SSRI induced serotonin transporter degradation - now reversible

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PeskyPeater

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Acute and chronic effects of nicotine on serotonin uptake in prefrontal cortex and hippocampus of rats​

Abstract​

We sought to investigate the effect of nicotine exposure (chronic and acute) on serotonin transporter (SERT) activity in two regions of the brain important for behavioral effects of nicotine. We first looked at the effects of chronic nicotine exposure (0.7 mg/kg nicotine, twice a day for 10 days) on [(3)H]5-HT uptake in prefrontal cortex (PFC) and hippocampus of rats. A significant increase in [(3)H]5-HT uptake was observed in synaptosomes prepared from both regions. To rule out the possibility that the increases were due to the last injection given, in a separate set of experiments a single injection of nicotine was administered the evening before sacrifice. No change in uptake occurred in either region, suggesting that the increases in uptake caused by nicotine was an effect of chronic exposure and not to an acute treatment. SERT binding studies, using prefrontocortical or hippocampal membrane preparations, revealed that chronic nicotine exposure significantly increased B(max) which correlated to an increase in SERT density. Lastly, we looked at the short-term effect of nicotine on [(3)H]5-HT uptake. Rats received a single nicotine injection 15-75 min before sacrifice. PFC synaptosomes displayed a time-dependent increase in uptake, whereas hippocampal synaptosomes showed an increase at only one time point.

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Nicotine regulates 5-HT1A receptor gene expression in the cerebral cortex and dorsal hippocampus.

Abstract​

The 5-HT1A receptor has been shown to be important in mediating the behavioural effects of nicotine. It is possible that nicotine administration might regulate the levels of 5-HT receptors in limbic and cortical regions, and such regulations may underlie adaptive responses to nicotine in the CNS. The effects of acute and chronic systemic (–)-nicotine administration on 5-HT1A receptor gene expression were measured in 15 rats by in situ hybridization, in the cerebral cortex, dorsal hippocampus and lateral septum. In the cortex, acute nicotine significantly increased the expression of 5-HT1A receptor mRNA 2 hr and 24 hr after injection. Similarly, acute nicotine significantly increased 5-HT1A receptor mRNA in the dentate gyrus (DG), CA3 and CA1 regions of the dorsal hippocampus 2 hr and 24 hr after injection. Chronic nicotine significantly decreased 5-HT1A receptor mRNA in the cortex 2 hr after the final injection, but was without effect at 24 hr or 72 hr. These data demonstrate that nicotine regulates 5-HT1A receptor gene expression in the cortex and hippocampus. The rapid regulation of expression of 5-HT1A receptor mRNA leads to the hypothesis that nicotine-induced 5-HT release may alter the postsynaptic sensitivity to 5-HT. (PsycINFO Database Record (c) 2016 APA, all rights reserved)
 
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PeskyPeater

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Effects of Evodia rutaecarpa Acupoint Sticking Therapy on Rats with Insomnia Induced by Para-Chlorophenylalanine in 5-HT1Aand 5-HT2A Gene Expressions

Abstract​

The main feature of insomnia is difficulty in starting or maintaining sleep. 5-HT1A receptor and 5-HT2A receptor are two subtypes of the classic central 5-HT neurotransmitter closely related to sleep and wakefulness. To observe the effects of Evodia rutaecarpa acupoint sticking therapy on the mRNA expressions of 5-HT1A and 5-HT2A in the hypothalamus, brainstem, and hippocampus of insomnia rats induced by para-chlorophenylalanine (PCPA). Ten rats were randomly selected as the normal group, and 80 PCPA insomnia model rats were randomly divided into eight groups, including a model group, a positive control group (diazepam group), a low-dose E. rutaecarpa acupoint sticking therapy group (Yongquan acupoint group and Shenque acupoint group; the same applied below), a middle-dose E. rutaecarpa acupoint sticking therapy group, and a high-dose E. rutaecarpa acupoint sticking therapy group. The normal group and the model group did not receive treatment. The positive control group was given diazepam through intragastric administration, and the three-dose E. rutaecarpa acupoint sticking therapy groups were divided into the Yongquan acupoint group and the Shenque acupoint group. After seven days of administration, the rat hypothalamus, brainstem, and hippocampus tissues were taken, and a real-time polymerase chain reaction method was used to detect the mRNA expressions of 5-HT1A and 5-HT2A. E.rutaecarpa acupoint sticking therapy significantly upregulated 5-HT1A mRNA expression and downregulated 5-HT2A mRNA expression in rats with insomnia caused by PCPA. No significant differences were found in the expression between the two acupoints and the expression among the three brain tissues. E. rutaecarpa acupoint sticking therapy can improve insomnia. The mechanism may be related to the upregulation of 5-HT1A mRNA expression and the downregulation of 5-HT2A mRNA expression in brain tissue.
 

