'Dopamine Deficiency' and Tolerance

[dooble]

I hope I can make myself clear on this one.

I suffer from anorexia (as a teenager), which has since developed into OCPD (Obsessive-compulsive personality disorder) with serious anxiety, insomnia and RLS.

I've read some studies linking OCPD with D3 receptor malfunction, but I cannot find out whether it means D3 receptor is hyperactive or not responsive or something else (my knowledge of pharmacology is very limited). Also RLS and anorexia according to some studies seem to have something to do with dopamine.

Now suppose there is a disorder such as 'dopamine deficiency' with lower dopamine levels in the brain. I could easily see how this could lead to problems in the reward system and further develop into OCPD.

Recently I've tried Bupropion and it seems to completely erase my OCPD symptoms (plus give me a little high similar or even better to pregabalin or low grade street speed).

However I am afraid of taking Bupropion everyday (now I take it once a week), because I am afraid the effects will stop working. This is the usual problem with antidepressants and other drugs, isn't it?

But, IF there is such a thing as dopamine deficiency, shouldn't bupropion just raise brain dopamine to the level where it is supposed to be? I don't see how tolerance could develop here. If the dopamine deficient system has been balanced back to a 'normal' state, tolerance would require that the receptors adapt to the normal dopamine levels and start to require more dopamine.

In short, my question is: if there is such a thing as dopamine deficiency, which can be cured with stable dose of dopaminergic drugs, will tolerance arise? Dunno if anyone can give a precise answer, but I'd like to hear some opinions.

P.S. I probably will not start taking Bupropion daily cause I like the subtle high. It is, however, the first drug with which I find myself hard to control my intake. And as an ex-anorectic, I've been easily able to regulate MJ, benzo, and even opiate intake.

 

[sekio]

The problem with that model is that things are rarely as simple as a global neuronal deficit of dopamine... in fact you'd see symptoms similar to Parkinson's disease in that case, not malaise and depression...

Malfunctioning postsynaptic receptors are kind of a different thing than lacking the dopamine levels in the first place.

 

[Lightning-Nl]

All of your symptoms are most likely caused by a lack of blood pressure, due to sodium deficiency. In addition to that, if it is a 'dopamine' issue' it is more than likely caused by a certain lack of dopamine in the mesocortical projection. That, or as sekio said - malfunctioning receptors in the same area. Personally, I believe you don't have any malfunctioning relationship of Dopamine in the Mesocortical pathways.

You said you're ex-anorexic. You are more than likely very sodium deficient. Honestly? Get some gel capsules that can hold up to a gram of substance, and start taking 'Salt' supplements. I've started doing the same thing (not because I'm anorexic, but because I have all the same symptoms you describe) and... it's working. And by working, I mean it's REALLY working. However, if you are still anorexic... do not do this! You could give yourself a heart attack.

 

[dooble]

Nah those days are way over, also I take daily supplements nowadays. I also realize any disorder is not likely to be explained by a simple deficiency in one or another monoamine. However I strongly suspect there's something wrong with the reward system in case of OCPD. Anyway maybe it is more a case of malfunction in some receptor (as some studies indicate, the D3 receptor) than an overall deficiency in dopamine.

So yeah, raising dopamine levels is not likely the best option. So far cycling drugs in a reasonable manner has proved to be the best cure for me.

 

[Lightning-Nl]

I strongly suspect there's something wrong with the reward system in case of OCPD. So yeah, raising dopamine levels is not likely the best option. So far cycling drugs in a reasonable manner has proved to be the best cure for me.

OCPD is more than likely caused by an overabundance of dopamine rather than a lack thereof. However, you describe symptoms of both overactive dopamine behavior (OCPD, anxiety), but also a lack of dopamine neurotransmission (RLS, insomnia). I'm actually the exact same and due to what I know about Dopamine and the neuroscience in general - it actually sounds to me like you're adrenergic system is actually deficient.

I say this because of the research that's been done on DBH Deficiency, ADHD, RLS, and REM Sleep Movement Disorder. Dopamine actually has moderate affinity for adrenergic receptors. So if the body has a lack of Epinephrine or Norepinephrine - the body has no choice but to release Dopamine as a substitute for Norepinephrine. I personally believe that's why my symptoms are so odd and my case is so different from others. I don't know anything about you - but it could be our cases are similar.

Personally - I'd very much like to try a course of L-DOPS treatment.

 

[Erikmen]

The problem with that model is that things are rarely as simple as a global neuronal deficit of dopamine... in fact you'd see symptoms similar to Parkinson's disease in that case, not malaise and depression...

