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The KING of "PSSD" Research Articles; Total Exploration of All Aspects of Post SSRI Sexual Dysfunction

king pssd articles research total exploration all aspects pssd the king post ssri sexual dysfunction e.d

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#1 Area-1255

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Posted 30 November 2014 - 06:00 AM


It is an incredibly long-article, and the formatting changes would ruin the quality, I will post some key points as I can, but the main link is below. FEEL FREE TO COMMENT, LEAVE FEEDBACK!

 

http://area1255.blogspot.com/2014/11/insights-into-pssd-collection-of-data.html

 

 

PSSD is an immensely maddening, depressing and sometimes even psychologically and even physically debilitating; it is characterized by two main points. 

 
You have used anti-depressants in the past, specifically of the selective serotonin reuptake inhibitor (SSRI) class - see this page or read below to see which drugs fall in this category. 
You have one of or many of the serotonergic induced sexual deficits - which may be delayed ejaculation in men, lack of orgasm for both men and women,  severe erectile dysfunction or lack of arousal in women and dramatically reduced or even absent libido in either sex.
 
 
Drugs in this class (SSRI) include (trade names in parentheses): (Highlighted are common USA brands)
 
citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital)
dapoxetine (Priligy)
escitalopram (Lexapro, Cipralex, Seroplex, Esertia)
fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND))
fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox, Floxyfral)
paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc)
sertraline (Zoloft, Lustral, Serlain, Asentra, Tresleen)
 
 
 
 
Now this is going to be a long article, so bear with me. I would like to point out some major and minor (but relevant) differences between each drug. One of the most distinguishable traits of all SSRI's, with the exception only of those with a short half life (and these are used for other purposes) ~ is that each SSRI not only generally has a very long half-life, but also that each drug tends to have prominent effects on liver enzymes; generally CYP3A4 and CYP2C19 or cytochrome P450. The implications of this binding are many, one of the main problems here is that by these drugs binding to liver enzymes, depending on which one ~ there is a possibility of changing the breakdown of other drugs, or delaying their elimination - this can lead to amplified side-effects of other drugs and thus further causes physiological disturbances especially if the other drugs have even so much of a parallel in regards to their mechanism of action. 
 
 
Let's take the anti-depressant drug LUVOX aka fluvoxamine for example...this drug inhibits cytochrome P450(!). This is an enzyme involved with breakdown of drugs, as well as estrogen metabolism(See Here), consequently, drugs that inhibit this enzyme may increase the concentration of other drugs, such as blood pressure pills like metaprolol(TOPROL). In doing so, this is seen as a mechanism apart from it's primary mechanism, which is serotonin reuptake inhibition. Depending on the person, the inhibition of this enzyme may lead to estrogen deficiency or excess(R1)(R2)(R3). For some , excess may be more apparent, but it is also possible to have symptoms of high estrogen levels when indeed one has low levels, especially when on a drug like fluvoxamine (luvox) the reason for this is because elevated prolactin can mimic the effects of elevated estrogen, and luvox and other SSRI's are also capable of inducing large increases in prolactin levels.
 
Now in regards to what these studies imply, the issues are compounded by a lack of knowledge, and there is no direct mandate that doctor's should get their patient's frequent bloodwork on hormones and other bio-factors. There are only indirect and out of context "suggestions" ~ mostly in medical literature that was preceded by and prompted by, numerous complaints of drug side-effects.
 
 
This is deeply disturbing.
 
 
 Now another big no-no, in fact one that is warned about ON-LABEL, is combining these anti-depressant drugs with NATURAL inhibitors of these enzymes, related cytochrome enzymes, or downstream , fairly related enzymes - one of the most discussed is GRAPEFRUIT JUICE.
 
By combining grapefruit juice you may increase the risk of overdosing on multiple drugs, and if you then take a second inhibitor, like LUVOX; the effects are then ADDITIVE....which essentially means that combining one simple 6oz glass of grapefruit juice with luvox, and then a blood pressure pill - could very easily KILL you or land you in the hospital with nearly uncontrollable bouts of panic, or immobilization stress and severe HYPOTENSION...if you do survive such a combination, the almost total loss of oxygen delivery during the periods of treatment and recovery may result in permanent nerve and blood vessel damage!

 


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#2 Area-1255

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Posted 30 November 2014 - 04:41 PM

 

J Androl. 2006 Sep-Oct;27(5):679-85. Epub 2006 May 25.

Doxazosin and serotonin (5-HT) receptor (1A, 2A, and 4) antagonists inhibit 5-HT-mediated human cavernosal contraction.
Abstract

