From our Main Article here, we can see there is a multitude or reasonings, contributors, genetic changes and changes in individual proteins that lead to the onset of PSSD; Post-SSRI-Sexual-Dysfunction.
There are a few things to take into consideration.
-Chronic elevation of cortisol due to SSRI use, and prolactin increases as well as possibly estrogen, throw sex hormones off whack and thus this represents a major pathway in which PSSD occurs; TESTOSTERONE AND PROGESTERONE DEFICIENCY.
-There is a persistent de-sensitization of pre-synaptic 5-HT1A serotonin receptors, which renders this receptor less sensitive to serotonin activation or blockade, because these are autoreceptors; that normally act to inhibit serotonin release, as well as the release of dopamine, glutamate and acetylcholine - it is likely this reason that contributes to a hypodopaminergic state , then the postsynaptic receptors induce cortisol and prolactin release, lowering testosterone and dopamine further in both men and women. With serotonin now less on the presynaptic side, it floods both these postsynaptic receptors and all other available receptors that also have contractile or anti-sexual effects.
-5-HT2A/2C complex is reduced in terms of receptor expression, and the hypo-dopaminergic state induced by 5-ht1A dysfunction, furthers this issue , and since 5-ht2C receptor (but not 5-ht2A) initiates oxytocin-induced sexual response - there is a general oxytocin deficiency or response deficiency induced by the chronic downregulation of this complex.
-5-HT3/4 receptors are receiving too much serotonin due to the lessering of the other receptors, and these receptors are highly contractile and cause both overstimulation and prolactin increases; both of which will lower sexual functioning, in terms of both libido , state of mind and vascular enabling.
-Dopamine receptor expression is decreased, and due to excessive post-synaptic inhibition by serotonin at multiple now enabled subtypes, we have that issue as well as a HYPO GLUTAMATERGIC state ....glutamate and histamine, as well as dopamine, all play positive roles in sexual response....
5-HT1A,5-HT6,5-HT1B,5-HT1D, all lower glutamate, histamine, acetylcholine, dopamine etc....these receptors receive more activity due to the presynaptic de-sensitization of 5-ht1A's, and the downregulation of the type 2 serotonin complex.....
**DOWNREGULATION OF SEROTONIN TYPE 2 IS NOT BAD IN ITSELF, THOUGH THE 2C IS IN A WAY, WE SHOULDN'T WORK TO RESTORE EXPRESSION OF THESE, BUT RATHER, WORK TO , ON A BROAD LEVEL, PICK UP WHERE WE LEFT OFF**
Questions will always be made in terms of why dopamine agonists don't work for everyone, one would theorize they would help, but without looking at all factors, and fixing the hormonal issue if it applies, they won't work, because dopamine receptors are under expressional/tonic control by sex hormones, especially free testosterone.
In addition, the 5-ht1A issues, especially the postsynaptic activation of, causes the inhibition of penile erection directly, and will block the effects of dopamine agonists of erectile responses.
There are a few things to take into consideration.
-Chronic elevation of cortisol due to SSRI use, and prolactin increases as well as possibly estrogen, throw sex hormones off whack and thus this represents a major pathway in which PSSD occurs; TESTOSTERONE AND PROGESTERONE DEFICIENCY.
-There is a persistent de-sensitization of pre-synaptic 5-HT1A serotonin receptors, which renders this receptor less sensitive to serotonin activation or blockade, because these are autoreceptors; that normally act to inhibit serotonin release, as well as the release of dopamine, glutamate and acetylcholine - it is likely this reason that contributes to a hypodopaminergic state , then the postsynaptic receptors induce cortisol and prolactin release, lowering testosterone and dopamine further in both men and women. With serotonin now less on the presynaptic side, it floods both these postsynaptic receptors and all other available receptors that also have contractile or anti-sexual effects.
-5-HT2A/2C complex is reduced in terms of receptor expression, and the hypo-dopaminergic state induced by 5-ht1A dysfunction, furthers this issue , and since 5-ht2C receptor (but not 5-ht2A) initiates oxytocin-induced sexual response - there is a general oxytocin deficiency or response deficiency induced by the chronic downregulation of this complex.
-5-HT3/4 receptors are receiving too much serotonin due to the lessering of the other receptors, and these receptors are highly contractile and cause both overstimulation and prolactin increases; both of which will lower sexual functioning, in terms of both libido , state of mind and vascular enabling.
-Dopamine receptor expression is decreased, and due to excessive post-synaptic inhibition by serotonin at multiple now enabled subtypes, we have that issue as well as a HYPO GLUTAMATERGIC state ....glutamate and histamine, as well as dopamine, all play positive roles in sexual response....
5-HT1A,5-HT6,5-HT1B,5-HT1D, all lower glutamate, histamine, acetylcholine, dopamine etc....these receptors receive more activity due to the presynaptic de-sensitization of 5-ht1A's, and the downregulation of the type 2 serotonin complex.....
**DOWNREGULATION OF SEROTONIN TYPE 2 IS NOT BAD IN ITSELF, THOUGH THE 2C IS IN A WAY, WE SHOULDN'T WORK TO RESTORE EXPRESSION OF THESE, BUT RATHER, WORK TO , ON A BROAD LEVEL, PICK UP WHERE WE LEFT OFF**
Questions will always be made in terms of why dopamine agonists don't work for everyone, one would theorize they would help, but without looking at all factors, and fixing the hormonal issue if it applies, they won't work, because dopamine receptors are under expressional/tonic control by sex hormones, especially free testosterone.
In addition, the 5-ht1A issues, especially the postsynaptic activation of, causes the inhibition of penile erection directly, and will block the effects of dopamine agonists of erectile responses.
Psychopharmacology (Berl). 1992;108(1-2):47-50.
5-HT1A receptor agonists prevent in rats the yawning and penile erections induced by direct dopamine agonists.
Simon P1, Guardiola B, Bizot-Espiard J, Schiavi P, Costentin J.
Author information
Abstract
The new compound (+) S-20499, an amino chromane derivative (8[-4[N-(5-methoxychromane-3yl)N-propyl]aminobutyl] azaspiro[4-5] décane-7,9 dione), is a high affinity full 5-HT1A agonist. We have investigated its effects on dopaminergic transmission. (+) S-20499 displayed a 10(-M affinity for D2 dopamine (DA) receptors, 100 fold lower than for 5-HT1A receptors. The hypothermic effect of the drug was reversed by haloperidol in mice, suggesting that it behaves as a direct dopamine agonist. However, increasing doses of (+) S-20499 induced neither yawning nor penile erections, which constitute characteristic responses of direct DA agonists administered at low doses. In addition, (+) S-20499 prevented the apomorphine (100 micrograms/kg SC) induced yawning and penile erections. This inhibition appears to result from the stimulation of 5-HT1A receptors since it is an effect shared by both buspirone (from 5 mg/kg) and 8-OH-DPAT (from 0.10 mg/kg). In addition, when rats are treated with the 5-HT1A receptor antagonist tertatolol (2-5 mg/kg; SC), increasing doses of (+) S-20499 elicit the expected yawns and penile erections. It is concluded that the 5-HT1A agonist property opposes to that of D2 dopamine receptor stimulation with regard to yawning and penile erections.
PMID: 1357709 [PubMed - indexed for MEDLINE]