Lokzo

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Effects of Evodia rutaecarpa Acupoint Sticking Therapy on Rats with Insomnia Induced by Para-Chlorophenylalanine in 5-HT1Aand 5-HT2A Gene Expressions

Abstract​

The main feature of insomnia is difficulty in starting or maintaining sleep. 5-HT1A receptor and 5-HT2A receptor are two subtypes of the classic central 5-HT neurotransmitter closely related to sleep and wakefulness. To observe the effects of Evodia rutaecarpa acupoint sticking therapy on the mRNA expressions of 5-HT1A and 5-HT2A in the hypothalamus, brainstem, and hippocampus of insomnia rats induced by para-chlorophenylalanine (PCPA). Ten rats were randomly selected as the normal group, and 80 PCPA insomnia model rats were randomly divided into eight groups, including a model group, a positive control group (diazepam group), a low-dose E. rutaecarpa acupoint sticking therapy group (Yongquan acupoint group and Shenque acupoint group; the same applied below), a middle-dose E. rutaecarpa acupoint sticking therapy group, and a high-dose E. rutaecarpa acupoint sticking therapy group. The normal group and the model group did not receive treatment. The positive control group was given diazepam through intragastric administration, and the three-dose E. rutaecarpa acupoint sticking therapy groups were divided into the Yongquan acupoint group and the Shenque acupoint group. After seven days of administration, the rat hypothalamus, brainstem, and hippocampus tissues were taken, and a real-time polymerase chain reaction method was used to detect the mRNA expressions of 5-HT1A and 5-HT2A. E.rutaecarpa acupoint sticking therapy significantly upregulated 5-HT1A mRNA expression and downregulated 5-HT2A mRNA expression in rats with insomnia caused by PCPA. No significant differences were found in the expression between the two acupoints and the expression among the three brain tissues. E. rutaecarpa acupoint sticking therapy can improve insomnia. The mechanism may be related to the upregulation of 5-HT1A mRNA expression and the downregulation of 5-HT2A mRNA expression in brain tissue.

I want to try this herb. Anyone found a good vendor?
 
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PeskyPeater

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I want to try this herb. Anyone found a good vendor?
Im using it right now from an acupunture vendor in Amsterdam (Green Nature Co Ltd Hong Kong). Be careful to apply a low dosage and take with some aspirin to prevent liver issues.
Here is a study about it's potential liver damaging effects in medium and high dosages. Unless it is prepared in licorice. See here: Hepatotoxicity Comparison of Crude and Licorice-Processed Euodiae Fructus in Rats With Stomach Excess-Cold Syndrome

Discussion​

... It has been reported that the acute toxicity of EF is dose-dependent (Huang et al., 2012; Sun et al., 2012). In this work, the hepatotoxicity of EF was found to be dose-dependent on various approaches and toxicology indexes. For an adult, the range of clinical dose of EF is very wide with 1–70 g/day, and the pharmacopeial dose is 2–5 g/day. The low dose in this work was set at 1.05 g/kg/day, and equivalent to 10 g/day for an adult. Fortunately, no significant hepatotoxicity was observed for the low dose of CEF and LPEF, which indicates that the pharmacopoeia dose may be a safe one during short-term ingestion of CEF or LPEF. It can be inferred that most cases of toxic and side effects of EF may be generally caused by long-term use of large doses.

Chinese medicine has noted the toxicity of EF since ancient time, and EF is marked with “mild toxic” and “toxic” in TCM books. Drug processing and compatibility are often used to reduce or eliminate its toxic and side effects. Licorice processing is one of the commonly used processing techniques for CEF. After processing with licorice, a series of physical, chemical, and biological changes occurred in EF, in which the contents of organic acids significantly decreased and quinolone alkaloids increased a little. As interpreted above, caffeoyl gluconic acids and quinolone alkaloids are potential hepatotoxic components in EF. The increase and decrease of toxic components are closely related to the detoxification mechanism of drug processing. In addition, licorice is good at moderating all kinds of toxic herbs probably through antagonism. Liquiritin and glycyrrhizic acid in licorice have been reported to have detoxification effect (Wu et al., 2020; Xiao et al., 2021). Accordingly, the hepatotoxicity of LPEF is significantly lower than that of CEF. We speculate that licorice processing combines the effects of drug processing and compatibility, and further studies on the material basis and mechanism of detoxification are underway.


Aspirin attenuates liver fibrosis by suppressing TGF‑β1/Smad signaling - PubMed
Aspirin alleviates hepatic fibrosis by suppressing hepatic stellate cells activation via the TLR4/NF-κB pathway - PubMed
 
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Frankdee20

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Great share. That Sensory Processing Sensitivity study is very interesting too.

Are PSSD and post-SSRI anhedonia things you deal with? Let us know if you see results with these herbs.

There was a report of a person with PSSD and blunted perception after SSRIs who profoundly improved with high-dose inositol. He said it made his vision have depth again, colors saturated again, butterflies in stomach again, plus the relief of PSSD.