Penile erection results from the balance between relaxation and contractile mechanisms of the corpus cavernosum. Only a few studies suggest a role for endogenous contractile agents such as 5-hydroxytryptamine (5-HT). Our aim was to confirm the possible role of 5-HT in human erection. The effect of 5-HT on human cavernosal tissues, as well as those of doxazosin (shown previously to have 5-HT inhibitory action), ketanserin (5-HT (2A) receptor antagonist), NAN-190 (5-HT (1A) receptor antagonist), and SB 203186 (5-HT (4) receptor antagonist) on 5-HT-mediated effects, were assessed using the organ bath technique, including electrical field stimulation study (EFS). Results are presented as median (mg/mg = mg contraction/mg of tissue). Consistent 5-HT-mediated (10(-3) M) contractions were demonstrated (n = 18; 63 mg/mg). These contractions were inhibited with ketanserin by 90% (n = 8), NAN-190 by 68% (n = 12), and SB 203186 by 55% (n = 12). Doxazosin showed a similar 5-HT inhibitory action in a concentration-dependent manner (10(-4) M; 94% reduction; n = 8, 10(-6) M; 68.3% reduction; n = 8). Our EFS studies indicated the presence of neuronally derived 5-HT and that a majority of the nonnoradrenogenic contraction (54%) was mediated via 5-HT(2A) receptors. These findings suggest that 5-HT may play a role in the human detumescence process via 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors. Neuronally released 5-HT is probably an important contractile neurotransmitter in the erectile process. Doxazosin, ketanserin, and 5-HT(1A) and 5-HT(4) receptor antagonists may be useful as part of combination therapy used to treat erectile dysfunction.

PMID:   16728720   [PubMed - indexed for MEDLINE]    Free full text
 
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#3 Area-1255

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Posted 12 December 2014 - 10:31 PM

http://en.wikipedia....5-HT1A_receptor

http://www.ncbi.nlm..../pubmed/1357709

 

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.
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(-8) 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]  
 
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#4 Flex

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Posted 12 December 2014 - 10:42 PM

I find it great that You care for issues,

this is one of the things that can decrease the quality of life to a good extend.

 

Keep on.


Edited by Flex, 12 December 2014 - 10:43 PM.

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#5 Area-1255

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Posted 12 December 2014 - 10:58 PM

I find it great that You care for issues,

this is one of the things that can decrease the quality of life to a good extend.

 

Keep on.

I wouldn't have done all of the research my brotha, if I didn't care...it is definitely a harsh issue that is underappreciated, and certainly under-emphasized by big pharma!


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#6 Babychris

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Posted 12 December 2014 - 11:02 PM

You speak about Delayed ejaculation, I have noticed more of a premature ejaculation, to the point that ejaculation can come before or very shortly after erection.

 

-Erection is very hard to obtain, does not maintain easily

-Dick is thiner and erection size is reduced

-Dick odor is reduced if not abolished too

-Something feels weird in the brain like as I can feel the part of the brain (that's hard to explain) involved in the condition.

-Anxiety seems aat least partially related to the condition

-Heavy Eyelids too

-Kind of restlessness and irritability could be related to serotonin disturbance too

-Hard to watch a movie or to keep something in interest for a long time

 



#7 Area-1255

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Posted 12 December 2014 - 11:14 PM

You speak about Delayed ejaculation, I have noticed more of a premature ejaculation, to the point that ejaculation can come before or very shortly after erection.

 

-Erection is very hard to obtain, does not maintain easily

-Dick is thiner and erection size is reduced

-Dick odor is reduced if not abolished too

-Something feels weird in the brain like as I can feel the part of the brain (that's hard to explain) involved in the condition.

-Anxiety seems aat least partially related to the condition

-Heavy Eyelids too

-Kind of restlessness and irritability could be related to serotonin disturbance too

-Hard to watch a movie or to keep something in interest for a long time

That is all typical of anhedonia related to dopaminergic dysfunction, yours might also have an adrenaline issue as well. 

Serotonin receptors are involved in these adrenergic responses, and many serotonin receptors trigger startling, anxiety and lack of pleasure.


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#8 Area-1255

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Posted 13 December 2014 - 10:05 PM

5-HT5A may be involved as well in the startle response induced by serotonin. 

This has been my experience as well, that using a partial agonist to this receptor, such as valerian extract, had greatly stopped stimulants from causing me to be jumpy.

Therefore, it must be that the cross noradrenergic-serotonergic activation of 5-HT5A is one mechanism in which stimulants may increase nervousness.

 

 
J Neurosci. 2013 Jun 12;33(24):10011-20. doi: 10.1523/JNEUROSCI.4733-12.2013.
The 5-HT5A receptor regulates excitability in the auditory startle circuit: functional implications for sensorimotor gating.
Abstract

Here we applied behavioral testing, pharmacology, and in vivo electrophysiology to determine the function of the serotonin 5-HT5A receptor in goldfish startle plasticity and sensorimotor gating. In an initial series of behavioral experiments, we characterized the effects of a selective 5-HT5A antagonist, SB-699551 (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), on prepulse inhibition of the acoustic startle response. Those experiments showed a dose-dependent decline in startle rates in prepulse conditions. Subsequent behavioral experiments showed that SB-699551 also reduced baseline startle rates (i.e., without prepulse). To determine the cellular mechanisms underlying these behaviors, we tested the effects of two distinct selective 5-HT5A antagonists, SB-699551 and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine), on the intrinsic membrane properties and synaptic sound response of the Mauthner cell (M-cell), the decision-making neuron of the startle circuit. Auditory-evoked postsynaptic potentials recorded in the M-cell were similarly attenuated after treatment with either 5-HT5A antagonist (SB-699551, 26.41 ± 3.98% reduction; A-843277, 17.52 ± 6.24% reduction). This attenuation was produced by a tonic (intrinsic) reduction in M-cell input resistance, likely mediated by a Cl(-) conductance, that added to the extrinsic inhibition produced by an auditory prepulse. Interestingly, the effector mechanisms underlying neural prepulse inhibition itself were unaffected by antagonist treatment. In summary, these results provide an in vivo electrophysiological characterization of the 5-HT5A receptor and its behavioral relevance and provide a new perspective on the interaction of intrinsic and extrinsic modulatory mechanisms in startle plasticity and sensorimotor gating.

