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Anti-addictive agents

I did 6 months of group CBT (group was advised because of the shaming aspect of sex addiction, to get it out there in front of others). It didn't do shit for my violent craving even though the therapist who ran it was well-known in the sex addiction world and was a good guy. I guess being in a group did help somewhat to limit my relapses and we would go for "fellowship" afterwards in a nearby pub - the alcohol would work a bit to lower my craving would you believe it. But you can't live like that in the long-run its fucking crazy. (I still feel like I messed up unbelievably - how could I have missed finding out about ibogaine or whatever a few years back - none of this shit would have happened).
 
Overcoming said:
I can't think of how else to frame my question, but is the trip as "hardcore" as people make it out to be? What kind of preparation do you need to do?
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Yeah it's really intense. I found it to not produce fear though. The sort of preparation you need to do is to get yourself centered, take a week or more off work, eat healthy beforehand, don't eat at all a number of hours beforehand, avoid liquids for hours beforehand (you want to not have to use the bathroom during it if possible as it's very difficult to move in a flood dose). A clinic is best really, I did it at home but I have tripped who knows how many times, many hundreds certainly. You have to have a sober sitter watching you the whole time which could up to 3 days, for me it was 3 days anyway. Also you need to get your heart checked out to make sure you're not at risk for death... the (few) deaths from ibogaine have been due to heart problems.

Not sure whether ibogaine would work for sex addiction or not. It did kinda just help me to become a more aware and controlled person in general. It also doesn't seem to work for everyone.
 
Do you have any ideas on why it doesn't work for everyone?

I would take it, but I don't think a dissociative right now would be sensible. I am already dissociated in my DP/DR (which is a dissociative disorder). :(
 
I don't think anyone can answer that question... it's like asking, why do some people have meaningful, paradigm-shifting experiences on psychedelics, and some people don't despite having enjoyable trips.
 
Fair enough. I was also asking that question in mind of pharmacology and individual differences that may lead to a therapeutic effect in some, and not in others. I have never had a paradigm inducing shift on psychdelics mind you. Nothing that has lasted. At the time I didn't regret it, although now I absolutely regret my overall drug use. I wish that I had never touched any drugs whatsoever.

Anyway, I have a problem in the here and now that needs dealing with.
 
serotonin2A said:
There really isn't any criteria that exists to define an excessive increase in gene or protein expression. Remember, there isn't even a consistant way to measure expression level because studies don't normally measure the absolute amount of protein present (there isn't an easy way to do that), but rather typically use indirect measures such as immunostaining intensity, western blot, or cell counting. Those are usually comparative methods (ie, this tissue section has a higher level then this other tissue section). It is often impossible to compare those results across studies because of sensitivity differences. Mass-spec methods can be used to detect protein levels directly but are rare.


Often, increases induced by non-natural manipulations (e.g., viral constructs, drug administration) are classified as overexpression, whereas increases induced by natural means (stress, sex, etc) are classified as expression increases.



See what I wrote above. Usually overexpression is used in the context of an artificial manipulation, whereas increase is usually used for changes induced by natural means.
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Genetic (i.e., non-viral) overexpression of ΔFosB in a set of neurons can be objectively determined based upon the occurrence of the virally-induced behavioral phenotype following chronic exposure to a stimulus in conjunction with measurements of its expression (see the definition I quoted earlier).
The behavioral phenotype induced by ΔFosB overexpression in D1-type NAcc MSNs is mentioned in the review that I mentioned earlier:
"It is well characterized that ΔFosB overexpression in the NAc increases reward drive and substance consumption (73,76,77), whilst decreasing aversion sensitivity (54)."


serotonin2A said:
Medium spiny neurons (MSNs). Cocaine, ethanol, THC, fluoxetine, and social defeat stress in resilient mice induce expression in D1 MSNs; haloperidol induces expression in D2 MSNs; morphine, heroin, sucrose, calorie restriction and juvenile environmental enrichment induce expression in D1 MSNs and D2 MSNs:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834048/#!po=54.1322
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I read this paper a while back (based upon this timestamp, roughly 2 years ago). This table in that paper is particularly informative IMO. NB: "chronic" in this context is 7 days of exposure.

My statement about what set(s) of neurons that the paper you previously quoted was referring to was a bit more general than this though. As you probably know, ΔFosB is induced in a number of brain regions besides the NAcc by addictive drugs, including the prefrontal cortex, VTA, and rostromedial tegmental nucleus (the last one by stimulants alone), potentially among others.

I think it would be interesting if sufficiently long-term exposure to social defeat stress causes ΔFosB overexpression in D1-type NAcc shell MSNs, because those MSNs are responsible for assigning incentive salience and ΔFosB in those neurons positively modulates that cognitive process. If that's indeed the case, I wonder what the clinical implications are.

Sorry for the late reply; as I mentioned earlier, I was busy this week.
 
