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Upregulating Dopamine Receptors; Is there anyway to do this?

K

Knight

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Apr 26, 2012
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Till last month, I was on anti-depressants for the past 3 years for mild-moderate depression. The doctor cycled me through Escitalopram, Sertraline, Duloxetine, Desvenlafaxine, Reboxetine, Amytryptyline, Doxepin, Imipramine, Clomipramine, Desipramine, Pramipexole, Diazepam, Lorazepam, Clonezapam, Mirtazapine, Buproprion and more in various doses and various combinations without any effect. All they did was numb my brain; like applying a topical anaesthetic to your brain.

I didn't realise this earlier but I had the ability to feel happy (although I was depressed) till I started taking Desvenlafaxine 2.5 years ago. By happiness I mean the feeling you get when you accomplish something, seeing your better half, seeing your parents after a long period of time, etc. Now, I can't feel happy. My depression has been resolved (read end of post). My thinking is that since Desvenlafaxine is a SNRI, the norepinephrine inhibition caused too much dopamine to be released in my synapses, causing my receptors to desensitise. I know I am oversimplifying a complex problem, so correct me if I am wrong. But if my thinking is right, how do I resensitise my dopamine receptors?


How I resolved my depression?
My depression had gotten to the point that my doctor suggested Electro-convulsive Therapy. I couldn't feel anything but negative emotions. One day, I literally went to the doctor crying requesting something that will make me feel happy, give me some hope and his idea was to increase the dosage of my meds which hadn't worked the slightest bit in the past three years no matter what the dosage. I decided to take matters in my hands and got hold of some MDMA. I took about 100mg of it and it hit within 10 mins and in 3-4 hours I had epiphanies that resolved my depression. My problem was psychological rather than neurological. I know this was a dangerous thing to do but I was at my wits end. It's been a month, I am off my meds, my mood has been like never before and I feel great.
Now, I am just trying to see if I can help my body heal some of the damage the anti-depressants caused so I can reach baseline and FEEL HAPPY!!

So again how do I upregulate my dopamine receptors?
 
I think you need to ask yourself what you hope to achieve through upregulating dopamine receptors. Neurochemistry is rarely as simple as increased dopamine receptors = increased ability to feel happiness. Nor would upregulation be permanent.

Even if you could upregulate dopamine receptors with some sort of dopamine antagonist, and assuming for a minute that upregulated dopamine receptors bring about the kinds of effects you're hoping for, these changes won't last much longer than the amount of time you're taking this new drug. Considering the list of medications you've recently cycled through, and the fact that you're feeling something positive without daily medication, do you really want to add another medication to that list?

I also think it's unlikely that any of the above drugs would cause permanent damage to your dopamine system. The brain has an incredible ability to restore itself, but I'll let someone with more specific knowledge on those drugs comment on that point.
 
The best and most reliable way is by eating well, excercising, and leading a life full of novel, stimulating activity.

As a side benefit you will also get in shape & have stories to tell your future children.

Drugs essentially do not "upregulate dopamine receptors" in the way you are expecting them to (instant happiness). Dopamine receptors control a wide variety of things in the brain including muscle motion, impulsivity, etc. - people who have "experimented" with dopaminergic drugs can end up with motor tics, or as a hypersexual gambling addict, etc.
 
sekio said:
The best and most reliable way is by eating well, excercising, and leading a life full of novel, stimulating activity.

As a side benefit you will also get in shape & have stories to tell your future children.

Drugs essentially do not "upregulate dopamine receptors" in the way you are expecting them to (instant happiness). Dopamine receptors control a wide variety of things in the brain including muscle motion, impulsivity, etc. - people who have "experimented" with dopaminergic drugs can end up with motor tics, or as a hypersexual gambling addict, etc.
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This is one story that I could have skipped :) But I understand what you guys are saying. I know neurochemistry is not that simple otherwise we would have figured out what actually causes depression and an effective way to treat it.

I guess I will let nature take its own course and see where it takes me. Thanks for all your help and kind words.
 
nmda antagonists upregulate D2 and D3; also D aspartic acid is said to reverse stimulant tolerance.
 