PMID:   23761896   [PubMed - indexed for MEDLINE]    Free full text

 

 

 

Brain Res Mol Brain Res. 2005 Aug 18;138(2):191-7.

Valerian extract and valerenic acid are partial agonists of the 5-HT5A receptor in vitro.
Abstract

Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA(A) receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT(5a) receptor, but only weak binding affinity to the 5-HT(2b) and the serotonin transporter. Subsequent binding studies focused on the 5-HT(5a) receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep-wake cycle. The PE extract inhibited [(3)H]lysergic acid diethylamide (LSD) binding to the human 5-HT(5a) receptor (86% at 50 microg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC(50) curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC(50) of 15.7 ng/ml for the high-affinity state and 27.7 microg/ml for the low-affinity state. The addition of GTP (100 microM) resulted in a right-hand shift of the binding curve with an IC(50) of 11.4 microg/ml. Valerenic acid, the active constituent of both extracts, had an IC(50) of 17.2 microM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT(5a) receptor.

PMID:   15921820   [PubMed - indexed for MEDLINE]

 

 

We can conclude then that 5-HT5A receptors in the SPN and other areas can do the following when activated.

 

  • Reduce serotonin release as an autoreceptor, and downregulate 5-HT1A's to compensate for the reduction of serotonin. 5-HT5A and 5-HT1A are inter-reactive receptors, and act on a behavioral parallel , eyeing each other down for signaling, when one receptor is activated, the other autoreceptor decreases etc.
  • They are negatively coupled to adenylyl cyclase, so activating them reduces cyclic AMP!
  • They increase behavioral excitation in response to loud noises, probably by acting locally to reduce serotonin activity where it would normally reduce these responses, or by reducing cAMP in discernment areas of the temporal lobe and vestibular neuronal networks.

 

ALSO IN REGARDS TO VALERIAN, THE FOLLOWING.

 

 

 

 

Valerian appears to have few side effects. There is one case report of an overdose,66 and one report of a possible hazardous interaction with fluoxetine. 67

Makes sense that the specific effects of VALERINIC ACID / VALERIAN EXTRACT in terms of partial agonism of 5-HT5A would be.

 

  • Antagonize the autoreceptor part, raising serotonin, while agonizing the receptors in the SPN to reduce cyclic AMP.
  • Modulating other autoreceptors as a direct interactive or downstream effect of modulating 5-HT5A activity.

 

 

 

Has anyody had any experience with Valerian extract in terms of auditory startle, and Insomnia?

What benefits did you experience with valerinic acid/valerian root?


Edited by Area-1255, 13 December 2014 - 10:18 PM.

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#9 Area-1255

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Posted 21 January 2015 - 04:27 AM

Due to the unfortunate closing of PSSD forums, I have opened an alternative PSSD forum..

 

http://area-1255.forumotion.info/

 

http://area-1255.for...ies-conclusions


Edited by Area-1255, 21 January 2015 - 04:28 AM.

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#10 Babychris

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Posted 28 January 2015 - 06:12 PM

Didn't get everything you have tried to point on the action of Valerian... 


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#11 Area-1255

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Posted 28 January 2015 - 06:38 PM

Didn't get everything you have tried to point on the action of Valerian... 

It's a partial agonist to 5-HT(5)A autoreceptor, it probably would alter the feedback on the 5-HT(1)A autoreceptor; but it's too early to tell as we don't have enough research to fully define the 5A receptor at this point....it's a mere possibility we can manipulate serotonin release through that autoreceptor, or blocking it may upregulate the 1A autoreceptors. 


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#12 Flex

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Posted 12 May 2015 - 06:22 PM

I wonder whether anyone has tried Dimebon aka Latrepirdine for 5-ht5a inhibition

http://en.wikipedia....ki/Latrepirdine

 

It seems to have pretty strong affinity for 5-ht5 altough it also inhibits a certain subset of NMDA receptors and L-type calcium channels.

Dont know if they may be problematic in terms of PSSD

 

Btw: the 5-ht6 inhibition looks also interresting in terms of cognition and acetylcholine release.

 

 


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#13 SerP3nT

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Posted 21 May 2015 - 10:34 AM

I wonder whether anyone has tried Dimebon aka Latrepirdine for 5-ht5a inhibition

http://en.wikipedia....ki/Latrepirdine

 

It seems to have pretty strong affinity for 5-ht5 altough it also inhibits a certain subset of NMDA receptors and L-type calcium channels.

Dont know if they may be problematic in terms of PSSD

 

Btw: the 5-ht6 inhibition looks also interresting in terms of cognition and acetylcholine release.

my bro tried it. my hamster brother. he like a lot!!


Edited by SerP3nT, 21 May 2015 - 10:34 AM.

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#14 Flex

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Posted 28 May 2015 - 12:22 AM

Dont know whether I mentioned this but anyway:

 

I used in March Escitalopram at few separate days over ca. 2-3 weeks.

I would estimate the dose as arround 30mg in total.

 

The first time I´ve taken 5mg and had the week after a better affect and was nearly non-anxious at all.

After one (10mg) or a half (5mg), later I´ve experienced an increase in anxiety and got a flush in my face when I was embarrased and nervous but I didnt connected the dots.