Malfunctioning postsynaptic receptors are kind of a different thing than lacking the dopamine levels in the first place.

Couldn´t ever argue with that.

 

[Zeds(NCO2CH2CH3)2]

These dopamine deficiency theories are all flawed there is little empirical evidence. With FMRI and PET you can only measure function or usage as a relation to time etc but NOT True CONCENTRATION. You might say what about isotopic labeling etc you might say what about spectrophotometry using dyes etc but NONE of the methods give anything related to total concentration in relation to function.

Standalone Dopamine isn't even that important as itself for euphoria and mood properties it's just an intermediate key that unlocks thousands of doors.

Zedsdead

 

[Lightning-Nl]

[...]

Your post gave me cancer.

these dopamine deficiency theories are all flawed there is little empirical evidence.

Please actually learn how MRI scan works, how PET scans work and how their functions are entirely different before posting something that isn't even relevant. Yes, we can see under active dopaminergic activity in MRI scans. In fact, just read about Parkinsons Disease and that should give you enough of an explanation to see just how wrong you are.

Standalone Dopamine isn't even that important

Wow... just wow. Please educate yourself. Yes, dopamine is not the only mechanism involved here - but 'standalone dopamine' is absolutely necessary to normal bodily function. I would love to insult you right now, but I learned my lesson after I got a temp-ban for calling someone 'retarded' - so let's just leave it at that.

for euphoria and mood properties

Dopamine, in itself, does not cause euphoria. In fact, high dopamine release actually leads to anxiety, tachycardia, and even psychosis. It contributes to mood properties, but Dopamine, in itself, is in no way responsible for solely regulating your mood.

 

[Zeds(NCO2CH2CH3)2]

Swampfox you obviously are intoxicated and most likely don't have a degree so I'm going to explain this in simplest terms.

My post discussed how you cannot accurately measure concentration of Dopamine at all. You can measure activity that is it.

You bring up the Parkinsons example and yes FMRI and PET (notably two Different Techniques if you couldn't understand this from my posts wording) do show decreased activity but that data is NOT correlative to other conditions.

I don't understand how you are arguing with me when I say Dopamine isn't even that important as a standalone molecule. It's a key intermediary signaling molecule bottom line. You obviously didn't even read the paragraph because if you did instead of quoting broken pieces of the statement then you might even actually learned something.

Also your posts in other threads are wildly amusing with your so called problems. Now let's get back on topic.

 

[sekio]

Hey now, hey now, let's all play nice here. We're all scholars, not children. No need to be aggressive towards each other. Let's pretend we were all mature scientists working to discover the mysteries of the mind within a well established framework.

Like Zed says, dopamine is just one piece to the multifaceted puzzle that we call the brain. From what I understand you can indeed extrapolate synaptic dopamine concentration in the brain by using fMRI (e.g. pre-load your patient with a bunch of radioactive L-DOPA precursors or whatever, to aid in diagnosis of conditions like Parkinson's), but like you said, measuring dopamine levels in the brain on general doesn't really correlate to any specific mood or state, because the presence of dopamine in the synapse doesn't necessarily mean it causes receptor activation, and like I always say, location matters a lot. DA release in motor centres of the brain is going to have much different effects on the psyche than DA release in the nucleus accumbens.

It also doesn't help that fMRI and PET are not really as high resolution as we'd need them to be to get a true functional map of dopamine usage. We're limited to low resolution images either in the time or space dimensions or both.

Given that dopamine is also given IV as a cardiac support drug (not sure how much passes the BBB due to polarity and the 2 free hydroxide groups), I think we would know if administration causes rewarding behaviour. But as far as I know, an IV push of dopamine will just mess with BP and heart rate mostly. Hence why people use drugs like releasing agents, reuptake inhibitors, even postsynaptic D1/D2 agonists.

I've also in the past covered how dopamine release in the NAcc is not a direct reward chemical but rather an "error prediction signal" used to train the mind to respond to unexpectedly good outcomes from otherwise typical behaviours.

 

[Lightning-Nl]

Swampfox you obviously are intoxicated and don't have a degree...

Ha! And you do? Please show me the certificate. There is a whole lot of information that you seem to be missing here. Even if you do have a degree in something - I've talked with several people that all had degrees in either pharmacology, or psychiatry (two of these psychiatrists had PhD's in psychiatry) and told them things that even they didn't know - i.e your point is invalid.