Happiness is more of a state of mind
You're mistaking pleasure for happiness

Truly, maybe you could try a DRI or DRA antidepressant

Or you need to work on the reasons you're depressed overall

as for upregulating, all I can think of is eating foods high in tyrosine

SSRIs are peculiar, they can permanently alter brain chemistry after a few months of use and stopping, that's one of the many reasons I refuse to try them
 
methylphenidate is a reuptake inhibitor, same with cocaine so that could do the trick. selegine is also useful as it inhibits MAO but i'm unsure of what you're after in your question if i'm honest.

my personal favourite are amphetamines because they produce a hell of a lot of dopamine and release it into your brain. dextroamphetamine is starting trials to be used in major depression, although it reduces the serotonin in the brain dopamine is highly stimulated. i don't know what you mean by your post but essentially amphetamine will boost your dopamine.

hella addictive though and it will run out so as above posters have said, exercise and just generally being healthy with eating styles and lifestyle is what will do the best.

techincally i don't think anything UPregulates them but rather inhibits and creates dopamine.

try taking l-tyrosine with a 50mg pyrox tablet beforehand, use about 1000mg - 2000mg and see if your mood improves. it's not likely you will remain stable on l-tyrosine for a long time but it can demonstrate your lack of dopamine

don't use ECT its a stupid treatment that is dangerous and provides no clinical benefit apart from having your brain zapped and turned into a zombie. fuck that.
 
Nachtrune said:
Some suggest to add dopamine agonists to an SSRI regimen to counter-act side effects. But for me there are too much reports of tolerance and prolonged withdrawal from DA's - and even worse, the chance for extrapyramidal problems ...

I found NMDA antagonists to be the best yet (temporary, but repeatable) known relief for that SSRI induced mad/sadness. Of course, nothing is without a price, I've been using these now far too often and nobody knows what that induces for other changes in my brain and it has a definitely "chemical" or druggy touch to it (not that prescription meds are different in this point, compared to a good dose of a neuroleptic I find the latter much worse) ... but it works. Just keep the dosage as low as possible and be very, very careful for psychotic / personality-changing "side-effects". A risky, because (as far as I know) untested, but successful combination against social inhibitions / apathy was MXE with Pregabalin. Pregabalin works on its own, but without an NMDAA the tolerance skyrockets. DXM with Bupropion was a heavy, euphoric ride (for weeks) too - one that is definitely not worth the real risk and side effects on the cardiovascular system. And it was very borderline to mania.

The other things that sometimes gives a break into that bright, peaceful, "feels like long, long ago" state of mind are serotonin agonists (tryptamines) in sub-hallucinogenic dosages. But chances are that they could cause the opposite, anxiety, looping thoughts etc. - especially when you are on an SSRI or have ceased one recently. And tolerance is massive. (But then AMT was used as an antidepressant in Russia, and at least some anecdotal reports say that this one works for longer periods of time - don't know if this one brings the same emotional blunting as SSRIs. And of course as being RC-only currently, daily usage is really nothing to recommend.)

Pure dopamine is - at least in my experience - not that solution you're searching for. Maybe a really pure DRI would be, but every DRI available has siginificant NE action too and Dopamine gets partly broken down into NE itself ... What you could try here would be Methylphenidate (I found the racemic MPH to be better(!) than Dex-MPH about mood lifting) / Amphetamine combined with something like Clondine that counter acts the Norepinephrine.

Also there are some positive, but also neutral reports for the Racetams - my favorite here is Nootropil. This one is very potent and feels much lighter than the Aniracetam I've tried previously. But have yet to try the Nootropil for a longer amount of time to be sure about it.

--

Would really be interesting if there's something to prevent tolerance to serotonin agonists (have to try this one day with my beloved NMDAAs- mmh, will most likely be more psychedelic than anything else). This could probably make what SSRIs should have been ..... or Tianeptine (suspected serotonin reuptake accelerator)?