I´ve taken eventually 5mg and some chinese herbs (guess mainly: gastrodia ellata, Andrographis paniculata and perhaps rehmannia glutinosa) and the day after 10mg again.

( btw, I´m using 45mg Mirtazapine for 2 years for my chronic insomnia)

 

I became a kind of anxious-psychotic after the 10mg which relieved after 1-2 hours. Now I´ve looked for something to get the Escitalopram flushed out of my body but only found st.johns wort extract to have such effects

(something like cyp450 activator), tough its can act also as an inhibitor.

 

So, I became after the St.johns wort even more positive but that was the evening where my PSSD started. 

I felt on the day after or the 2nd one some:

 

- penile anestesia

- asexuality

- errection problems

 

Thankfully, I havent developed a full blown PSSD, but it was enough to be problematic also in terms of shyness and especially worser cognition !!

Havent used any Escitalopram since this day.

 

I´ve tried of course, IIRC, all of the chinese herbs above, Shrooms and Weed (after 2 Years) but with no great improvement.

Weed made it actually worser. Interrestingly, Thunbergia laurifolia which gave me an amphetamine like effect in the recent time, didnt work anymore (!) perhaps due to the effects of 5-ht1a on K+channels

 

After several weeks it got a bit better but not that great.

I´ve stumbled upon petes story on the very nice and thoughtful  (caution irony!) pssd forum where he reported that Vitamine K has reversed his PSSD.

pete's recovery

http://www.pssdforum...ilit=pete#p2879

 

A thought struck me.

 

I was taking Vitamine K drops sometimes to milden the anticoagulant effects of the Chinese herbs !

Then I´ve tried it a few times (i.e. about 5ml in total) and the symptoms got better !

 

I cant say that I´m 100% but it relieved the penile anestsia nearly complete and helped with the other symptoms as well

 

--> I´m taking this one: KA-VIT Tropfen

containing: Phytomenadion / Vitamin K1

(german drug registration number)PZN:  06681001

Dont overdose Vitamin K ! it clumps Your blood at high doses and You might get a stroke or heart attack because of this

 

I smoked again weed 6 days ago and taken 1 pill of pramipexole(dont mix it! could afaik reduce tyrosine hydrooxilase expression) 3 days ago and I feel now even more recovered,

though when taking St.johns wort with rhodiola, it still blunts my libido and errection.

 

Btw: had also good results with Glutamine matrix i.e. a mix of L-Glutamine,L-Glutamine AKG,N-Acetyl L-Glutamine,L-Glutamine Peptide

also in regards of blunted emotions caused by PSSD but it was only transiently


Edited by Flex, 28 May 2015 - 12:32 AM.


#15 SerP3nT

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Posted 13 June 2015 - 03:30 PM

^ awesome post ^ 



#16 Area-1255

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Posted 02 October 2015 - 03:42 AM

HOW TO PREVENT / REVERSE DOPAMINE RECEPTOR DOWNREGULATION 

 

Also...

 

 

 

Inhibition of sexual behavior by dopamine antagonist or serotonin agonist drugs in castrated male rats given estradiol or dihydrotestosterone
Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 07/1980; 13(1):57-67. DOI: 10.1016/0091-3057(80)90121-5

ABSTRACT

Four experiments were performed to determine whether the activational effects of two behaviorally active neural metabolites of testosterone, estradiol (E2) and 5??-dihydrotestosterone (DHT), on male rats' sexual behavior possibly result from the action of either steroid at dopaminergic or serotoninergic synapses. In Experiment 1 lower doses of the dopamine receptor antagonist, spiperone, were needed significantly to reduce mounting and intromission rates in castrated males implanted with silastic capsules containing E2 as opposed to DHT. However, in Experiment 2 increasing doses of another dopamine receptor blocker, clozapine, were equally effective in suppressing males' sexual behavior, regardless of whether they were implanted with E2 or DHT, suggesting that these testosterone metabolites may both normally contribute to the activation of masculine sexual behavior by enhancing dopaminergic neurotransmission. In Experiment 3 administering increasing doses of the serotonin reuptake blocker, fluoxetine, caused an equal suppression of sexual behavior in castrated males implanted with E2 of DHT. In Experiment 4 no differential suppressive effects of the serotonin receptor agonist, 5 methoxy-N,N-dimethyltryptamine were obtained in castrated rats implanted with E2 or DHT. It is suggested that these testosterone metabolites may both contribute to the activation of masculine sexual behavior by suppressing activity at serotoninergic synapses.

Inhibition of sexual behavior by dopamine antagonist or serotonin agonist drugs in castrated male rats given estradiol or dihydrotestosterone - ResearchGate. Available from: http://www.researchg...drotestosterone [accessed Oct 1, 2015].

 


Edited by Area-1255, 02 October 2015 - 03:43 AM.

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#17 Flex

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Posted 11 October 2015 - 11:28 PM

I read into the pssd forum and the conesus is that presynaptic 5-ht1a receptors are desentitated but I personally have some difficulties to accept it to 100%

If so, then You should have overall increased 5-ht to a same degree, thus making You less or more anxious, alter perhaps Your sleep & etc.

 

Aynway it seems that the causes of 5-ht1a desentitation differ among the SSRI´s

 

Chronic administration of venlafaxine fails to attenuate 5-HT1A receptor function at the level of receptor-G protein interaction.

