Change your receptors, change your set point

[BentBuddha]

This is a fascinating article on the up and down regulation of dopamine and serotonin receptors in the brain, as well as insulin. It's a long read, but very well written.

 

Of particular interest to me was the brain scan images of dopamine receptors of ppls brains depending on their activities. The difference between smokers and non smokers really stood out, as well as in the second image between unrestricted eaters and restricted.

 

Would love to see scans of serotonin receptors. Perhaps in my searches I'll come across some. If so, will post links.

 

http://gettingstronger.org/2010/10/change-your-setpoint/

[Altostrata]

Another interesting new topic!

 

The article addresses natural ways to deal with depression, addiction, and diabetes.

 

Please note:

 

- The author of the article takes the "organic imbalance model" at face value. No organic imbalance of any type has ever been demonstrated in mood disorders such as "depression." The "chemical imbalance" theory is a myth promulgated to sell drugs.

 

It's equally unlikely there is any "organic imbalance" in addiction.

 

There are "organic imbalances" in diabetes. They are documented via physical evidence -- blood tests and organ studies.

 

Lumping depression, addiction, and diabetes together as "receptor" issues is a highly questionable premise.

 

- Neuroimaging is on its way to being the new "chemical imbalance" theory. Brain scans are a highly questionable way of observing activity in the brain, see http://www.danielbor.com/dilemma-weak-neuroimaging/

 

The dopamine theory of addiction parallels the "chemical imbalance" theory of depression, and is as valid.

 

Thus, this is horsesh*t as well: "What is particularly interesting is that these low levels of dopamine receptors are also characteristic of drug addicts and alcoholics."

 

- The article lacks citations and seems to have taken most of its information from Wikipedia.

 

Reader beware.

 

- The article contains an intelligent observation about downregulation of serotonin receptors by antidepressants, and its possible consequences in worsening depression.

 

- You cannot get an "excess of serotonin" from diet. Serotonin is one of the most common hormones in the body, and most of it occurs in the gut to aid digestion.

 

- This is true "...phenomenon of receptor downregulation together with excess neurotransmitter has been noted with other antidepressants, such as MAO inhibitors and buproprion, that stimulate the production or prolong the lifetime of dopamine in the synapse. This can lead to tolerance and withdrawal effects."

 

- This is NOT true "In short, in all these cases — obesity, addiction, and depression — receptors are becoming less sensitive to a signaling compound as a reaction to excessive levels of that compound. So too much insulin and leptin lead to insulin and leptin resistance, too much dopamine to a downregulation of dopamine receptors.

 

- The author is focused on weight loss and addiction, and has little to contribute regarding recovery from antidepressant withdrawal.

 

From the article:

 

HOW TO UPREGULATE YOUR RECEPTORS.

 

....

Step 1: Strenuous exercise. Regular, intense exercise can upregulate your insulin receptors. In Dr. Bernstein’s Diet Solution, Richard Bernstein explains the role of exercise in actually reversing insulin resistance by growing new muscle tissue, and by increasing the density of glucose transporter receptors in muscle and other tissues. While his advice is directed primarily towards diabetics, it applies more broadly to anyone with some degree of insulin resistance That includes most of us.

 

....

Furthermore, the exercise must be strenuous and “anaerobic” – not aerobic.

 

....

Glucose transporter (GLUT4) receptors are upregulated by intense exercise. A study reported in the New England Journal of Medicine showed that this upregulation begins to happen within hours, but significant and sustained improvement requires repeated exercise sessions over several weeks. When insulin levels are kept low, the glucose transporters migrate from a location inside the cell to protrude beyond the cell surface, becoming more available to bind glucose and shepherd it into the interior of the cell. With time, the cells can actally express or “grow” additional receptors, increasing the overall rate of glucose transport. This increased response rate is synonymous with “insulin sensitivity”.

This is probably true, but applies to insulin regulation -- the only condition mentioned in the article that has objective measures.

 

Strenuous exercise may not be beneficial for people who are depleted by antidepressant withdrawal syndrome. Strenuous exercise elevates cortisol, while most people with antidepressant withdrawal syndrome are suffering from an iatrogenically induced excess of cortisol.

 

The benefits of anerobic exercise extend not only to upgregulation of insulin receptors, but also to maintaining high levels of dopamine “reward” receptors. A study of exercised rates by McRae et al at University of Texas showed that regular exercise has a protective effect on D2 dopamine receptors, while keeping levels of dopamine (DA) and dopamine metabolite (DOPAC) low. Unexercised rats saw both a decrease in D2 receptor density and an increase in circulating dopamine.