Berberine seems to have great benefits alone, so this combination is intriguing.
I believe inositol reverses desensitization of certain receptors. For me, it created strong anxiety and depersonalization.
 

Lokzo

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Im using it right now from an acupunture vendor in Amsterdam (Green Nature Co Ltd Hong Kong). Be careful to apply a low dosage and take with some aspirin to prevent liver issues.
Here is a study about it's potential liver damaging effects in medium and high dosages. Unless it is prepared in licorice. See here: Hepatotoxicity Comparison of Crude and Licorice-Processed Euodiae Fructus in Rats With Stomach Excess-Cold Syndrome




Aspirin attenuates liver fibrosis by suppressing TGF‑β1/Smad signaling - PubMed
Aspirin alleviates hepatic fibrosis by suppressing hepatic stellate cells activation via the TLR4/NF-κB pathway - PubMed

Yes very interesting man I did remember reading a little bit about that actually. It’s so fascinating with Chinese medicine how they combine certain herbs to offset the damaging effects of other herbs.
 

Frankdee20

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Yeah that’s the same with me, I also responded very poorly to inositol it gave me some really weird anxiety.
I wonder what the most likely pathway responsible for causing that reaction could be. It has been linked to the 5HT2A receptor, and acetylcholine.
 
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The Potential Benefits of Palmitoylethanolamidein Palliation: A Qualitative Systematic Review
Palmitoylethanolamide increases serotonergic neurotrans-
mission through the serotonin receptor 5HT1 and downregu-
lates 5HT2A/C receptors. CB1 agonists are reported to reduce
the reuptake of dopamine and serotonin.
103,104
Deletions of CB1 receptors in animals reduce synaptic serotonin caused
by selective serotonin reuptake inhibitors. [105]

[105] Aso E, Renoir T, Mengod G, et al. Lack of CB1 receptor activityimpairs serotonergic negative feedback. JNeurochem. 2009;109(3):935-944

Serotonergic and endocannabinoid systems are important substrates for the control of emotional behaviour and growing evidence show an involvement in the pathophysiology of mood disorders. In the present study, the absence of the activity of the CB1 cannabinoid receptor impaired serotonergic negative feedback in mice. Thus, in vivo microdialysis experiments revealed increased basal 5-HT extracellular levels and attenuated fluoxetine-induced increase of 5-HT extracellular levels in the prefrontal cortex of CB1 knockout compared with wild-type mice. These observations could be related to the significant reduction in the 5-HT transporter binding site density detected in frontal cortex and hippocampus of CB1 knockout mice. The lack of CB1 receptor also altered some 5-HT receptors related to the 5-HT feedback. Extracellular recordings in the dorsal raphe nucleus (DRN) revealed that the genetic and pharmacological blockade of CB1 receptor induced a 5-HT1A autoreceptor functional desensitization. In situ hybridization studies showed a reduction in the expression of the 5-HT2C receptor within several brain areas related to the control of the emotional responses, such as the DRN, the nucleus accumbens and the paraventricular nucleus of the hypothalamus, whereas an over-expression was observed in the CA3 area of the ventral hippocampus. These results reveal that the lack of CB1 receptor induces a facilitation of the activity of serotonergic neurons in the DRN by altering different components of the 5-HT feedback as well as an increase in 5-HT extracellular levels in the prefrontal cortex in mice.
 

Frankdee20

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What causes the brain zaps ? Dysregulated GABA ?
 

Tidal

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Did anyone ever have any luck with trying this to upregulate SERT?

I have anhedonia from taking fluoxetine and have unsuccessfully tried berberine, evodia fructus and pure evodiamine seperately.

I think the pure evodiamine should be the most powerful but it has poor bioavailability and I probably didn't take enough as I don't know what dose would be needed in humans.

It's infuriating how complex and difficult it is to upregulate SERT in the dorsal raphe and hopefully resensitize 5ht1a autoreceptors
 

Tidal

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I believe inositol reverses desensitization of certain receptors. For me, it created strong anxiety and depersonalization.

This is what led me to take myo inositol. I already had depersonalization but I got terrible cognitive problems and muscle twitching/spasms after taking it which haven't abated.

I wonder what the most likely pathway responsible for causing that reaction could be. It has been linked to the 5HT2A receptor, and acetylcholine.

Could you elaborate on the acetylcholine part please?
 

Frankdee20

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This is what led me to take myo inositol. I already had depersonalization but I got terrible cognitive problems and muscle twitching/spasms after taking it which haven't abated.



Could you elaborate on the acetylcholine part please?
It’s been mentioned whenever I look up what exactly it does in the brain, but seems rather vague. It is definitely a second messenger system. It has been linked to 5HT2A (nasty anxiety receptor) and D2 receptors. Not sure if it unregulated both. Some trials used grams upon grams for OCD. Personally, I do not like the effects, but perhaps my anxiety from it came via acetylcholine. Too much will do that to me, especially fish oil.
 
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