However, the lack of effect of chronic sertraline treatment on 5-HT1A receptor-stimulated [35S]GTPgammaS binding is in contrast to what has been observed previously following chronic administration of the SSRI fluoxetine, and suggests that different SSRIs may regulate somatodendritic 5-HT1A autoreceptor function differently depending on their pharmacology.

Our data also suggest that the desensitization of somatodendritic 5-HT1A autoreceptors observed in electrophysiological studies following chronic venlafaxine administration is not at the level of receptor-G protein interaction.

http://www.ncbi.nlm....pubmed/16035959

 

however some say that the cause is not at the g-protein level:

 

Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors

Therefore, it appears that 5-HT1A autoreceptor desensitization plays a minor role in enhancing the effect of chronic SSRI on extracellular 5-HT. It remains to be established whether other adaptive changes occurring after chronic treatment with SSRIs such as the desensitization of terminal 5-HT1B receptors or of the NMDA receptors controlling 5-HT release (Nowak et al., 1996; Pallotta et al., 2001) contribute to the enhancement of extracellular 5-HT.

http://www.ncbi.nlm....les/PMC1574969/

 

This one has some further suggestions but the g-protein might be altered according to them:

 

Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration.

Region-specific differences in the regulation of 5-HT(1A) receptor function may be based on compensatory changes distal to the receptor, such as regulatory changes at the level of effector (e.g. adenylyl cyclase or ion channel), or at the level of the G protein such as changes in G protein expression, or phosphorylation of the G protein. It may be that the increase in serotonin neurotransmission, due to somatodendritic autoreceptor desensitization following agonist or antidepressant treatment, to normo-sensitive 5-HT(1A) receptors in certain brain regions (e.g. hippocampus or cortex) and to sub-sensitive 5-HT(1A) receptors in other brain regions (e.g. amygdala or hypothalamus) underlies the therapeutic efficacy of these drugs.

http://www.ncbi.nlm....pubmed/12559389

 

Btw: according to the escitalopram/citalopram paper above, desentitation doesnt occured in rat which where anesthenized, so perhaps therefore are some results contrary

 

This one states again something different:

 

Differential regulation of serotonin-1A receptor stimulated [35S]GTPγS binding in the dorsal raphe nucleus by citalopram and escitalopram

Although citalopram and escitalopram have been shown to desensitize somatodendritic 5-HT1A autoreceptors, our data suggest that the mechanism(s) of desensitization may differ.
Perhaps the differences between the effects of chronic administration of citalopram or escitalopram on the regulation of 5-HT1A receptor function in the dorsal raphe nucleus may
be accounted for by allosteric modulation of the action of escitalopram by R-citalopram. It is not unreasonable to propose that longer binding to and therefore greater inhibition of the
serotonin transporter by escitalopram may result in greater activation of 5-HT1A receptors and regulation of 5-HT1A receptor function at the level of receptor-G protein interaction, as
opposed to regulation of 5-HT1A receptor function distal to receptor-G protein interaction. It would be of interest to determine whether differences in the mechanism of somatodendritic
5-HT1A autoreceptor desensitization are related to antidepressant drug efficacy, therapeutic response or clinical outcome.

http://www.ncbi.nlm..../nihms43816.pdf

 

This one made me wonder:

Differential Regulation of 5-HT1A Receptor-G Protein Interactions in Brain Following Chronic Antidepressant Administration

Our data suggest that the capacity of the 5-HT1A receptor to activate G protein is reduced in serotonergic cell body areas following chronic fluoxetine administration. No significant change in postsynaptic 5-HT1A receptor-stimulated [35S]GTPgammaS binding was observed in any of the forebrain areas examined following chronic treatment with either antidepressant. Thus changes in postsynaptic 5-HT1A receptor-mediated responses reported to follow chronic SSRI or tricyclic antidepressant administration appear to occur more distal to receptor-G protein interaction, perhaps at the level of effector, or involving changes in neuronal function at the system or circuit level.

http://www.nature.co...l/1395838a.html

 

I didnt had the time to read & comprehend it but why are they talking so much about the post 5-ht1a, if no changes in the g-proteins (or any other) were proved ?

Could it be that the pre 5-ht1a receptors in the Raphe dont have such a great impact but theres a synergy with the post 5-ht1a ?

 

Acute and chronic effects of citalopram on 5-HT1A receptor—Labeling by [18F]MPPF and—Coupling to receptors-G proteins

 

Chronic citalopram did not modify 5-HT1A receptor density in any of the brain regions studied. In addition, this treatment did not modify 8-OH-DPAT-stimulated [35S]-GTPγS binding in DR, although a significant increase was observed in frontal cortex and hippocampus. [18F]MPPF appears to be an efficient radioligand to quantify specifically 5-HT1A receptor density in brain imaging. The delayed therapeutic efficacy of citalopram did not appear to be linked to either a downregulation of 5-HT1A receptors or to a 5-HT1A receptor-G protein decoupling process in serotonergic neurons, but to increased functional sensitivity of postsynaptic 5-HT1A receptors.

http://onlinelibrary.../syn.20588/epdf

 

Anyway, How about to find ways to decrease the function of postsynaptic 5-ht1a or overexpress them like D2 receptors in Dyskinesia?

Because some people form the PSSD forum reported some very good improvements with Zinc

Admittely I believe the effect is due to 5-ht1a deactivation however it also activates SERT and some other things.