What this means is that exercise helps the body to regulate itself overall.

 

Step 2: Calorie restriction and intermittent fasting.

Again, the research and concepts to which the article refers apply only to insulin regulation and weight loss, which appears to be the writer's main focus.

 

Step 3: Deconditioning and extinction. Pleasure reward circuits do not change overnight. But the good news is that there is plenty of evidence that these reward circuits can be extinguished by classical conditioning techniques. I’ve discussed these deconditioning techniques in depth on the Psychology and Diet pages of this blog, and I’d recommend looking there for details. Extinction involves merely refraining from the undesired behavior (eating, addictive drugs) and allowing the cravings to happen without reinforcing them. It may surprise you how quickly your reward circuits recover, and it is very likely that this involves upregulation of dopamine receptors, so that the brain is more easily “satisifed” without the previously craved behavior.

"It is very likely that this involves upregulation of dopamine receptors" -- oh, really??? Gross, unfounded speculation.

 

Deconditioning is more active than extinction; it requires actively exposing yourself to cues which normally set off the addictive response. This may sound extremely difficult, but is attested to by extensive research, as well as the personal experience of several people who have posted here on the Forum, including myself.

How does this differ from refraining from the "addictive" behavior? Not ingesting addictive substances = not being addicted.

 

One of the more successful applications of active deconditioning is the Sinclair Method, which has been used successfully to extinguish alcoholism while training the former alcoholic to drink moderately. The key is the use of a dopamine blocker, naltrexone, to block the reward circuits during exposure.

Naltrexone treatment for alcoholism is highly controversal. Do not experiment with naltrexone.

 

Any type of extinction should benefit from simultaneous reinforcement of healthy alternative sources of pleasure, while engaging in exercise and intermittent fasting to rebuild the density and sensitivity of receptors. Unless you increase your level of dopamine receptors, you’ll always be vulnerable to the temptation of any pleasure that can “fill your pleasure deficit”.

In other words, a lifestyle change.

 

THE RECEPTOR CONTROL THEORY. Based upon a synthesis of extensive evidence, I’m putting forward in this post an alternative to the classic set point theory of Gordon Kennedy: the receptor control theory. This is a general hypothesis of biological regulation which applies to more than just weight control; it applies to any homeostatic variable that is controlled by cellular receptors — even, for example, pleasure and motivation....

Here the author veers off into his own personal theory of how the human body works. Since he relies a great deal on generalizing the "chemical imbalance" theory, the foundation for his thinking is very shaky.

 

The pleasure budget. The receptor control theory goes beyond weight management to explain more generally the regulation of pleasure in your life. If you have ample dopamine receptors, then a wide variety of stimuli– including food, social interactions, work, and other interests– should provide you with sufficient pleasure to make life not just bearable, but interesting. However, if you end up with an undersupply of dopamine receptors — whether it be from birth, addictions or unremitting stress — then your baseline pleasure “set point” will be low and you’ll be vulnerable to depression, low self-esteem and other aspects of unhappiness. Addictive escapes may provide temporary (but unsustainable) bursts of dopamine, serotonin, and other feel-good neurotransmitters, but at the cost of further downregulating dopamine receptors and feeling worse later on.

His speculations about dopamine receptors and lack thereof are nonsense.

 

It may be the case that all of us have a certain “pleasure budget” — perhaps we need a certain amount of pleasure every week, and we’ll find a way to get it, one way or another....

 

....behavioral changes such as diets which cut off one source of pleasure may require us to find a way to replace that source of pleasure, or else risk rebounding from the diet and regaining the weight we lost.

It's a fairly well-established principle that diets don't work, what you need is a change in habits -- a lifestyle change.

 

The good news here is that there are proven ways to raise our “pleasure” set point. The bad news is that they require significant and sustained effort – no quick fixes. And yet it is the most sustainable way to increase pleasure in life. To paraphrase a saying about fishing sometimes attributed to the Bible: “Give someone a neurotransmitter and they’ll feel good for an hour; teach someone to grow more receptors and they’ll feel good all the time.”

If "growing more receptors" means positive lifestyle changes, this is true.

 

Explanations. The receptor control theory explains a number of observations that cannot be accounted for by classical set point theory:

 

1. Biology is not destiny. Individuals do differ genetically in their tendency to gain weight or to be prone to addiction or depression. You are born with a certain density of receptors and this can be influenced further during prenatal and postnatal development. But it is not the end of the story. The types of foods you eat and the frequency of eating have strong effects on insulin and leptin sensitivity. Likewise, exercise, hard work and a stoic practices can sensitize your dopamine receptors and make you happier and less prone to depression.

