# sensitize dopamine receptors



## michael10364 (Feb 4, 2011)

Deleted.


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## crayzyMed (Nov 2, 2006)

TouchyBoy said:


> someone also has data on how much is the up-regulation of D2 receptors by NMDA antagonism?


NMDA antagonists and dopamine

(PMID: 1382178) Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat.
D2 binding studies carried out in MK-801 chronically treated (0.3 mg/kg/day per os, for 50 days) and control rats revealed an increased receptor density in treated animals without a significant change in receptor affinity.

(PMID: 7770607) Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior.

(PMID: 10443547) Adaptations of NMDA and dopamine D2, but not of muscarinic receptors following 14 days administration of uncompetitive NMDA receptor antagonists.
The same treatment with amantadine did increase [3H]raclopride binding to dopamine D2 receptors by 13.5%.

(PMID: 10214758) Decreased striatal dopamine-receptor binding in sporadic ALS: glutamate hyperactivity?
In drug-naïve, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole.

(PMID: 12832726 Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats.
We can conclude that repeated administration of AMA, given together with IMI, induces the up-regulation of dopamine D2 and D3 receptors in the rat brain.

(PMID: 10096038) Modulation of dopamine D2 receptor expression by an NMDA receptor antagonist in rat brain.
In the striatum, a significant increase in striatal dopamine D2 receptor mRNA levels was shown in animals treated with CPP.

(PMID: 14997010) Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice.
The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.


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## crayzyMed (Nov 2, 2006)

michael10364 said:


> are you experiencing any anhedonia? i dont know if all people that experience DAWS are going through the same thing. but imjust very anhedonic, and i tried a dose of ritalin only to find itmake me worse. i also tried tianeptine. they onlymade me more anhedonic. the methoxetamin is thought to be a dopamine reuptakeinhibitor.. that makes me nervous to take it. and as being an nmda antagonist, i've been taking magnesium and using dextromethorphan with no results. maybe i need a higherdose? maybe methoxetamine is more potent?? or am i just missing something.maybe this is just me seeing the glass half empty.


If ritalin didnt help you, you seem simular to G4D, i recommend ketamine or methoxetamine, they have some dopamine reuptake but thats not really how they work.


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## Vini Vidi Vici (Jul 4, 2009)

ok so like.......... i dont understand, like anything regarding the difference in function of D2 and D3 auto/postsynaptic-receptors. ---- specifically..............

D2 pre-synaptic Agonism reduces Excitatory [glutamate/aspartate/acetylcholine] release and reduces Dopamine synthesis by like tyrosine hydroxylase or something........<> Post-synaptic Agonism,..........is theoretically I think a generally good thing. So if someone uses a selective D2 agonist [with higher agonist affinity for the pre-synaptic....] then subsequently, if tolerance developed, or they stop using it /ect........ you would have like horrible symptoms of painfulness. Not only are post-synaptic D2 downregulated, but the pre-synaptic receptors failure to attenuate Excitatory crap release....... sucks.

Pramipexole, however, is apparently, a D3 [or D2/3 complex ] receptor agonist......

Like my question, is, what do D3 receptors do ? both the pre and post synaptic ones................ are they similar , to D2 ?

--- oh, and while we're on the topic, perhaps someone[*] could possibly know information regarding all the various [like alot....] of D4-receptor subtypes, and their Function?


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## Vini Vidi Vici (Jul 4, 2009)

:teeth

how closely are the functions of D2/3/4 auto/post-receptor correlated-linked-ish-something, to the functions of pre/post-synaptic Muscarinic Acetylcholine receptors, ( M2 and M4, for example, not excluding the other subtypes ) ??

Another question......

[[ How significant, is the M1-muscarinic receptor's enhancement of Excitatory/glutamate/NMDA activity....... like agonizing, [which ? pre or post-synaptic..?] ---- cuz M1 activation enhances/activates Nitric oxide synthase activity, -------- which could be either good or neutral or bad, since Nitric oxide can be horrible or awesome, depending on Glutathione levels and the overall level of Nitric oxide [ like neurotoxic in high concentrations ? but good in low amounts, ] but then it could just react with other random Radical oxygen/nitrogen speices, therefore causing a variable effect dependent on the levels of avaliable reactants,


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## Vini Vidi Vici (Jul 4, 2009)

*RGS9-2* modulates *D2* dopamine receptor-mediated *Ca2+ channel* inhibition in rat striatal cholinergic interneurons.
http://www.ncbi.nlm.nih.gov/pubmed/15534226

--------------------------------------------#

*Differing effects of copper,zinc superoxide dismutase overexpression on neurotoxicity elicited by nitric oxide, reactive oxygen species, and excitotoxins.*