 

This could be a possible target i.e. the opposite of the sugessted lol so a pro-depressie state lol:

RGS inhibition at Gαi2 selectively potentiates 5-HT1A–mediated antidepressant effects

http://www.pnas.org/.../11086.full.pdf

 

therer are sparse informations about herbs and RGS interactions. The following might be promising at the first glance but PKC activation doesnt help because its afaik frequently activated.

but might maybe explain why Huperzine helps somewhat (?)

Anyway: 

 

Identification of Protein Kinase C Activation as a Novel Mechanism for RGS2 Protein Upregulation through Phenotypic Screening of Natural Product Extracts

Indolactam V, a known protein kinase C (PKC) activator, which selectively increased RGS2 protein levels in a time- and concentration-dependent manner. Similar results were obtained with phorbol 12-myristate 13-acetate as well as activation of the Gq-coupled muscarinic M3 receptor. The effect on RGS2 protein levels was blocked by the nonselective PKC inhibitor Gö6983

http://molpharm.aspe.../86/4/406.short

 

and heres something about RGS4 btw

 

Recent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds

From the Indian medication, three plants (Rauvolfia serpentina, Withania somnifera, and Mandukparni) were selected for the investigation of their role in the management of schizophrenia by using the tools of bioinformatics. The active molecules from these plants were docked with RGS-4 protein (regulator for G protein signaling-4) considered to be responsible for schizophrenia. The docking of RGS-4 protein with the combinations of reserpine, withanolide, and asiaticoside from Rauvolfia serpentina, Withania somnifera, and Mandukparni, respectively, showed that such combination therapy could be helpful in the management of schizophrenia [8].

http://www.hindawi.c...am/2014/979730/

 

RGS6 is also interresting for Dopamine transmission or cell protection in parkinson

 

Sidenote: this is why I want to learn more about g-proteins

 

Regulators of G-protein-coupled receptor–G-protein coupling: antidepressants mechanism of action

Our knowledge concerning the basic mechanisms underlying the phenomenon of desensitization, internalization, downregulation and resensitization of the G-protein-coupled receptor has been advanced during the last decade. The present review discusses the possible involvement of regulators of G-protein-coupled receptor-G-protein coupling: beta-arrestins, G-protein-coupled receptor kinases and phosducin-like proteins, as well as beta-arrestins alternative signaling events, in the pathophysiology, diagnosis and treatment monitoring of mood disorders and in the mechanism of action of antidepressant medications.

Regulators of G-protein-coupled receptor-G-protein coupling: Antidepressants mechanism of action - ResearchGate. Available from: http://www.researchg...anism_of_action [accessed Oct 12, 2015].

http://www.researchg...anism_of_action

 

lol this is not a text wall but almost a book


Edited by Flex, 11 October 2015 - 11:50 PM.


#18 Flex

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Posted 17 October 2015 - 07:47 PM

lol I had the same idea like the guys below but just enduringly^^:

 

By understanding the flexible nature of GPCR phosphorylation if may be possible to develop agonists or allosteric modulators that promote a subset of phosphorylation events on the target GPCR and thereby restrict the action of the drug to a particular receptor mediated signalling response.

G-protein-coupled receptor phosphorylation: where, when and by whom

http://www.ncbi.nlm....les/PMC2268057/


Edited by Flex, 17 October 2015 - 07:47 PM.


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#19 a355584

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Posted 07 February 2016 - 04:53 PM

Looking for a cure: are why focusing on the right way?

Everyone knows the main theory about the pathogenesis of PSSD: the excessive release of serotonin (which has a mixed but essentially inhibitory role on sexual functions) by the serotonergic neurons (concentrated in the raphe nuclei of the midbrain) caused the "desensitization" of 5-HT1A autoreceptors (that act as sentinels that regulate the release of a substance according on how much there is already in circulation, this mechanism is also called negative feedback)[1].
The "down regulation" of the 5-HT1A autoreceptors is instead caused by chronic and excessive activation by its natural "agonist" (serotonin) that is made available in abnormal quantities by the use of SSRIs. It is therefore natural to think to the autoreceptors as something that is "damaged" by excessive competition and that can be cured using an antagonist that lead him to be again "sensitive."

At this point that we have to do a reflection: the autoreceptor is a sentinel, a switch that if "on" sends a chemical signal. What the cell (neuron) have to do when it receives this chemical signal is written in the genes, that is in the sequence of the DNA; how much it should do (that is, how much to increase or decrease the release of serotonin) it depends on the genes expression.
Essentially two mechanism regulate gene expression:

• Binding of chemical groups directly to DNA (covalently) that function as silencers or activators. The main inhibitor is the methyl group that, binding at particular points of the promoter sequences, silences gene expression. The protein that bind methyl groups to DNA is the DNMT.

• The other is the tangling of the DNA around proteins (called histones): if the DNA is wrapped on itself, the molecular machines that should read the instruction contained in the DNA, cannot bind the DNA because there isn’t sufficient space. The ability of a histone to compact a DNA molecules (and thus repress gene expression) depends on the presence of particular molecules bound to the histone. The main one is the acetate group: if it binds to histone, forces him to expand and so molecular machines can come in and gene expression is activated.

The acetyl groups are linked to histone by HAT and detached from it by HDAC. Also histones can be methylated in some particular positions, and this has mixed effects on gene expression.

