mattyb post_id=5562 time=1512135500 user_id=95 said:
namaste post_id=5543 time=1512086285 user_id=50 said:
Good stuff as always, Ghost.
I was curious if you've ever looked into the effect that antidepressants have on synapse growth, especially in the adolescent brain. In the review paper "Antidepressants and Adolescent Brain Development" the authors state:
Unsurprisingly, there are indications that antidepressant treatment during adolescence may cause lasting perturbations in normal developmental processes, altering dendritic spine development and synaptic outgrowth. For example, chronic treatment of rats with fluoxetine from P21 until P42 prevented the normal age-related increase in dendritic spine density in the CA1 region of the hippocampus.
Is there anything in the literature that might tie this together with the mineral/hormone theory? Is there any possibility that this retardation in development/growth is reversible? Sometimes I wonder if those of us who took these medications at a younger age have issues beyond mineral imbalances. Unless, of course, all of this is interrelated.
The authors also discuss 5-HTT and receptor density:
Two separate groups have investigated SSRI-induced changes in 5-HTT density in various regions of the adolescent rat brain following chronic SSRI administration. In contrast to the often-found decrease or null effect on 5-HTT binding density observed in adults, both studies report regional increases in 5-HTT binding in their younger cohort.
Interestingly, Wegerer et al. provide evidence that the regional increases in 5-HTT density endure into adult life,[105] in contrast to the rapid recovery of SSRI-induced 5-HTT downregulation in adults.[119] Lasting changes in 5-HTT may explain the increases in anxiety-like behavior and sexual dysfunction observed in adult rats that have been treated with SSRIs during adolescence
@mattyb @gbolduev
I think spending too much time oh 5-htt is a waste of time. It is a receptor, therefore it's density and behavior is subject to alterations from other more intrinsic stimulus. It's a sodium dependent transporter that's also reliant on cytosolic potassium and extracellular sodium and chloride, it's no surprise PSSD could upregulate it's density since PSSD is alkalosis. Less available minerals = more receptors required. High cell potassium and low Na+ and Cl- would change the density phenotype. Low serum Na+ and Cl- means less "prepping" of serotonin which decreases the rate of binding to the receptor, while high cytosolic K+ means faster recycling of the receptor for further binding.
SSRIs downregulate Na/K ATPase. This will disturb distribution of ions.
SERT is essential becuase it is one of a few things that we know from the literature that SSRIs can decrease. PSSD being alkalosis is conjecture, and that's not really the consensus of the community. Yes, it's a theory, but if we'd have figured out the exact cause of PSSD, we wouldn't be here.
You are right that SERT is Na+ dependent, but SSRIs decrease SERT, and not increase it. This is pretty specific to SSRIs, and that's (imo) why you don't see PSSD from other AD drugs really.
Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level.
https://www.ncbi.nlm.nih.gov/pubmed/10575045
Effects of the antidepressant fluoxetine on the subcellular localization of 5-HT1A receptors and SERT
http://rstb.royalsocietypublishing.org/content/367/1601/2416.short
" 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
http://www.jneurosci.org/content/22/15/6766.full
Antidepressant-induced internalization of the serotonin transporter in serotonergic neurons
http://www.fasebj.org/content/22/6/1702.full
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.
http://www.ncbi.nlm.nih.gov/pubmed/11245702
"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)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118509/
“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: https://pssdlab.wordpress.com/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.
...
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.