Anyways, this is a forum about drugs. And I'm technically always 'under the influence' of drugs since I take 40 milligrams of racemic amphetamine daily, and .5 milligrams of alprazolam in the morning and in the late afternoon. But since these drugs are prescribed to me for legitimate reasons - I hardly consider that being considered 'intoxicated'. I did take 650 milligrams of Aspirin due to a migraine today - so is that intoxication as well?

My post discussed how you cannot accurately measure concentration of Dopamine at all. You can measure activity that is it.

This is incorrect. You can get measures of dopamine, serotonin, and norepinephrine levels by performing a spinal tap. Granted - these aren't exact concentrations, but they allow doctors to make close to accurate estimates of neurotransmitter levels.

You bring up the Parkinsons example and yes FMRI and PET (notably two Different Techniques if you couldn't understand this from my posts wording) do show decreased activity but that data is NOT correlative to other conditions.

The specific data on parkinsonia isn't attributable to other conditions because this is one specific disease we're talking about. However, in individuals with ADHD - MRI scans easily allow you to see lack of noradrenergic and dopaminergic neurotransmission in patients with the disorder.

Example - fMRI imaging

I don't understand how you are arguing with me when I say Dopamine isn't even that important as a standalone molecule. It's a key intermediary signaling molecule bottom line. You obviously didn't even read the paragraph because if you did instead of quoting broken pieces of the statement then you might even actually learned something.

Your two statements are totally contradictory of each other. Dopamine has to be present in sufficient amounts in order to be the key signaling neurotransmitter that it is. But then again, you assumed I was intoxicated - so I'll let that slide by assuming the same about you.

Also your posts in other threads are wildly amusing with your so called problems.

You have no idea who I am, or what I've been through, are going through, and what my 'so called' problems are. This statement leads me to believe that you're either a psychiatrist with the absurd idea that anyone who needs controlled substances are drug abusers, a nurse practitioner or a substance-abuse therapist. Having the misfortune of dealing with all these kinds of people - I find their total lack of respect and judgemental behavior towards their unfortunate patients to be 'wildly amusing' as well.

Also, I learned plenty from both of your posts. You're a bigot that judges a book by it's cover. Your total lack of respect is mind numbing. Having dealt with so many of you in my very long journey through are incredibly flawed medical system - it angers me to even look at people like you.

Hey now, hey now, let's all play nice here. We're all scholars, not children. No need to be aggressive towards each other. Let's pretend we were all mature scientists working to discover the mysteries of the mind within a well established framework.

Agreed. Now lets get back to talking about something productive.

 

[Lightning-Nl]

Just thought I'd point this out since were on the topic of dopaminergic activity. Using the image above, I illustrated the parts of the brain that are lacking activity in ADHD patients.

Green = Amygdala/Nucleus Accumbens
White = Mesocortical projection
Blue = Locus Coeruleus noradrenergic pathways

As you can clearly see - in patients with ADHD there is a huge lack of activity in mesocortical dopamine pathways (result = locomotor agitation), underactive amygdala/nucleus accumbens activity (result = lack of emotional impulse control), and underactive activity in the noradrenergic pathway from the Locus Coeruleus (result = lack of attention). Quite interesting really...

 

[dooble]

Heh it always gets me kinda scared to post anything on drug-related forums because of the immediate threat of insane flaming.

Anyway sekio I took a look at one of your posts considering dopamine in the topic "What are chills?". The following statement is really interesting:

Dopamine is not a "reward" horomone. It is released in anticipation of reward - release is highest when there is only a 50% chance of getting a reward, at random. If you give a mouse a reward 100% of the time he presses the button, there's no longer a dopamine release.

This could basically explain why during my studies I got into a workaholic state. The initial release of getting actual work done was overwhelming, but decreased over time and led me to chase the high by working more. These kinds of routines or what ever you wanna call them have bugged me all my life. I've always tried to seek a new rewarding activity, but of course they all ultimately fail. Even meditation and relaxing wear out in the end if you do not work hard to develop it. These kinds of problems however are probably better cured otherwise than by drugs, but meh I'm too interested in pharmacology.

Ah fck it I'm way over my depth. Maybe dopamine doesn't matter if I just give myself some chemical compensation after achieving the reward which in itself does not give me any gratification. Or, in a more acceptable manner, when you get 100% reward but no pleasure, you start working towards a bigger reward that is more harder to achieve and you might get that dopamine fix again (if it is even necessary).

Oh and SwampFox56, I've also wonder whether it might be abundance of dopamine in OCPD rather than lack of it. Or any imbalance in the brain. The main reason I've suggested myself to believe the hypothesis of lack of dopamine is because I really do not like the idea of dopamine antagonists and because Bupropion helped my symptoms so much. But I'll definitely try to look for some adrenergic solutions. If I remember correctly Bupropion should enhance NE transmission and so on.