SSRIs activate gene silencing

It’s well known that SSRIs activate the gene-silencing mechanisms. During the assumption has been seen[2][3][4][5][6][7][8][9][10]:

• Increase in the expression of certain proteins that carry methyl groups (called MeCP2 and MBD1)

• Increase the mRNA synthesis of HDAC2 gene (the HDAC of a particular subtype of histone)

• There’s a decreased acetylation in the histone "H3" in three areas of serotonin projection: the caudate-putamen (striatum), the frontal cortex and the dentate gyrus (5-HT neurons are extensively arborized, and their axons reach all brain areas).

All this suggests the induction of gene silencing.
Now we can rethink to the neuron such a stubborn person who does something of wrong: we told him to correct his behavior (the autoreceptor send his message to the cell) but he will not change his behavior (excessive release of serotonin) because he is a person who does not listen what we told to him (reduced gene expression).

So we cannot think to reactivate the negative feedback mechanism only binding them an antagonist because who is stuck in a situation of "off" is not the autoreceptor, but the DNA is to be.

The right strategy therefore have to be the reactivation of gene plasticity which can then be guided in the right direction by the use of an antagonist of the 5-HT1A autoreceptors.

A possible partial theoretical confirmation of this hypothesis is the results of a study in which rats whit an animal model of tardive dyskinesia (a disorder in some ways similar to the PSSD) had a partial remission of the disease using a HDAC inhibitor[11].

How to induce gene expression plasticity

Firstly, we recall the main objectives:

• To promote the demethylation of DNA by inhibiting DNMT: the new synthesized DNA is less methylated and then whit an increased gene expression.

• Inhibit the deacetylation of histones, in particular inhibiting HDAC

• Encourage the acetylation of histones, in particular by increasing the activity of HAT

It has also been seen that the increase of histone acetylation is accompanied by a demethylation of DNA, that is, the two events have a synergistic effect[12]. It 'important to note first of all that these effects are time and dose dependent, ie the effects are proportional to the dose taken and manifests itself after some time.

Several compounds can do this. Most of them are natural occuring compounds and found in green tea but this does not mean that they are little effective: some are very promising for the treatment of other diseases in which the gene expression change is crucial. Other are drugs are already used for other purposes[13][14][15][16][17][18][19][20][21][22].
Unlucky, often they have a low biodisponibility and a short half-life, than high and multiple doses should be necessary.
Most promising are listed for first.

 

EPIGALLOCATECHINE GALLATE (EPCG)

One of most studied, well caracterized and most effective natural compound that influence gene expression. Is one of major component of green tea extract. It can easily cross blood-brain barrier and is demonstrated that directly bind DNA19[23][24][25]. It is DNMT1, DNMT3, HDAC1 inhibitor and a MeCP2 inhibitor using Mg2+ as cofactor. Increase amount of glutathione and indirectly the acetilation of histone H3 and H4. Unlucky it is also a weak inhibitor of HAT, has a very low biodisponibility and may be hepatotoxic. Has been demonstrated that minimum effective dose in order to induce genetic effect is 800 mg 2 times a day. The ingestion of high grade, dried green extract, which contains a lot of different catechine, gallate and flavonoid, is more effective then the ingestion of pure EPGC: all the “gallate” and “chatechin” compounds are generally HDAC and DNMT inhibitor and they have a synergistic effect. They’re generally recognized as safe.

QUERCITINE

A flavonoid, is a strong enhancer of H3 and H4 histone acetylation, thus activates SIRT1 and SIRT6 mediated deacetylation; Inhibit DNMT and LSD1 (histone demethylating protein). It is also a weak MAOI. Was found to be active at a concentration of 75-100 um.

GENISTEINA (and less DAIDZEINE and BIOCIANINE A)

They are phytoestrogens and belongs to the category of isoflavones. They are strong inhibitor of HDAC (mostly HDAC1) and DNMT (mostly DNMT1 and DNMT3); less strong inhibitor of MeCP2. Was proved to demethylate ipermethylated genomes without lead to ipomethylation. It has a strong and synergic effect whit other DNMT and HDAC inhibitor.
It is an estrogen receptor agonist and then may produce non-hormonal effects.

SODIUM BUTIRRATE

It is a strong and natural occurring HDAC inhibitor and one of most studied. It has a lot of other positive effects and has been demonstred to be neuroprotective.

VALPROATE and SULPIRIDE

Valproate is an anticonvulsive and a mood stabilizer drug that act as a strong HDAC inhibitor and this may account of its anticonvulsive and mood stabilizing effects. Sulpiride is a very effective antidepressant (I want to recommend to everyone because is a fantastic drug whit a rapid onset and persisting effect specially on ruminative though, anxiety and bad feeling). It was found that a combination of the two drugs in clinically relevant doses activate brain demethylation. This effect was studied on GABA neurons but may occur also in other type of neurons[26][27][28].

CURCUMINE

Strong inhibitor of HDAC, HAT, DNMT, MeCP2. Has been shown to be able to induce demetilation of hypermethylated zone of DNA, in a stronger way than genisteine. Because its potent HAT inhibitor activity it may be a second line treatment or can be used to prevent ssri’s induced modification of genetic expression.

LUTEOLINE

Luteolin is a flavone, a type of flavonoid. Increase histone acetylation, particularly H3 e H4, inhibiting their HDAC and activating SIRT6-mediated deacetylation; Inhibit DNMT and LSD1 (histone demetylating protein). Thus, weak diminish phosporylation on H3 and H4 and is a weak indirect antagonist of DNMT.