--

All this has really something of "chasing the dragon" ... longing for a feeling that I'm not even sure that it's real or just the reality that the world is so grey and depressive ... are these "happy" people all around really that happy and me depressed, or is it all an illusion?
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personally i have used SSRI's and NMDA antagonists (DXM mostly) and found that they were both as rubbish as each other. DXM had a plethora of horrible side effects, such as i couldn't urinate for hours on end even at lower dosages. the reason that you had such a euphoric ride with bupropion is most likely because it inhibits the CYP2D6 enzyme which is used to process DXM. it would have meant that it would have been extremely potent at any level of dosage. pregabalin in my experience is not as great as its made out to be. it made me just feel as if the world were numb to me, no happiness involved at all.

tryptamines... ah yes, trazadone, my old favourite. that made me hallucinate and have vivid nightmares. i took it once (at non anti- depressant levels) for sleep and felt as if id been teleported into another galaxy or universe. like you said, i got the opposite effects from them so be careful, i don't know about you, but they ruined my head for a while afterwards.

MPH is a great booster, but tolerance builds so quickly and that initial honeymoon phase of euphoria and balanced feelings alongside with concentration is short lived. hence why amphetamine combined could be a good idea, but dosage would have to be correctly monitored and changed according to what it is doing to your body. as you need more and more you can develop psychosis too, which is all too un-common around where i live due to amphetamine abuse. i have been on that side of the stick once and yet i still continue to abuse amphetamines, because they are the only thing i need to keep going through the day. they keep me uplifted and energized and able to focus on everything i do. i cycle on and off between them and MPH.

as for something to prevent tolerance to serotonin agonists would be relatively difficult to find as thats a whole other story. tianeptine looks promising, but most likely would cause a depletion or overstimulantion of serotonin in our brain over time, causing us to suffer horrible withdrawals over time if we were taken off the drug and as such would remain effective for x amount of time, then slowly return back to a sense of "normalness" so to speak. we cannot remain high forever unfortunately.

adding a dopamine agonist to an SSRI is essentially balancing our the chemicals in your brain so that you have both elevated dopamine and serotonin, of which (dopamine) will be depeleted slightly, its as if one goes up ones comes down unless you can boost them both. tolerance build up is extremely rapid and withdrawal is long and painful hence why i haven't ceased use of amphetamines/mph, but rather of SSRI's which i can tell you wasn't pleasant in the slightest either, the continual brain zaps were driving me crazy along with the psychosis i was building up to with d-amph.
 
Nachtrune said:
Yes, looks very possible with the CYP2D6 (and probably also 3A4) so that I had high levels of DXM instead of quickly metabolizing it to DXO and 3-MM - I remember one occasion where I tried Wellbutrin to augment the Venlafaxine and as less as 200 mg or so of DXM were full-blown psychedelic without anesthesia or dissociation. Normally I could take the double amount and it just dissociated me. DXM is quite "druggy", at least since I know MXE - that one has it's own synthetic feelings too, but purely psychical compared to the physical discomfort of DXM. But this varies much from person to person, the low dosages (<200mg/d) were acceptable for me until I made the mistake with combining it ...

Isn't trazodone a piperazine? For me it works as a sleep aid, but not a good one.. and have heard of the bunch of "nice" effects it could have..

Pregabaline is overhyped, I fully agree to this. The only way it "works" for once is by taking a megadose ... this would really be an effect I'd like to have constantly. At least it's outstanding in fighting social anxiety ... but when taking it as prescribed, regularly at normal dosages it's more numbing and a bit like I had a neuroleptic expected to feel. Interestingly when combined with low-dose MXE the two are like a different drug ... not that ride of overdosing, but also far from the numbing. The only real physical side effect I have this way is an annoying dry mouth for the first few hours. Sometimes there's an own weird touch to the emotional world.. this is very difficult to describe. Am really unsure if this should be a warning sign to stop. (Un)luckily I'm able to follow school and all on this - better than without, at least concerning social interaction and since the anxiety and stress from that is a real problem for me, I do better marks when on drugs ... :/

Yes, had the same thought, that anything that raises neurotransmitters (be it an SSRI or an other way like Tianeptine) will cause depletion and dependence over time ... interestingly, the NMDA antagonists seem to have a different behavior, at least for me they are much easier to withdraw and seem to "plateau" at some point with tolerance.
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precisely, thats most likely what happened with the dxm. wellbutrin is an extremely potent inhibitor, i'm surprised you werent told about the effects it can have when you were prescribed it.

yes i am wrong, trazadone is a piperazine, sorry my head is a bit switched off at the moment. i meant amytriptiline, which i haven't heard any good reports of when used for depression but rather a sense of detachment from the world and everything in it. doesn't sound too pleasant.