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This assessment with the doctor had better come through ASAP, im fucking dying out here guys thinking i have go to a hospital or something
 
serotonin2A said:
Remember, there isn't even a consistant way to measure expression level because studies don't normally measure the absolute amount of protein present (there isn't an easy way to do that), but rather typically use indirect measures such as immunostaining intensity, western blot, or cell counting.
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That's not true at all. We use droplet digital PCR to perform absolute quantification of transcripts, and ELISA for protein quantification. For my research, an ELISA is time-consuming, but it's reliable, sensitive and can be incredibly accurate.
 
Charles_Voynich said:
That's not true at all. We use droplet digital PCR to perform absolute quantification of transcripts, and ELISA for protein quantification. For my research, an ELISA is time-consuming, but it's reliable, sensitive and can be incredibly accurate.
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It may not have been clear from my post, but I was specifically referring to measurement of ΔFosB in relevant studies that we have been discussing. Most studies measuring ΔFosB expression in a cell- and brain region-specific manner use immunohistochemistry or Western Blot for detection. I never said there aren't other methods that could be used to detect and measure ΔFosB expression for the same purposes, but those methods are not typically used by studies relevant to the present topic.
 
serotonin2A said:
It may not have been clear from my post, but I was specifically referring to measurement of ΔFosB in relevant studies that we have been discussing. Most studies measuring ΔFosB expression in a cell- and brain region-specific manner use immunohistochemistry or Western Blot for detection. I never said there aren't other methods that could be used to detect and measure ΔFosB expression for the same purposes, but those methods are not typically used by studies relevant to the present topic.
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So, what's the reason they don't? There are obviously Taqman probes for ΔFosB, so I'm not sure why they're not used for absolute quantification. I also don't know what you're getting at with the methods not being relevant; I'm a fan of using whatever it takes to get the data you need, regardless of how "standard" your methods are.
 
Seppi said:
Genetic (i.e., non-viral) overexpression of ΔFosB in a set of neurons can be objectively determined based upon the occurrence of the virally-induced behavioral phenotype following chronic exposure to a stimulus in conjunction with measurements of its expression (see the definition I quoted earlier).
The behavioral phenotype induced by ΔFosB overexpression in D1-type NAcc MSNs is mentioned in the review that I mentioned earlier
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.

Studies can definitely measure expression level and changes in expression, but that doesn't mean that there is an objective standard for defining an "expression increase" vs. "overexpression". The data that would need to be shown is that stress paradigms increase expression to a significantly greater degree than drug administration paradigms, but I haven't been able to locate such evidence. It is entirely possible that the effect of drug abuse and stress on DFosB are being described in different terms ("expression increase" vs. "overexpression"), but that terminology isn't what should be used to form a conclusion -- that should be based on the expression level in the studies.

I would bring to your attention that the review article linked to the quote you posted contained the following passage:

"Interestingly, forms of psychogenic chronic stress including restraint stress (51,64), social defeat (65,66), and chronic unpredictable stress (67) have also been shown to increase DFosB in dynorphin and enkephalin-containing medium spiny neurons (68). This is thought consequential to serum response factor (SRF) expression, as genetic deletion of SRF in the NAc was related to pro-depressant phenotypes (65).
It is suggested that DFosB expression may encompass a stress coping response (69,70), possibly by increased brain sensi-
tivity to neural reward pathways (71). This is consistent with research showing that DFosB induction is essential for a behavioral response to antidepressant fluoxetine, following social defeat (72)."

Again, it is useful to point out that the review is indicating that an increase in the level of DFosB expression is a common effect of both stress and drug abuse. There isn't any indication in their summary that there is a difference in the relative effect on DFosB expression.
 
Charles_Voynich said:
So, what's the reason they don't? There are obviously Taqman probes for ΔFosB, so I'm not sure why they're not used for absolute quantification. I also don't know what you're getting at with the methods not being relevant; I'm a fan of using whatever it takes to get the data you need, regardless of how "standard" your methods are.
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There are two reasons. First, for any given study, there is usually no absolute need to perform a strict quantification. The studies just want to measure a response to some manipulation, and relative changes are good enough to identify and quantify a relative change. It is very easy to collect brain sections and then immunostain them for DFosB and then a few cell type-specific markers, and that is trpically sufgicient to test the hypothesis. Second, it is extremely difficult to look at expression levels using the techniques you mentioned in a manner that is cell- and region-specific. Groups are working on ways to run flow cytometry so that you could sort all of the cells in a brain section micropunch -- which would allow some of those other techniques to be used -- but that still is not common and would be much more time and resource intensive compared to current methods.
 
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serotonin2A said:
There are two reasons. First, for any given study, there is no absolute need to perform a strict quantification. The studies just want to measure a response to some manipulation, and relative changes are good enough to identify and quantify a relative change.
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Right, an entire method of gene expression quantification was developed which was extraneous and unnecessary. I don't buy that for a minute.

Of course, whenever I do gene expression I'm looking for relative changes, but we still use ddPCR because you get unparalleled accuracy and predictability from a single PCR reaction. As far as gene expression goes, there's absolutely no way to get that amount of statistical power in such a short period of time.