Overexpression of Cu,Zn superoxide dismutase (SOD1) reduces ischemic injury in some stroke models but exacerbates injury in a neonatal stroke model and in other settings. The current study used a SOD1 transgenic (SOD1-Tg) murine cortical culture system, derived from the same mouse strain previously used for the stroke models, to identify conditions that determine whether SOD1 overexpression in neurons is protective or detrimental. The nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine, spermine-NONOate, and diethylamine-NONOate produced less death in SOD1-Tg neurons than in wild-type neurons (p < 0.01). Also, NO produced markedly less 3-nitrotyosine in SOD1-Tg cells. In contrast, the superoxide generator menadione produced significantly greater death and nearly twice as much 2'7'-dichlorofluorescein fluorescence in SOD1-Tg neurons than in wild-type neurons, suggesting increased peroxide formation in the SOD1-Tg cells. No significant difference was observed in the vulnerability of the two cell types to H2O2, the product of the SOD reaction. Overexpression of SOD1 also had no effect on neuronal vulnerability to glutamate, N-methyl-D-aspartate, or kainate. These observations suggest that SOD1 overexpression can reduce neuronal death under conditions where peroxynitrite formation is a significant factor, but may exacerbate neuronal death under conditions of rapid intracellular superoxide formation or impaired H2O2 disposal.

******----*-i dont understand what this article is attempting to conclude.......like, as in , im asking if anyone can understand and translate the primary objective portrayed .......?

http://www.ncbi.nlm.nih.gov/pubmed/10698074


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## michael10364 (Feb 4, 2011)

would ketamine be much better at upregulating D receptors than dextromethorphan?


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## broflovski (Feb 1, 2011)

michael10364 said:


> would ketamine be much better at upregulating D receptors than dextromethorphan?


There is some data for ketamine as potent D2 receptor agonist. The relevant fragment of discussion here on the forum.
Shouldn't it therefore _downregulate _ receptor rather than upregulate? Or, precisely, NMDA-antagonists lacking direct D-agonism must be more efficient than ketamine at upregulating D receptors...


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## crayzyMed (Nov 2, 2006)

broflovski said:


> There is some data for ketamine as potent D2 receptor agonist. Shouldn't it therefore _downregulate _ receptor rather than upregulate?


NMDA antagonism upregulates D2 and D3 expression, because you know, ketamine is sexy.


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## broflovski (Feb 1, 2011)

crayzyMed said:


> NMDA antagonism upregulates D2 and D3 expression, because you know, ketamine is sexy.


Ketamine is sexy, I'd take it :yes 'Party monster'... 
But more in details... Ketamine increases D2 and D3 expression via NMDA antagonism - yes. But it is not the same as upregulation AFAIK. Simple increase in number of receptors may not give an increased overall dopaminergic transmission/response cuz 1) affinity of that receptors may be diminished 2) there may not be enough ligand for all that new receptors to activate. Taking it together with ketamine's putative downregulating affect on affinity of the receptors, that must take place, like with any other agonist, we see rather a controversial picture. Even if the net result is nevertheless D-upregulation, why, again, NMDA-antagonists lacking direct D-agonism must not be more efficient than ketamine at upregulating D receptors?


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## crayzyMed (Nov 2, 2006)

http://www.mindandmuscle.net/forum/...s-against-mdma-and-amphetamine-neurotoxicity/

This thread will have answers for you, make sure to pop a load of amp as its a ****load of info there.


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## crayzyMed (Nov 2, 2006)

> Even if the net result is nevertheless D-upregulation, why, again, NMDA-antagonists lacking direct D-agonism must not be more efficient than ketamine at upregulating D receptors?


Because NMDA antagonism upregulates dopamine like I react when looking at a hot chick, regardless of dopamine agonism this is why they work against damn stim tolerance.


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## crayzyMed (Nov 2, 2006)

> one of which is associated with schizoid personality


Shizo is associated with a load of other things too, exess D2 expression doesnt automatically cause shizo.


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> ok so like.......... i dont understand, like anything regarding the difference in function of D2 and D3 auto/postsynaptic-receptors. ---- specifically..............
> 
> D2 pre-synaptic Agonism reduces Excitatory [glutamate/aspartate/acetylcholine] release and reduces Dopamine synthesis by like tyrosine hydroxylase or something........<> Post-synaptic Agonism,..........is theoretically I think a generally good thing. So if someone uses a selective D2 agonist [with higher agonist affinity for the pre-synaptic....] then subsequently, if tolerance developed, or they stop using it /ect........ you would have like horrible symptoms of painfulness. Not only are post-synaptic D2 downregulated, but the pre-synaptic receptors failure to attenuate Excitatory crap release....... sucks.
> 
> ...


