My theory - Etiology of PSSD and potential treatment.
Posted: Wed Jul 14, 2021 1:51 pm
This theory is outdated.
Hi, i already created 2 topics about PSSD etiology but i will repeat some of the informations, because this will be complementary topic.
PSSD is iatrogenic dysfunction where brain homeostasis is dysfunctional due to the previous taking of the SSRI. It manifests in sexual symptoms but not only, it also includes things like anhedonia, lack of imagination, lack of emotions, low energy. Symptoms appear first during taking SSRIs and do persist after discontinuation. Now let's have a look at what SSRIs really do to our brains:
The most known effect SSRIs induce in our brain is downregulation of presynaptic 5-HT1A receptor in raphe nuclei, which was previously thought to mediate the effects of the SSRI. The idea is that dysregulated (too much)serotonin flow inhibits dopamine flow in the brain and dopamine is known to enhance sexual function, thus reduced dopamine=reduced sexual function. But this idea does have major flaws. Now i will tell you why PSSD is not too much serotonin:
1. Neither 5-HT1A agonists or antagonists help rebalance homeostasis, they may induce crash or help temporarily but they do not reverse the changes and they do not help relief PSSD in a major way.
2. Dopamine precursors, agonists and reuptake inhibitors do not help relieve PSSD symptoms in a way that would indicate that the problem lies in dopamine transmission.
3. It is known that the effect of the SSRI is also mediated by 5-HT2B receptor, while it's function is poorly understood it is known that this receptor is involved in more pleiotropic way in neural transmission than 5-HT1A - which would explain sexual side effects but not the others.
4. 5-HT2B is necessary for SSRIs to work:
"We demonstrate for the first time that 5-HT2B receptors are expressed by serotonergic neurons of the raphe nuclei, which is consistent with a positive regulatory role for these receptors in synaptic 5-HT homeostasis.
""Based on the results presented herein, the activation of 5-HT2B receptors is necessary for acute and chronic SSRI actions, and chronic stimulation with a 5-HT2B receptor agonist is sufficient to mimic SSRI effects in wild type mice."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
5. Chronic 5-HT2B agonism mimics SSRIs effect in novelty-suppressed feeding in mices:
"Direct chronic activation of 5-HT2B receptors appears sufficient to induce chronic SSRI-like effects in the NSF test." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
6. Blocking 5-HT2B receptor block SSRIs effect:
"Altogether, these results confirm that a lack of functional 5-HT2B receptors is sufficient to abolish the chronic actions of SSRIs at the cellular level."
"5-HT2B receptors are required for SSRI antidepressant acute and long-term effects, possibly by presynaptic modulation of extracellular 5-HT levels."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
7. Every SSRI is 5-HT2B agonist:
"Fluoxetine and all other SSRIs are 5-HT2B Agonists - Importance for their Therapeutic Effects" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207076/
8. SSRIs changes the way 5-HT2B receptor on astrocytes works, in effect this receptor no longer does the work it's supposed to do:
"In contrast editing of the receptor was obvious after 3 days of treatment, and after 7 days the edited receptor no longer responded to serotonin by an increase in activity measured as the ability of serotonin to evoke release of 3H-inositol phosphate (IP) from labeled IP3 or phosphorylation of ERK1/2." https://www.hindawi.com/journals/jst/2014/593934/
9. Another role of 5-HT2B receptor:
5-HT2B "Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca2+ ions from intracellular stores (PubMed:8143856, PubMed:8078486, PubMed:8882600, PubMed:18703043, PubMed:23519215, PubMed:28129538)."
10. After inositol connects with it's receptor IP3, it raises intracellular calcium, which produces calcium eflux from endoplasmic reticulum, since SSRIs induce changes in 5-HT2B receptor it no longer is able to evoke release of inositol phosphate, it does not raise intracellular Ca2+ and whole process is disrubted.
11. SSRI's at first induce Ca+2 release which explain why some people benefit from reinstating SSRIs at first, but after continous intake SSRIs abolish Ca2+ increase and that is the moment where sexual side effects kick in.