"Exercise, hard work and stoic practices" don't do anything in particular to dopamine receptors -- for many, that would be a healthy lifestyle.

2. Obesity is not a constant. Both the weight gain of individuals as they age, and the obesity epidemic of recent decades are often blamed on “calorie imbalance”: eating too much and exercising too little. But this doesn’t explain why this caloric imbalance is happening now as opposed to earlier. Sometimes the uptick in obesity is blamed on the increasing availability of tasty high-calorie food and a less active lifestyle. But that explanation cannot be right, because there has always been tasty food. And as Kolata has shown, controlled interventions to reduce calories and enforce more activity have a poor track record. The reason that body weight set points are rising has more to do with changes in the amounts of food and exercise, as it does with specific types of food, eating patterns and exercise–and the long term hormonal influences of these changes on receptor sensitivity.

This may be true. Again, referring to insulin, etc.

3. Permanent weight loss is still possible. ....Certain diets are quite effective in the short term, including low carbohydrate diets, low glycemic diets, and the Shangri-La Diet (which temporarily suppresses appetite). These diets will temporarily change levels of hormones, neurotransmitters and other signalling compounds to induce satiety and weight loss....

Another specious reference to a non-existent neurotransmitter imbalance.

 

....However, unless appetite circuits are permanently “re-wired” by upregulating hormonal and neural receptors, weight loss will be temporary. Appetite will remain vulnerable to coming back like a tiger, and you may return to your old set point weight — perhaps even plus a few pounds....

This is correct. Weight control depends on lifestyle changes. "Upregulating receptors" is questionable.

 

The best way to upregulate metabolic and appetite receptors is by strenuous exercise, intermittent fasting or deconditioning. Given enough time, persistent and habitual dietary changes can lead to permanent weight loss, particularly when combined with reduced eating frequency, intense exercise, and deconditioning.

Given that his theory of upregulating receptors is probably false, his methods are idiosyncratic. However, they represent a lifestyle change that apparently works for him.

 

Biological basis for Hormetism. The receptor control theory also provides us with a some biological underpinnings for Hormetism and Stoicism, as advocated in this blog. Hard work –tough, uncomfortable and challenging activities–can lower our metabolic and pleasure set points, helping us to lose weight and making us less vulnerable to addictions, cravings and depression. What is exciting to me is that this theory may provide a possible biological basis for the psychological Opponent-Process Theory of Richard Solomon. The basis is located not in transient chemical messengers like neurotransmitter and hormones, but rather in the adpatable receptors located throughout our body on every cell. These receptors are part of the hardware or firmware of our bodies and brains. Receptors are a part of us that cannot be changed overnight, but can only be changed with persistent effort. (And they will not disappear so readily either).

More nonsense about receptors. Yes, every cell has receptors. They enable to body to self-regulate. Living in a healthy way optimizes this self-regulation.

 

I will be the first to acknowledge that at this point the receptor control theory is just that — a theory.....

Thank God. Now take out all the references to "chemical imbalance" in mood and addiction and concentrate on weight control mechanisms, and you might have something.

[Altostrata]

BentBuddha, please take any reference in any article to "neurotransmitter imbalance" as a giant red flag.

[Rhiannon]

I haven't read the article but just want to say that when anyone talks about being able to see receptors or neurotransmitters with a brain scan that's a red flag to me.

 

Unless there is some new amazing technology that just came out that somehow hasn't made the news, there is no way to see neurotransmitter receptors without cutting a brain open, making slices, fixing them with fixative, and looking at them with a very powerful microscope. (Probably an electron microscope, which is a very expensive device and only found in research type labs.)

 

Possibly there is some horrible way to watch neurotransmitters in action in a living mammal brain. They do all kinds of horrible things to rats. But mostly the techniques are pretty crude and when it comes to looking at actual cells in action, in the studies I've seen it's usually cells in culture, removed from their environment and context.

 

As far as I know, the brain scans in existence today detect only the changes of blood flow to different parts of the brain. Alto, or somebody, let me know if I'm wrong about that.

[Rhiannon]

Buddha, it just occurred to me reading this thread that you might feel like you just got jumped on for posting an article of interest to you and possibly to other people to.

 

Sorry, me and Alto are science nerds--okay, well, speaking for myself only, I am definitely a science nerd! I'm just really frustrated with all the cartoons and things they use to sell these drugs when the fact is it's all speculation and imagination, but people trust it because it sounds like science and it looks good and they use persuasive actors. So many people end up harmed as a result, so many lives ruined.