APIGENINE

A flavone, is a HDAT inhibitor (soprattuto H1 and H3) and weak activator of SIRT6 mediated deacetylation. Apigenin may also stimulate adult neurogenesis. Concentration over 5-10 um are not recommended because gaba agonism and other central effects. It is a weak MAOI.

DIALLIL SULFIDE, ANACARDIC ACID and GARLIC

A lot of compounds in garlic and broccoli are HDAC and DNMT inhibitor, then high grade dried garlic extract and to eat broccoli may be strongly recommended.

SAM, vitamins B and ZINC

S-Adenosil-Methionine is the natural transporter of methyl groups and work in a synergic way whit DNMT, than induce methylation. Its natural counterpart is S-Adenosil-Omocisteine, a strong demethylating agent which expression increase during the use of HDAC inhibitor: this mean that there’s a synergistic effect between increase of acetylation and the activation of demethylation. For this reason, the supplement of SAMe is not recommended.

The vitamins of group B are used to carrier and bind methyl group, then supplementation of high amount of B vitamins is not recommended if the increase of demethylation is wanted.

The Zn2+ ion is he natural cofactor of HDAC, then the uses of Zn2+ supplements may increase their activities.

I hope that a combination of the induction of gene’s plasticity and the antagonism to serotonin receptors may help to recover from the disease.  


[1] Mechanisms of control of 5-HT neurons are:

  • self-inhibition through 5-HT1A autoreceptors (activation of these receptors by 5-HT diminish neuronal firing and produce a negative feedback regulation of transmitter release)
  • 5-HT1B/1D receptors, located on nerve terminals, respond to 5-HT released locally in the terminal fields inhibiting further transmitter release.

 These 2 mechanisms ensure tight feedback control of the activity of serotonergic neurons and of terminal 5-HT release.
Thus, a prolonged treatment whit ssri may lead to a reduction of binding site for serotonin on SERT, then its ability to reuptake serotonin is chronically diminished.
Chronic administration of selective serotonin reuptake inhibitors (
but not amitriptyline) results in the desensitization of 5-HT1A somatodendritic autoreceptor function in the dorsal raphe but not in hippocampus, and also results in the desensitization of physiological responses mediated by postsynaptic 5-HT1A receptors.
In general, changes in 5-HT
1A receptor number have not been observed following chronic administration of antidepressants.
A study (Julie G Hensler, 2002) ipotizes that the desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal and median raphe following chronic SSRI treatment do not appear to be mediated by changes in 5-HT1A receptor binding but may be due to a reduced capacity of the 5-HT1A receptor to activate G protein. By contrast, no significant change in postsynaptic 5-HT1A binding following chronic antidepressant treatment.
 

[2] Newton SS, Duman RS (August 2006). “Chromatin remodeling: a novel mechanism of psychotropic drug action”. Mol. Pharmacol. 70 (2)
 

[4] The genetics of selective serotonin reuptake inhibitors, Kroeze
 

[5] Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology, Csoka
 

[6] Faure C, Mnie-Filali O, Haddjeri N (February 2006). Long-term adaptive changes induced by serotonergic antidepressant drugs”. Expert Rev Neurother
 

[7] Palotás M, Palotás A, Puskás LG, et al. (December 2004). “Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram”. Int. J. Neuropsychopharmacol
 

[8] Kálmán J, Palotás A, Juhász A, et al. (November 2005). “Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression–evolution of antidepressants and the role of the “neuro-immune” system”.
 

[9] Yamada M, Yamada M, Higuchi T (July 2005). “Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy”. Prog. Neuropsychopharmacol. Biol. Psychiatry
 

[10] Boehm C, Newrzella D, Herberger S, Schramm N, Eisenhardt G, Schenk V, Sonntag-Buck V, Sorgenfrei O (2006). “Effects of antidepressant treatment on gene expression profile in mouse brain: cell type-specific transcription profiling using laser microdissection and microarray analysis”.

[11] RGFP109, a histone deacetylase inhibitor attenuates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset: a proof-of-concept study, Johnston TH
[12] Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling, Sarkar S
[13] Green tea polyphenols for prostate cancer chemoprevention: A translational perspective J.J. Johnson

[14] Flavonoids Influence Epigenetic-Modifying Enzyme Activity: Structure-Function Relationships and the Therapeutic Potential for Cancer Gilbert, E.R.; Liu, D.

[15] Epigenetic activities of flavonoids in the prevention and treatment of cancer, Christian Busch
[17] Epigenome, Cancer Prevention and Flavonoids and Curcumin, Višnja Stepanić

[18] Dietary Polyphenols May Affect DNA Methylation, Mingzhu Fang

[19] Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain disease, Ronald Ross Watson,Victor R. Preedy

[20] Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids, Won Jun Lee

[21] The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells, Zhu WG
[22] Epigenetic changes induced by curcumin and other natural compounds, Simone Reuter
[23] Green Tea Polyphenols in drug discovery - a success or failure?, Thomas J. Smith
[24] Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E, Chow HH
[25] Molecular targets of (-)-epigallocatechin-3-gallate (EGCG): specificity and interaction with membrane lipid rafts, Patra SK
[26] Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation, Dong E
[27] Selective DNA Methylation of BDNF Promoter in Bipolar Disorder: Differences Among Patients with BDI and BDII, D'Addario C.

 

[28] Valproate induces DNA demethylation in nuclear extracts from adult mouse brain, Erbo Don

 


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