 

[Zeds(NCO2CH2CH3)2]

Swampfox brother you must realize I am just trying to get you to understand more fundamental concepts.

My original argument being that all of these deficiency problems people claim they have are not result of concentration but a result of different receptor function and activity.

This concept of activity is universal.

I was merely trying to elucidate that in people with add/adhd alzheimers etc, they may as well contain same neurotransmitter concentration we don't know at all. We cannot determine this but in order to even do any FMRI or PET scans we have to ASSUME they have a relatively similar constant gaussian distribution in their produced data and similar variance when we compare them. Concentration can never come into effect because it is unreasonable to measure, people just outright attempt to correlate concepts which cannot be related.

For example the layman might looking at your pictures may say wow I guess activity or concentration is increased of Dopamine (completely disregarding the study). As in reality your pictures only show change in haemodynamic response. See below.

You are posting these FMRI pictures but you need to understand what a t value is. In most specific terms the t value is a statistical weighted averageof different spatial planes taking a 3d representation in change in of a certain region in respect to time by using pixel density as a somewhat grid. These produce the nonlinear manipulative data set.

But what is FMRI actually doing? FMRI is using haemodynamic response I. E most known as BOLD response simply known as change in regional blood flow on a multiple axis grid which has regions averaged and correlated to produce t values which statistically sound results at times.

The problem is you still aren't following me when I am saying that you can't measure concentration or activity directly. In your above example you are showing that amphetamine increases regional blood flow or BOLD in a statistically significant matter. You should post the p values too. That is it, you may relate it to activity but this remains hard right now.

I can continue arguing with you for ages honestly because the brain is indeed Pandoras box, people attempt to build models of it ala reading forums and blaming conditions on certain molecules. However in the end you see what all scientists see in that there are missing pieces of the puzzle and the resultant clinical disease states are NOT AS simple as you think they are to be in your basic mental model, so please don't rage when someone is teaching you things that are ACTUALLY useful if you just took a second to think.

Zedsdead

 

[Lightning-Nl]

[...]

Oh, don't worry, I grasped that concept a long time ago. Actual functional efficiency at a receptor is what's the most important part of any neurotransmitters key signaling function. But again, that neurotransmitter has to be released in order to send that signal. So maybe we both got confused because I was trying to explain that there is a lack of release (neurotransmission) of dopamine and norepinephrine in are current models of understanding of those with ADHD.

And yes, the brain is Pandora's box. Even though we've learned an exponential amount about the brain in the last 100 years - I would say we only understand 5% or less of the what/when/where/how/ and why of the brain. That's why I speculate so much. Because everything in the brain is connected. Dopamine receptor agonism will tell other parts of the brain to release Serotonin (for instance). But many Serotonin receptors send the signal to slow down Dopaminergic neurotransmission. It's the endless cycle of downstream activities that really matter.

 

[Thou]

Sorry for being the guy to ask the layman's question, but why is it that fMRI and PET scans aren't used in the medical field to detect psychological ailments as opposed to say, someone with a pen and paper and a pharmacy doing guesswork in a white coat?

I suffer from ADHD-pi, MDD, Panic disorder, Generalized anxiety disorder, agoraphobia, obsessive compulsive tendencies (see reference "just right" OCD), and unexplained neuropathy.

Why are we wasting so much money in this fucking country running in circles rather than moving forward like reasonable, scientific intellectuals with progresssion as a primary goal?



Hint: $

 

[endotropic]

Sorry for being the guy to ask the layman's question, but why is it that fMRI and PET scans aren't used in the medical field to detect psychological ailments as opposed to say, someone with a pen and paper and a pharmacy doing guesswork in a white coat?

I suffer from ADHD-pi, MDD, Panic disorder, Generalized anxiety disorder, agoraphobia, obsessive compulsive tendencies (see reference "just right" OCD), and unexplained neuropathy.

Why are we wasting so much money in this fucking country running in circles rather than moving forward like reasonable, scientific intellectuals with progresssion as a primary goal?



Hint: $

I think this article gives a pretty good summary of why this hasn't taken off yet: Diagnostic Brain Imaging in Psychiatry: Current Uses and Future Prospects

Bottom line: our ability to functionally analyze a living brain is much more limited than most people realize. It's one thing to find a difference between two large groups of people, quite another to pick out a meaningful abnormality in one individual.

 

[Thou]

Read the paper, nevermind.