 

Thank you for your contribution of this article. I'll read it when I have a little more time. As long as people realize that pretty much everything that's said about neurotransmitters and neuroscience is speculation and hypothesis--NOT established fact like, say, the law of gravity--this kind of thing can be interesting to talk about.

 

Sorry we kinda jumped on you--it's not you we're jumping on, it's the pseudo$cience behind these drug$ that, when you really look beneath the surface or talk to the actual people who are doing the actual research, you find out is mostly sales propaganda and distortion.

[Rhiannon]

Okay, I was wrong. PET scans can detect uptake of radiolabeled tracers into different parts of the brain. That means they attach a radioactive chemical to a molecule of something the brain would naturally tend to take up and use, and they can detect where that substance ends up being concentrated in the brain.

 

Usually it's glucose but presumably they can inject radiolabeled neurotransmitters and see where they are being concentrated in the brain.

 

My guess is that's what this article was showing.

 

It's still a far cry from "here's a place where there's more dopamine concentration than in another place" to "so that means receptors are doing exactly this that or the other thing on the molecular level".

 

Let alone "the behavior of chemicals we inject into the body is an exact imitation of the behavior of chemicals the brain produces itself on site as needed" or "we can tell by where the brain chemicals are concentrated that genes in the brain must be upregulating themselves and creating new receptors."

 

Kind of a leap seems to me.

 

I have no objection to such leaps as long as they are labeled "hypothesis" (or "speculation") and not "fact."

 

Sadly, my skepticism is well informed by knowing a lot about the shenanigans that have been done in the name of "science." Which REAL scientists don't engage in, but unfortunately there are way too many people who just get the letters after their names.

[Todd]

Please note:

 

- The author of the article takes the "organic imbalance model" at face value. No organic imbalance of any type has ever been demonstrated in mood disorders such as "depression." The "chemical imbalance" theory is a myth promulgated to sell drugs.

 

It's equally unlikely there is any "organic imbalance" in addiction.

 

There are "organic imbalances" in diabetes. They are documented via physical evidence -- blood tests and organ studies.

 

Lumping depression, addiction, and diabetes together as "receptor" issues is a highly questionable premise.

 

- Neuroimaging is on its way to being the new "chemical imbalance" theory. Brain scans are a highly questionable way of observing activity in the brain, see http://www.danielbor.com/dilemma-weak-neuroimaging/

 

The dopamine theory of addiction parallels the "chemical imbalance" theory of depression, and is as valid.

 

Thus, this is horsesh*t as well: "What is particularly interesting is that these low levels of dopamine receptors are also characteristic of drug addicts and alcoholics."

 

- The article lacks citations and seems to have taken most of its information from Wikipedia.

 

Reader beware.

 

- The article contains an intelligent observation about downregulation of serotonin receptors by antidepressants, and its possible consequences in worsening depression.

 

- You cannot get an "excess of serotonin" from diet. Serotonin is one of the most common hormones in the body, and most of it occurs in the gut to aid digestion.

 

...

 

- The author is focused on weight loss and addiction, and has little to contribute regarding recovery from antidepressant withdrawal.

 

....

 

I will be the first to acknowledge that at this point the receptor control theory is just that — a theory.....

Thank God. Now take out all the references to "chemical imbalance" in mood and addiction and concentrate on weight control mechanisms, and you might have something.

 

Hi Altostrata and BentBuddha,

 

Thanks for the thoughtful critique of my blog article. I sincerely appreciate this kind of feedback, as it helps me to strengthen and refine my own thinking

 

I did want to respond on a few points:

 

1. I do not embrace or take at face value the organic imbalance model of depression or addiction. As I understand it "organic imbalance" usually refers to neurotransmitters. I see these as fleeting signals, comparable to software. In my receptor control theory, I'm looking at the more slowly changing "hardware" of the brain - neurons and their receptors.

