelzine or DMI."
Serotonin Clearance In Vivo Is Altered to a Greater Extent by Antidepressant-Induced Downregulation of the Serotonin Transporter than by Acute Blockade of this Transporter
Serotonin Clearance In Vivo Is Altered to a Greater Extent by Antidepressant-Induced Downregulation of the Serotonin Transporter than by Acute Blockade of this Transporter
Antidepressant-induced internalization of the serotonin transporter in serotonergic neurons
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But why does this matter? Well it matter because it describes 5-HT1A AR desensitization. I don't think that's been studied in Fin, but it should be, because I'd bet money that it impacts the 5-HT1A AR if it's as close to PSSD as we think it is.
If you knock out SERT in mice, you get desensitized 5-HT1A ARs.
Functional consequences of 5-HT transporter gene disruption on 5-HT(1a) receptor-mediated regulation of dorsal raphe and hippocampal cell activity.
Functional consequences of 5-HT transporter gene disruption on 5-HT(1a) receptor-mediated regulation of dorsal raphe and hippocampal cell activity. - PubMed - NCBI
"These data showed that 5-HTT gene knock-out induced a marked desensitization of 5-HT(1A) autoreceptors in the dorsal raphe nucleus without altering postsynaptic 5-HT(1A) receptor functioning in the hippocampus."
So the next question is: Does this matter, and does it last past taking the drug. The answer is YES. The changes to SERT that happen if you give and SSRI to young animal last even after the drug has stopped. So we know that SERT is changed, that is old news. The reason that it's so important is because we can use that to find out what is wrong. I agree with you that there isn't much more to study on SERT at this time, but the reason that we can even have the mineral theory make any sense for PSSD is because it ties us to Progesterone (and other sex hormones), which ties us to SERT, which we know is a target.
(Maciag et al., 2013)
Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry
“Here, we show that chronic neonatal (postnatal days 8–21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors.”
Ok so the final question is, why does 5-HT1A AR desensitization matter? Well it explains our symptoms. The minerals themselves don't explain our symptoms, they just explain how we got to the hormonal and neurological states that do.
If you want to read some of the early work by Sonny at the PSSD forum, I've saved that all here:
5-HT1A Desensitization Theory
I know that there are a lot of links in this reply, and I know they don't always get clicked so I'll paste something below that I wrote in 2015. This is why 5-HT1A AR desensitization matters. It ties into Prolactin and Dopamine and Oxytocin...So many of the things that are messed up in PFS/PSSD.
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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.