D4 plays the major role in the prefrontal cortex (D1 plays a minimal role) and is involved in cognition.

AFAIK there are only D3 postsynaptic receptors D2 and D3 are involved in depression and social behavor.


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> *RGS9-2* modulates *D2* dopamine receptor-mediated *Ca2+ channel* inhibition in rat striatal cholinergic interneurons.
> http://www.ncbi.nlm.nih.gov/pubmed/15534226
> 
> --------------------------------------------#
> ...


SOD is one of the major body's antioxidant, it concludes that this one can protect against damage caused by oxidative stress but not by excitoxiticy.


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## crayzyMed (Nov 2, 2006)

Vini Vidi Vici said:


> :teeth
> 
> how closely are the functions of D2/3/4 auto/post-receptor correlated-linked-ish-something, to the functions of pre/post-synaptic Muscarinic Acetylcholine receptors, ( M2 and M4, for example, not excluding the other subtypes ) ??
> 
> ...



I never contributed much to this site because of DAWS, so here I am. I'm currently researching this topic, and I may further update this when I learn new stuff. Feel free to contribute and discuss, you know the drill.

Studies:
9264077:
Presynaptic M1 & M2 have an inhibitory effect on D1 & D2 respectively.
----------------------
11589099:
Blockage of M3 receptors decreases the anticataleptic activity of muscarinic M1/M2 antagonists with respect to haloperidol.
----------------------
15869479 & 16216430: 
Tonic cholinergic input of the presynaptic muscarinic receptor on VTA & SNc modulate dopamine release in NAc & striatum respectively. Selective presynaptic blockade of M3, however, increases striatal, but not NAc, dopamine release. 
----------------------
12144929:
In nucleus accumbens, muscarinic M4 receptors, but not M1 recepors, exert a direct inhibitory control on dopamine D1-like receptor signalling. M4 receptor subtype is expressed abundantly in the striatum and various other forebrain regions.
----------------------
PMC17915:
M4 receptors exert inhibitory control on D1 receptor-mediated locomotor stimulation, probably at the level of striatal projection neurons where the two receptors are coexpressed at high levels.
----------------------
15574685:
The M1/M4-preferring muscarinic agonist xanomeline and the M2/M4-preferring agonist BuTAC reversed the apomorphine-induced disruption of PPI in a manner similar to that produced by the D2-like dopamine receptor antagonists haloperidol and olanzapine.
----------------------
19862686:
Preinfusion of scopolamine into the VTA diminished the facilitatory actions of cocaine on LDT stimulation-evoked NAc dopamine efflux through M5 receptors. They also suggest that the development of antagonists aimed at selectively disrupting M5 receptor function may be valuable in reducing abuse liability of psychostimulants.
----------------------
15292665:
M5 muscarinic and alpha7-nicotinic receptors, in combination, are important for prolonged dopamine release. polymorphisms of CHRM5 & CHRNA7 genes could be linked to hereditary schizophrenia.
----------------------
In conclusion:
Presynaptic muscarinic receptors in general, with the exception of M5, exert an inhibitory control on accumbal and striatal dopamine release. (This is why muscarinic antagonists are somewhat helpful in Parkinsonism).

M1 & M2:
Presynaptic M1 & M2 have an inhibitory effect on postsynaptic D1 & D2 respectively. Presynaptic M1 receptors play a major role in striatal dopamine regulation, but not accumbal dopamine regulation.
M3:
Presynaptic M3 receptors exert an inhibitory control on striatal release but do not modulate accumbal dopamine release, serving to counter excessive excitation of nigral dopamine cell activity.
M4:
In NAc, presynaptic M4 receptors exert a direct inhibitory control on dopamine D1-like receptor signalling, a feature not shared by presynaptic M1 receptors in that specific area. It also exert an inhibitory control on striatal dopmaine release, where presynaptic M1 receptors play a major role as well.
M5:
M5 subtypes on VTA and SNc dopamine neurons, contribute to the tonic excitatory regulation of forebrain basal dopamine transmission whereas presynaptic M3 receptors serve to counter excessive excitation of nigral dopamine cell activity.

Source:
http://www.mindandmuscle.net/forum/...ns/page__p__649686__fromsearch__1#entry649686


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## crayzyMed (Nov 2, 2006)

I personally beleive that alpha3beta4 antagonism also upregulates dopamine receptors, another example:


> Eur Neuropsychopharmacol. 2011 Feb;21(2):205-10. Epub 2010 Dec 4.
> Dose-dependent and sustained effects of varenicline on dopamine D2/3 receptor availability in rats.
> Crunelle CL, Schulz S, de Bruin K, Miller ML, van den Brink W, Booij J.
> 
> ...