 

2. While my blog post was never meant to be a peer reviewed science paper, but rather a spur to new thinking, it is not pure speculation. There are a number of good refences hyperlinked within the body of the article. There is evidence for reduced hippocampal mass and serotonin receptor (5-HT2A) in depression. While i agree that some neuroimaging studies are shaky, the work i cited by Volkow and others is solid. These are not regional "blood flow" studies, but careful stdies involving chemical labelling of 5-HT2A receptors :

 

http://news.wustl.edu/news/Pages/3388.aspx

 

3. You might find interesting some of the studies and personal accounts of individuals recovering from a problem that is somewhat related to healing from antidepressants: recovery from porn addiction. Take a look at this website, which makes the link to studies involving the slow healing or "rebooting" process of receptor normalization:

 

http://yourbrainonporn.com/rebooting-accounts

 

Thanks,

 

Todd

[Georgia]

 

 

2. While my blog post was never meant to be a peer reviewed science paper, but rather a spur to new thinking, it is not pure speculation. There are a number of good refences hyperlinked within the body of the article. There is evidence for reduced hippocampal mass and serotonin receptor (5-HT2A) in depression. While i agree that some neuroimaging studies are shaky, the work i cited by Volkow and others is solid. These are not regional "blood flow" studies, but careful stdies involving chemical labelling of 5-HT2A receptors :

 

http://news.wustl.edu/news/Pages/3388.aspx

 

3. Thanks,

 

Todd

 

In the study linked in your item 2, were the subjects in these studies "depressed people" , or were they "people who have been exposed to antidepressant drugs"? Something to think about.

[Altostrata]

Thanks for adding your comment, Todd.

 

I disagree strongly that recovering from porn addiction has anything whatsoever to do with recovering from antidepressant withdrawal or depression.

 

The brain volume studies are as suspect as the neuroimaging studies. I'm not going to take the time to refute this in detail. Please do some more research on your own. So far everything you've done in psychiatry or addiction is superficial and leans on information that is contested.

 

Your lumping depression, antidepressant withdrawal, addiction, and metabolic dysregulation together under a theoretical framework of receptor upregulation and downregulation is highly questionable. You may have found your research to be intellectually stimulating and have discovered some self-care methods that work for you, but I do not believe they are applicable (except in the very general way of leading a healthy lifestyle) for the readers on this site.

 

PS "Growing new receptors" is not really possible. They maintain a homeostasis. Except in the artificial situation of chronic downregulation by exogenous chemicals such as antidepressants, neuroreceptors all over the body upregulate and downregulate as a matter of course. That's how the body works. The inter-regulation of hormones is responsible for overall health.

[Todd]

I disagree strongly that recovering from porn addiction has anything whatsoever to do with recovering from antidepressant withdrawal or depression.

 

I'm not saying these phenomena are identical. I'm only saying that there is evidence of dowregulation of neurotransmitter receptors in both cases. Regarding specifically the effects of antidepressants, a down regulating effect od SSRIs on serotonin receptors has been documented, at least in a significant subset of cases:

 

Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression. [ http://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor: ^ a b Eison AS, Mullins UL (1996). "Regulation of central 5-HT2A receptors: a review of in vivo studies". Behavioural Brain Research 73 (1–2): 177–81. doi:10.1016/0166-4328(96)00092-7. PMID 8788498.]

 

PS "Growing new receptors" is not really possible. They maintain a homeostasis. Except in the artificial situation of chronic downregulation by exogenous chemicals such as antidepressants, neuroreceptors all over the body upregulate and downregulate as a matter of course. That's how the body works. The inter-regulation of hormones is responsible for overall health.

 

Growing new receptors is not really possible???

 

I am using the terms "upregulation" and "downregulation" to encompass changes in both the number and sensitivity of receptors, such as G-coupled protein receptors. Upregulation occurs by synthesis of new receptors, and downregulation by internalization and degradation of receptors. This is fairly conventional understanding, and applies to insulin receptors as well as serotonin (5-HTP2A) receptors.

 

http://en.wikipedia.org/wiki/Downregulation_and_upregulation

http://www.sciencedirect.com/science/article/pii/S0006899310001009

 

Todd

[Altostrata]

And with that, given the authority vested in me, I'm closing this topic.

 

Todd, your theory, which is on very shaky ground in any context, is irrelevant to the mission of this site, which is dealing with tapering off of psychiatric drugs and recovering from withdrawal syndrome.

 

Please review:

What will get you warned or banned

....

- Spouting nonsense about the causes of withdrawal syndrome. You'll need to do a lot of reading and credible citations to come up with original plausible theories.

 

Red flags for nonsense often found in pop psychiatry:

• Reliance on the "chemical imbalance" theory or that mental disorders are due to some kind of neurotransmitter deficiency.
• Reliance on neuroimaging or brain scans.
• Assigning specific functions to specific neurotransmitters ("dopamine is responsible for pleasure"). All neurotransmitters are multifunction; normal functioning depends on their all operating together.
• More to come, I'm sure.

....

 

BentBuddha, thanks for posting what you thought was an intriguing concept. In the future, please be aware of these red flags.