"In contrast to the ability of fluoxetine (and many transmitters) to acutely cause an increase Ca+2 , chronic treatment with fluoxetine rapidly abolishes or reduces transmitter and fluoxetine-induced Ca+2 increase." https://www.hindawi.com/journals/jst/2014/593934/
12. Current data states that astrocytes play dominant role in depression and SSRIs change how astrocytes work:
"They may play a key role in the antidepressant mechanism of SSRIs. Given the dominant role ascribed to neurons in the mechanisms of SSRIs and other psychiatric drugs it may appear surprising that studies found the major chronic impact of SSRIs in the fluoxetine-treated mice to be on astrocytes. However they are consistent with the growing evidence for a major role of these cells in major depression and its therapy studied in patients (Abdallah et al., 2014a,b), postmortem brain (Rajkowska and Stockmeier, 2013) or in models of this disease (Gosselin et al., 2009; Banasr et al., 2010)." https://www.frontiersin.org/articles/10 ... 00025/full
13. Two most succesfull supplements (inositol and SJW) in one way or another work via IP3. St john wort has direct affinity for IP3 receptor, and myo-inositol via metabolism changes in the body is converted to phosphatidylinositol.
It [St john wort] also acts as a receptor antagonist at adenosine, benzodiazepine, GABA-A, GABA-B, and inositol triphosphate receptors, which regulate action potentials caused by neurotransmitters (Chavez and Chavez 1997; Jellin et al. 2002).
PSSD is due to low intracellular Ca2+, because of 5-HT2B editing, SOC channels downregulation, VGCCs meddling, deactivating IP3 and RyR3 mediated Ca2+ release.
The rest is debatable.
15. People are not cured by inositol because they have low intracellular magnesium, which is necessary for phosphatidylinositol 3-kinase to work(it is also possible that inositol lowers magnesium levels):
"TRPM7 (Nadler et al., 2001) and TRPM6 (Schlingmann et al., 2002) were the first channels identified as being able to transport Mg2+ into mammalian cells. While Fleig and her group (Nadler et al., 2001) reported a preferential Mg2+ permeation through the LTRPC7 channel (i.e. TRPM7 based on the current nomenclature), genetic analysis (Schlingmann et al., 2002) indicated, more or less at the same time, that TRPM6, another member of the melastatin subfamily of TRP channels, exhibits a selective Mg2+ permeation."
"Interestingly, TRPM7 activation only takes place in the presence of a physiological cellular [Mg2+]i, whereas reducing this concentration below
its physiological level with EDTA- AM results in a PLC-mediated inactivation of TRPM7 activity, most likely via PIP2 depletion (Langeslag et al., 2007)."\
"The interaction between TRPM7 and phosphatidyl-inositol metabolites is further supported by the observation that TRPM7 is required for a sustained phosphoinositide-3-kinase signalling in lymphocytes
(Sahni and Scharenberg, 2008). In the presence of a physiological concentration of extracellular Mg2+, TRPM7-deficient cells rapidly down-regulate their rate of growth as a result of a
signalling deactivation downstream PI3-Kinase (Sahni and Scharenberg, 2008), the phenotype being rescued by supplementing the culture medium with Mg2+ (Sahni and Scharenberg, 2008)."
more info on the role of magnesium:
"Inhibition of IP3- induced Ca2+ release from the endoplasmic reticulum, chelation of cytosolic Ca2+, or inhibition of Ca2+ entry at the plasma membrane level all result in the complete inhibition of Mg2+ extrusion from the hepatocytes"
"in the absence of PKC activation or following RACK1 over-expression, RACK1 can bind to TRPM6, and possibly TRPM7, at the level of the kinase domain and inhibit the channel activity"
"Protein kinase C activation is only part of the integral response of hormones like angiotensin-II or vasopressin. The interaction of these hormones with their receptor, in fact, activates phospholipase C which,
in turn hydrolyses PIP2 to generate diacylglycerol (DAG) and IP3. In turn, these two molecules activate protein kinase C and IP3 receptor in the ER, respectively. Activation of the latter receptor results in a marked
but transient increase in cytosolic Ca2+, and in a more sustained entry of Ca2+ through the capacitative Ca2+ entry mechanism. Hence, Ca2+ signalling is an integral component of the cellular response elicited by these hormones.