Second, it is extremely difficult to look at expression levels using the techniques you mentioned in a manner that is cell- and region-specific. Groups are working on ways to run flow cytometry so that you could sort all of the cells in a brain section micropunch -- which would allow some of those other techniques to be used -- but that still is not common.
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Weird, I do that every day. Difficult does not mean impossible.
 
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Charles_Voynich said:
Right, an entirely method of gene expression quantification was developed which was extraneous and unnecessary. I don't buy that for a minute.

Of course, whenever I do gene expression I'm looking for relative changes, but we still use ddPCR because you get unparalleled accuracy and predictability from a single PCR reaction. As far as gene expression goes, there's absolutely no way to get that amount of statistical power in such a short period of time.



Weird, I do that every day. Difficult does not mean impossible.
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You use ELISA to measure expression of 2 or more proteins within individual neurons in a single brain region? We are not talking about studies using PCR, because that wouldn't measure accumulation of DFosB over an extended period of time. For these studies, there is a requirement to detect two proteins (or one protein and one transcript) in individual cells because the studies have to measure DFosB accumulation and classify the cell chemotype. The classification and measurement also has to be done in a manner that addresses regional differences within striatal subregions.

I never argued that the techniques you mentioned are generally extraneous and unnecessary, but they may be for certain applications. There are always a range of techniques that could be used to test a hypothesis. Given that immunocytochemistry is the standard way to conduct the analysis we are discussing, is it really surprising that it is common to see studies using it? It isn't even necessarily possible to get reviewers to allow you to use a relatively new approach when established procedures work very well.

EDIT: This is certainly an interesting discussion, but I'm not sure how it is really relevant to the topic we are discussing. You asked me a question about why studies were conducted a certain way -- you can certainly disagree with the rationale, but that doesn't change how the studies were conducted.
 
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serotonin2A said:
You use ELISA to measure expression of 2 or more proteins within individual neurons in a single brain region? We are not talking about studies using PCR, because that wouldn't measure accumulation of DFosB over an extended period of time. For these studies, there is a requirement to detect two proteins (or one protein and one transcript) in individual cells because the studies have to measure DFosB accumulation and classify the cell chemotype. The classification and measurement also has to be done in a manner that addresses regional differences within striatal subregions.
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No, I don't use ELISA for expression. In any case, you can probe for multiple different transcripts as a way to identify cell type within a given region, but that doesn't solve the accumulation problem. I guess the crux of this was I thought you were making global statements about quantifying expression and protein levels which were blatantly not true, but I guess since this is specific to dFosB, it makes sense. Sorry for the misunderstanding.

I never argued that the techniques you mentioned are generally extraneous and unnecessary, but they may be for certain applications. There are always a range of techniques that could be used to test a hypothesis. Given that immunocytochemistry is the standard way to conduct the analysis we are discussing, is it really surprising that it is common to see studies using it? It isn't even necessarily possible to get reviewers to allow you to use a relatively new approach when established procedures work very well.
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I used to worry a lot more about using non-standard methods, but considering the research I'm in, we need to re-invent the wheel fairly often, which has gotten downright enjoyable at this point.
 
Oh, I was done. Thus the "sorry for the misunderstanding".

serotonin2A said:
It is actually almost certain that 18-MC produces hallucinogenic effects. The goal of synthesizing 18-MC was to develop a version of ibogaine that doesn't produce effects on sigma-2 sites, because those interactions are believed to be the cause of ibogaine-induced tremor and purkinje cell degeneration. But 18-MC retains ibogaine-like kappa affinity:

https://www.google.com/url?q=http:/...ggTMAQ&usg=AFQjCNGm2d17gUF1cCXgjX9IvYROSGHrxg

The kappa receptor (KOR) is likely the primary mechanism for the hallucinogenic effects of ibogaine. Ibogaine has very interesting effects at KOR -- ibogaine and noribogaine are functionally-selective KOR agonists. Usually KOR agonists produce hallucinations and dysphoria; part of the stress response and withdrawal dysphoria is due to release of dynorphin, which activates KOR. The functional selectivity of ibogaine and especially noribogaine may allow them to induce a KOR-mediated hallucinogenic response without inducing dysphoria; furthermore, noribogaine may persistantly suppresses drug withdrawal by occupying KOR for an extended period, which would prevent dynorphin from binding.
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Honestly, I'm extremely glad I read this. We had been wondering for years why certain psychedelics seem to be used only for treating certain disorders when they're so pharmacologically similar. I knew that ibogaine was, in a sense, an outlier, but I hadn't spent that much time thinking about how different it might be. We wanted to see if any number of psychedelics could be used to "extinguish" a conditioned place preference in animals which had been given cocaine or morphine, but reading this, I'm actually not sure if that experiment would be a good idea.

I've done an awful lot of digging to find any articles I could where they used specifically ibogaine to extinguish a conditioned place preference, but I have yet to find anything. What there's a ton of is using ibogaine to block the acquisition of addiction, which is of course absolutely useless as a therapy.

Oh, for what it's worth, I've been working with ibogaine and it's plasticity-inducing effects in vitro, and oddly enough ibogaine itself doesn't do jack shit. Noribogaine kicks ass, though.
 
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