indeed that is the problem with pregabalin and neurotin in fact. its an overprescribed drug which isn't really that good, possibly if you have nerve damage, but not for long term anxiety treatments as it has been promised to do.

i think that nmda receptors are a lot different to serotonin/dopamine receptors in the fact that they can stand the abuse for a greater period of time. that is all really. your tolerance will continue to increase regardless of intake of whatever substance it is, and a return to baseline thoughts will return, possibly even worse than beforehand.

anything that comes up must go back down again. and this may be the case for you. you have to just wait it out until the balance of chemicals in your brain returns back to baseline.

http://www.psychologytoday.com/blog...-study-ssris-markedly-deplete-brain-serotonin

this is relatively new study that i found which proves that srri's are a cause of depression in themselves, if serotonin is what we are working with, in that they will deplete the brain of it long-term as they realise they do not need to produce as much, considering that they are reuptake inhibitiors. of course to begin with you will feel some benefits , but in the long-term your brain realises that it doesnt need to process as much serotonin and as a result doesn't produce as much. the same goes for dopamine reuptake inhibitors.
 
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Wow, so much information!!. I wish I could respond to all of you personally. Someone asked me why I want to "upregulate my Dopamine receptors and what I really wanted to achieve?"

I want to feel pleasure/euphoria/happiness again!!!

I shall you an example. Me and my wife tried 100 mg of 79% pure MDMA (I can vouch for the purity because of the source) again yesterday after a gap of almost a month or so. We had eaten a heavy meal that day so it took about 40 mins to comeup but when it hit, I started feeling the "lovey-dovey" effects. We talked about things and did all the entactogenic activities that MDMA is supposed to induce. However, there was a difference between her and my rolls. She was feeling euphoria. I was just feeling the entactogenic effects. I could literally see her in throes of euphoria as it hit her in waves and nothing for me. The roll lasted for 3 hours for me and then I just felt reallllllllllllly hyper. Like someone gave me a lot of coffee. I know someone may say that maybe the MDMA had some caffeine in it but trust me there wasn't. I don't like feeling buzzed in general and hence I took 1 mg of Alprazolam to kill the buzz and after 10 mins, I reached baseline and fell asleep. My wife on the other hand was still in it for a good 3 more hours. I could hear her singing, dancing, just being euphoric in general. And that's what I want as well.

I know each of us react to chemicals differently but I find it odd that I haven't felt pleasure/euphoria/happiness in the past 2.5 years and that makes me think that it's because of my brain chemistry rather than my lifestyle. I mean it's impossible that anyone won't feel even an iota of euphoria/pleasure in 2.5 years.

To the person who mentioned tianeptine, I was on it too albeit with other SSRIs but that didn't help. Tianeptine just gave me bad nightmares.

Someone said SSRIs are a cause of depression as well and I don't doubt that. I have read many studies that suggest that SSRIs are only effective in severe depression and have an efficacy of 11% compared to 8% for placebos in other kinds of depression. So that means SSRIs have an effective success rate of only 3%. 3%!!!! We wouldn't use condoms if they were effective only 3% of the time, would we? Would we use anti-biotics if they were effective only 3% of the time? Then why do the doctors insist on giving us something that is effective only 3% of the time for depression.

I really wish I hadn't used SSRIs. I have so many side effects to overcome. My libido is slowly returning to normal and my mood has improved thanks to MDMA.

I know cocaine, methyphenidate, crack, etc will cause dopamine to be released in large amounts in my brain but will my receptors react to them since I was giving medication that essentially kept large amounts of dopamine in my synapses effectively desensitising my receptors?

So yes I want to feel pleasure/euphoria/happiness preferably without the use of chemicals!!

Reading all the posts, I see that the gist of every post is to let my body reset on its own but damn it the wait is frustrating!!!
 
of course you will feel good taking mdma, there is no doubt about it. i think that due to your use of ssri's your brain can longer create so much serotonin as your wifes, explaining her euphoria lasting longer (i get the same when i take mdma, it lasts about 2 hours before i just start to feel cranked and weird) BUT, it will be able to with adequate rest from drugs! the reason that psychiatrists are giving you anti-depressants is because they make a lot of money. you have to continually pay fees to see the psychiatrist and you are most definately going to be hooked on whatever drug they put you on.

i wouldnt say go down the crack or cocaine route, thats just obscene and will end up ruining your life.

there is a drug called modafinil that i use sometimes when i feel low. it esentially works on a few of the same receptors as cocaine and is nowhere near as addictive as MPH/d-amps/coke.

frankly i would just wait. exercise, eat properly and wait. it will be a long hard bitch of a time, but in the long run its worth it.
 