Yet, the contribution of this second messenger in mediating Mg2+ accumulation is poorly defined. Liver cells loaded with Bapta-AM, which effectively chelates cytosolic Ca2+, are unable to extrude and accumulate Mg2+
following stimulation by phenylephrine and PMA, respectively (Romani et al., 1993b). The artificial increase in cytosolic Ca2+ elicited by thapsigargin administration also prevents Mg2+ accumulation (Romani et al., 1993b)
and actually induces a Mg2+ extrusion from the liver cell if applied for more than 3-5 min (Romani et al., 1993b; Fagan and Romani, 2001). Because of the different time-scale and amplitude of the changes in cellular Ca2+ and Mg2+ content
(Romani et al., 1993b), it is difficult to properly correlate these experimental variations. Cytosolic free Ca2+ transiently increases several orders of magnitude while cytosolic free Mg2+, which is already in the millimolar or submillimolar range,
increases by ~10-15% (Fatholahi et al., 2000) at the most, although in absolute terms this amount is far larger than the overall change in cytosolic Ca2+ mass."
"The experimental evidence that mammalian cells accumulate or extrude Mg2+ under a variety of experimental conditions suggests the presence of a sensor for the cytosolic Mg2+ concentration,
whereby the cell would operate accordingly either extruding the excess cation or accumulating it to restore the ‘set-point’. Compelling evidence for the presence of such a sensor mechanism is provided
by the observation that prolonged exposure to 0mM [Mg2+]o decreases cytosolic free Mg2+ concentration by approximately 50% in cardiac ventricular myocytes (Quamme and Rabkin, 1990),
MDKC (Quamme and Dai, 1990), or MDCT cells (Dai et al., 1997). The new cytosolic Mg2+ level is maintained as long as the cells are incubated in the presence of 0 mM [Mg2+]o,
but returns to the normal level as soon as [Mg2+]o is increased (Quamme and Rabkin, 1990; Quamme and Dai, 1990; Dai et al., 1997), in a frame of time that is directly proportional to the extracellular
Mg2+ concentration utilized (Quamme and Rabkin, 1990; Quamme and Dai, 1990; Dai et al., 1997). The process is prevented by the presence of the L-type Ca2+-channel inhibitors verapamil or nifedipine,
or La3+ in the extracellular milieu (Quamme and Rabkin, 1990). The absence of significant changes in cytosolic free Ca2+ concentration under these experimental conditions suggests a direct effect of these inhibitory agents
on the Mg2+ entry mechanism (Quamme and Rabkin, 1990). This observation led the authors to propose the operation of a specific Mg2+ channel in these cells, anticipating the identification of TRPM6 (Schlingmann et al., 2002)
and TRPM7 (Nadler et al., 2001) as specific Mg2+ channels."
source: https://www.ncbi.nlm.nih.gov/books/NBK507258/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896866/
https://www.tandfonline.com/doi/abs/10. ... 21.1929732
https://www.uniprot.org/uniprot/P41595
https://en.wikipedia.org/wiki/Calcium_channel
https://en.wikipedia.org/wiki/5-HT2B_receptor
https://link.springer.com/article/10.1007/BF01787021
https://academic.oup.com/icb/article/41/4/1009/2046729
https://journals.plos.org/plosone/artic ... ne.0206986
https://pubmed.ncbi.nlm.nih.gov/16688720/
https://www.jbc.org/article/S0021-9258(19)74306-3/pdf
https://onlinelibrary.wiley.com/doi/ful ... /cns.13634
https://onlinelibrary.wiley.com/doi/ful ... 10.06795.x
https://link.springer.com/article/10.10 ... 20-00569-0
https://www.ncbi.nlm.nih.gov/books/NBK92750/
https://www.nature.com/articles/tpj201124
https://www.tandfonline.com/doi/abs/10. ... 21.1929732
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556207/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539076/
https://web.williams.edu/imput/synapse/pages/IIA1.htm
https://pubmed.ncbi.nlm.nih.gov/24854234/
https://www.hindawi.com/journals/jst/2014/593934/
https://www.ahajournals.org/doi/full/10 ... 0.25714.D9
https://hal.archives-ouvertes.fr/hal-01 ... rt0206.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670669/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
https://pubmed.ncbi.nlm.nih.gov/9760040/
https://pubmed.ncbi.nlm.nih.gov/15629140/
https://journals.physiology.org/doi/ful ... 00006.2016
https://www.sciencedirect.com/science/a ... 3418306225
This theory contains outdated information
Hi, i already created 2 topics about PSSD etiology but i will repeat some of the informations, because this will be complementary topic.
PSSD is iatrogenic dysfunction where brain homeostasis is dysfunctional due to the previous taking of the SSRI. It manifests in sexual symptoms but not only, it also includes things like anhedonia, lack of imagination, lack of emotions, low energy. Symptoms appear first during taking SSRIs and do persist after discontinuation. Now let's have a look at what SSRIs really do to our brains:
The most known effect SSRIs induce in our brain is downregulation of presynaptic 5-HT1A receptor in raphe nuclei, which was previously thought to mediate the effects of the SSRI. The idea is that dysregulated (too much)serotonin flow inhibits dopamine flow in the brain and dopamine is known to enhance sexual function, thus reduced dopamine=reduced sexual function. But this idea does have major flaws. Now i will tell you why PSSD is not too much serotonin:
1. Neither 5-HT1A agonists or antagonists help rebalance homeostasis, they may induce crash or help temporarily but they do not reverse the changes and they do not help relief PSSD in a major way.
2. Dopamine precursors, agonists and reuptake inhibitors do not help relieve PSSD symptoms in a way that would indicate that the problem lies in dopamine transmission.
3. It is known that the effect of the SSRI is also mediated by 5-HT2B receptor, while it's function is poorly understood it is known that this receptor is involved in more pleiotropic way in neural transmission than 5-HT1A - which would explain sexual side effects but not the others.
4. 5-HT2B is necessary for SSRIs to work:
"We demonstrate for the first time that 5-HT2B receptors are expressed by serotonergic neurons of the raphe nuclei, which is consistent with a positive regulatory role for these receptors in synaptic 5-HT homeostasis.
""Based on the results presented herein, the activation of 5-HT2B receptors is necessary for acute and chronic SSRI actions, and chronic stimulation with a 5-HT2B receptor agonist is sufficient to mimic SSRI effects in wild type mice."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
5. Chronic 5-HT2B agonism mimics SSRIs effect in novelty-suppressed feeding in mices:
"Direct chronic activation of 5-HT2B receptors appears sufficient to induce chronic SSRI-like effects in the NSF test." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
6. Blocking 5-HT2B receptor block SSRIs effect:
"Altogether, these results confirm that a lack of functional 5-HT2B receptors is sufficient to abolish the chronic actions of SSRIs at the cellular level."
"5-HT2B receptors are required for SSRI antidepressant acute and long-term effects, possibly by presynaptic modulation of extracellular 5-HT levels."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
7. Every SSRI is 5-HT2B agonist:
"Fluoxetine and all other SSRIs are 5-HT2B Agonists - Importance for their Therapeutic Effects" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207076/
8. SSRIs changes the way 5-HT2B receptor on astrocytes works, in effect this receptor no longer does the work it's supposed to do:
"In contrast editing of the receptor was obvious after 3 days of treatment, and after 7 days the edited receptor no longer responded to serotonin by an increase in activity measured as the ability of serotonin to evoke release of 3H-inositol phosphate (IP) from labeled IP3 or phosphorylation of ERK1/2." https://www.hindawi.com/journals/jst/2014/593934/
9. Another role of 5-HT2B receptor:
5-HT2B "Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca2+ ions from intracellular stores (PubMed:8143856, PubMed:8078486, PubMed:8882600, PubMed:18703043, PubMed:23519215, PubMed:28129538)."
10. After inositol connects with it's receptor IP3, it raises intracellular calcium, which produces calcium eflux from endoplasmic reticulum, since SSRIs induce changes in 5-HT2B receptor it no longer is able to evoke release of inositol phosphate, it does not raise intracellular Ca2+ and whole process is disrubted.
11. SSRI's at first induce Ca+2 release which explain why some people benefit from reinstating SSRIs at first, but after continous intake SSRIs abolish Ca2+ increase and that is the moment where sexual side effects kick in.