I know each of us react to chemicals differently but I find it odd that I haven't felt pleasure/euphoria/happiness in the past 2.5 years and that makes me think that it's because of my brain chemistry rather than my lifestyle. I mean it's impossible that anyone won't feel even an iota of euphoria/pleasure in 2.5 years.
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You need to see a doctor or physiotherapist, we are totally unqualified to give you advice other than "eat healthy & excercise".

It's frustrating indeed, but if you go find activities that engange your brain (hobbies, sports, sex, food, literature, film) evenrtually you will feel much better. Take a holiday if you need to.

Also, lay off the monoamine-releasing drugs like MDMA/stimulants, they are not going to be good for you in the long-term. Mild usage once a month or whatever is fine, but just watch that you don't make yourself depressed.
 
sekio said:
You need to see a doctor or physiotherapist, we are totally unqualified to give you advice other than "eat healthy & excercise".

It's frustrating indeed, but if you go find activities that engange your brain (hobbies, sports, sex, food, literature, film) evenrtually you will feel much better. Take a holiday if you need to.

Also, lay off the monoamine-releasing drugs like MDMA/stimulants, they are not going to be good for you in the long-term. Mild usage once a month or whatever is fine, but just watch that you don't make yourself depressed.
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indeed. only abstinency from drugs will completely heal your receptors and allow them to function normally again. i don't suggest going to see a psychotherapist though as he will more than likely put you on more medication - most people who walk in walk out with a prescription for something or other.

try a natural supplement such as 5-htp, which is meant to boost the serotonin levels in the brain in a natural way. it also helps with sleep at night as it promotes the production of melatonin in the brain which is what we produce before we fall asleep.

with mdma/stims you will feel temporary relief covered by weeks of even worse depression. you can't expect the brain to produce at the same rate it has done beforehand after it has been forced to work so hard in producing the excess from the drug. personally the after effects of an mdma binge stay with me for a good week afterwards, depression and low-mood related symptoms. once it was so bad that i even considered suicide. but remember, you can go back to baseline normal with time, exercise eating healithy and rest.
 
synthetix said:
try a natural supplement such as 5-htp, which is meant to boost the serotonin levels in the brain in a natural way.
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"natural" doesn't equal safe. 5-HTP causes cardiac fibrosis if not co-administered with carbidopa to prevent enzymatic decarboxylation in peripheral tissue. Also, its unlikely to have any efficacy in treating depression.
 
synthetix said:
there is a drug called modafinil that i use sometimes when i feel low. it esentially works on a few of the same receptors as cocaine and is nowhere near as addictive as MPH/d-amps/coke.

frankly i would just wait. exercise, eat properly and wait. it will be a long hard bitch of a time, but in the long run its worth it.
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I'm one of those oddballs that loves modafinil more than amp. I just feel like a academic/sexual god on it. If it didn't give me rampant GI effects I'd be on it every day.

But, one of the things with SSRI's is long term downregulation of 5HT2A and a host of other receptors that are mainly involved in classic melancholic depression. If you have atypical depression... good luck :/

But, why do doctors prescribe antidepressants so widely?
1) Money to be made
2) Some people just want a drug,
3) In the cases they work, THEY WORK. I know several antidepressant success story people, but they're the exception rather than the rule.

I'll see if I can find this paper I had on antidepressant induced receptor expression changes. Its just what this thread needs

Edit: Grrr... its not in my reading list anymore :(
But IIRC it was: 5HT1A decreased, 5HT2A decreased, 5HT3 increased (controversial), B1 decreased, and upregulation of AMPA receptors.
It was also a remarkably consistent pattern regardless of the drug used too, which was very interesting to me.
 
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i think memantine is an agonist at the d2 receptor... could be wrong, it also acts as an antagonist at nmda receptors which should potentiate adderall
 
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