"In contrast to the ability of fluoxetine (and many transmitters) to acutely cause an increase Ca+2 , chronic treatment with fluoxetine rapidly abolishes or reduces transmitter and fluoxetine-induced Ca+2 increase." https://www.hindawi.com/journals/jst/2014/593934/
12. Current data states that astrocytes play dominant role in depression and SSRIs change how astrocytes work:
"They may play a key role in the antidepressant mechanism of SSRIs. Given the dominant role ascribed to neurons in the mechanisms of SSRIs and other psychiatric drugs it may appear surprising that studies found the major chronic impact of SSRIs in the fluoxetine-treated mice to be on astrocytes. However they are consistent with the growing evidence for a major role of these cells in major depression and its therapy studied in patients (Abdallah et al., 2014a,b), postmortem brain (Rajkowska and Stockmeier, 2013) or in models of this disease (Gosselin et al., 2009; Banasr et al., 2010)." https://www.frontiersin.org/articles/10 ... 00025/full
13. Two most succesfull supplements (inositol and SJW) in one way or another work via IP3. St john wort has direct affinity for IP3 receptor, and myo-inositol via metabolism changes in the body is converted to phosphatidylinositol.
It [St john wort] also acts as a receptor antagonist at adenosine, benzodiazepine, GABA-A, GABA-B, and inositol triphosphate receptors, which regulate action potentials caused by neurotransmitters (Chavez and Chavez 1997; Jellin et al. 2002).
PSSD is due to low intracellular Ca2+, because of 5-HT2B editing, SOC channels downregulation, VGCCs meddling, deactivating IP3 and RyR3 mediated Ca2+ release.
The rest is debatable.
15. People are not cured by inositol because they have low intracellular magnesium, which is necessary for phosphatidylinositol 3-kinase to work(it is also possible that inositol lowers magnesium levels):
"TRPM7 (Nadler et al., 2001) and TRPM6 (Schlingmann et al., 2002) were the first channels identified as being able to transport Mg2+ into mammalian cells. While Fleig and her group (Nadler et al., 2001) reported a preferential Mg2+ permeation through the LTRPC7 channel (i.e. TRPM7 based on the current nomenclature), genetic analysis (Schlingmann et al., 2002) indicated, more or less at the same time, that TRPM6, another member of the melastatin subfamily of TRP channels, exhibits a selective Mg2+ permeation."
"Interestingly, TRPM7 activation only takes place in the presence of a physiological cellular [Mg2+]i, whereas reducing this concentration below
its physiological level with EDTA- AM results in a PLC-mediated inactivation of TRPM7 activity, most likely via PIP2 depletion (Langeslag et al., 2007)."\
"The interaction between TRPM7 and phosphatidyl-inositol metabolites is further supported by the observation that TRPM7 is required for a sustained phosphoinositide-3-kinase signalling in lymphocytes
(Sahni and Scharenberg, 2008). In the presence of a physiological concentration of extracellular Mg2+, TRPM7-deficient cells rapidly down-regulate their rate of growth as a result of a
signalling deactivation downstream PI3-Kinase (Sahni and Scharenberg, 2008), the phenotype being rescued by supplementing the culture medium with Mg2+ (Sahni and Scharenberg, 2008)."
more info on the role of magnesium:
"Inhibition of IP3- induced Ca2+ release from the endoplasmic reticulum, chelation of cytosolic Ca2+, or inhibition of Ca2+ entry at the plasma membrane level all result in the complete inhibition of Mg2+ extrusion from the hepatocytes"
"in the absence of PKC activation or following RACK1 over-expression, RACK1 can bind to TRPM6, and possibly TRPM7, at the level of the kinase domain and inhibit the channel activity"
"Protein kinase C activation is only part of the integral response of hormones like angiotensin-II or vasopressin. The interaction of these hormones with their receptor, in fact, activates phospholipase C which,
in turn hydrolyses PIP2 to generate diacylglycerol (DAG) and IP3. In turn, these two molecules activate protein kinase C and IP3 receptor in the ER, respectively. Activation of the latter receptor results in a marked
but transient increase in cytosolic Ca2+, and in a more sustained entry of Ca2+ through the capacitative Ca2+ entry mechanism. Hence, Ca2+ signalling is an integral component of the cellular response elicited by these hormones.
Yet, the contribution of this second messenger in mediating Mg2+ accumulation is poorly defined. Liver cells loaded with Bapta-AM, which effectively chelates cytosolic Ca2+, are unable to extrude and accumulate Mg2+
following stimulation by phenylephrine and PMA, respectively (Romani et al., 1993b). The artificial increase in cytosolic Ca2+ elicited by thapsigargin administration also prevents Mg2+ accumulation (Romani et al., 1993b)
and actually induces a Mg2+ extrusion from the liver cell if applied for more than 3-5 min (Romani et al., 1993b; Fagan and Romani, 2001). Because of the different time-scale and amplitude of the changes in cellular Ca2+ and Mg2+ content
(Romani et al., 1993b), it is difficult to properly correlate these experimental variations. Cytosolic free Ca2+ transiently increases several orders of magnitude while cytosolic free Mg2+, which is already in the millimolar or submillimolar range,
increases by ~10-15% (Fatholahi et al., 2000) at the most, although in absolute terms this amount is far larger than the overall change in cytosolic Ca2+ mass."
"The experimental evidence that mammalian cells accumulate or extrude Mg2+ under a variety of experimental conditions suggests the presence of a sensor for the cytosolic Mg2+ concentration,
whereby the cell would operate accordingly either extruding the excess cation or accumulating it to restore the ‘set-point’. Compelling evidence for the presence of such a sensor mechanism is provided
by the observation that prolonged exposure to 0mM [Mg2+]o decreases cytosolic free Mg2+ concentration by approximately 50% in cardiac ventricular myocytes (Quamme and Rabkin, 1990),
MDKC (Quamme and Dai, 1990), or MDCT cells (Dai et al., 1997). The new cytosolic Mg2+ level is maintained as long as the cells are incubated in the presence of 0 mM [Mg2+]o,
but returns to the normal level as soon as [Mg2+]o is increased (Quamme and Rabkin, 1990; Quamme and Dai, 1990; Dai et al., 1997), in a frame of time that is directly proportional to the extracellular
Mg2+ concentration utilized (Quamme and Rabkin, 1990; Quamme and Dai, 1990; Dai et al., 1997). The process is prevented by the presence of the L-type Ca2+-channel inhibitors verapamil or nifedipine,
or La3+ in the extracellular milieu (Quamme and Rabkin, 1990). The absence of significant changes in cytosolic free Ca2+ concentration under these experimental conditions suggests a direct effect of these inhibitory agents
on the Mg2+ entry mechanism (Quamme and Rabkin, 1990). This observation led the authors to propose the operation of a specific Mg2+ channel in these cells, anticipating the identification of TRPM6 (Schlingmann et al., 2002)
and TRPM7 (Nadler et al., 2001) as specific Mg2+ channels."
source: https://www.ncbi.nlm.nih.gov/books/NBK507258/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896866/
https://www.tandfonline.com/doi/abs/10. ... 21.1929732
https://www.uniprot.org/uniprot/P41595
https://en.wikipedia.org/wiki/Calcium_channel
https://en.wikipedia.org/wiki/5-HT2B_receptor
https://link.springer.com/article/10.1007/BF01787021
https://academic.oup.com/icb/article/41/4/1009/2046729
https://journals.plos.org/plosone/artic ... ne.0206986
https://pubmed.ncbi.nlm.nih.gov/16688720/
https://www.jbc.org/article/S0021-9258(19)74306-3/pdf
https://onlinelibrary.wiley.com/doi/ful ... /cns.13634
https://onlinelibrary.wiley.com/doi/ful ... 10.06795.x
https://link.springer.com/article/10.10 ... 20-00569-0
https://www.ncbi.nlm.nih.gov/books/NBK92750/
https://www.nature.com/articles/tpj201124
https://www.tandfonline.com/doi/abs/10. ... 21.1929732
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556207/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539076/
https://web.williams.edu/imput/synapse/pages/IIA1.htm
https://pubmed.ncbi.nlm.nih.gov/24854234/
https://www.hindawi.com/journals/jst/2014/593934/
https://www.ahajournals.org/doi/full/10 ... 0.25714.D9
https://hal.archives-ouvertes.fr/hal-01 ... rt0206.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670669/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
https://pubmed.ncbi.nlm.nih.gov/9760040/
https://pubmed.ncbi.nlm.nih.gov/15629140/
https://journals.physiology.org/doi/ful ... 00006.2016
https://www.sciencedirect.com/science/a ... 3418306225
This theory contains outdated information