> Addict Biol. 2009 Sep;14(4):500-2. Epub 2009 Jul 24.
> Varenicline increases striatal dopamine D(2/3) receptor binding in rats.
> Crunelle CL, Miller ML, de Bruin K, van den Brink W, Booij J.
> 
> ...





> Affinity changes of rat striatal dopamine receptors in vivo after acute bupropion treatment
> 
> Purchase
> $ 31.50
> ...


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## crayzyMed (Nov 2, 2006)

^^ Those study's dont rule out there arent associations with other gene's either, for example polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes are indeed associated with shizo, but i do think there will be other associations too, and ppl that have those polymorphisms without shizo.



> . This is the first study supporting a strong association between the dopamine D2 receptor Taq A1 allele with schizoid/avoidant behavior


This study also doesnt state wheter this causes hypoactivity or hyperactivity, and there are loads of other factors too, amp abuse leads to severe dopamine downregulation, but still psychosis due to excess dopamine levels despite low receptor sensivity, or the opposite supersensivity and low dopamine.


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## crayzyMed (Nov 2, 2006)

Regarding the thread we MUST not forget reward requeres rythmic firing of several neurotransmitters activation of receptors, LDOPA while raising dopamine wont improve sa, anhedonia or depression, another example is varenicline wich causes depression despite upregulating dopamine.

Dopamine upregulation is NOT enough, it must involve CB1, mu opioid, 5HT2A, ALPHAB1 upregulation and upregulation of some muscarinic receptors.
Downregulation of kappa.

That covers most important things.

The only option to truly restart reward is ibogaine wich modulates all those receptors.

NMDA antagonism is enough is tolerance PREVENTION in most cases tough, but reversal is limited, as for example drugs of abuse upregulate kappa and nmda antagonists dont downregulate that.


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## crayzyMed (Nov 2, 2006)

Methoxetamine and ketamine also cause alot of adaptive changes much more then normal nmda antagonists wich is why ket "works like magic" for depression and now mxe nearly completely reversed G4D's induced DAWS despite memantine not doing much.


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## crayzyMed (Nov 2, 2006)

^^ It is indeed, i posted that before countering the argument its an adaptative change of low confidence.


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## crayzyMed (Nov 2, 2006)

Its not used daily, a small dose of ket abolishes depression in 90% of the subjects for several weeks, after another small dose is needed. (i think some studys said 10 day relief, other weeks, also depends on doses and dosing regime i think).



> would also be possible to use an NMDA antagonist 6 / 7, and 1 day a week ketamine for its antidepressant effect (based on studies that show lasts about 10 days of the effect of ketamine)?


I currently take DXM everyday (soon replaced with memantine) with small bumps of ket during the day, dont need as much ket for depression relief but i dont have depression, just to augment the anti tolerance effects, no need to take a day off, just take your ket dose.


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## crayzyMed (Nov 2, 2006)

> Could have the same functionality of memantine for all other uses?


I beleive so, i took the close analogue methoxetamine every 3 hours daily for several weeks for tolerance, but due to massive tolerance issues because of stopping mem months ago i cant report any results, i probably need to reset everything with ibogaine first.


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## crayzyMed (Nov 2, 2006)

Pretty insignificant, dont remember how much.


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## michael10364 (Feb 4, 2011)

i just know that cyproheptadine worked amazingly for my DAWS from adderall a few years ago. i dont know the exact way it worked tomake my D receptors sensitive again, but it just did. i tried it this time and developed toohigh a tolerance to it. i think it worked better last time because i had an SSRI help upregulate my dopamine receptors also.


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## michael10364 (Feb 4, 2011)

yeah i,ve been taking forskolin and so far it has had no effect on me whatsoever. what about methdilazine, i've read "methdilazine may have some serotonin antagonistic properties" any idea what receptors it might work on. i cant seem to find anything telling what specific receptors it works on


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## crayzyMed (Nov 2, 2006)

michael10364 said:


> i just know that cyproheptadine worked amazingly for my DAWS from adderall a few years ago. i dont know the exact way it worked tomake my D receptors sensitive again, but it just did. i tried it this time and developed toohigh a tolerance to it. i think it worked better last time because i had an SSRI help upregulate my dopamine receptors also.


Just try memantine mate.


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## stellium n scorpio (Aug 23, 2011)

Hi everyone. I have had anhedonia for 5 years and to say it is hell might be an understatement. Can you guys please give me your suggestions on the best treatment? I did some saliva tests and my dopamine level is fine, just a little above average. My 5hiaa was really low, pea was low and a and cortisol was low, but isocort gave me the worst fatigue I've ever experienced. It's supposed to do the opposite right. Even fish oil worsens my symptoms x10, as does tryptophan which in the beginning for a day or two gave me an amazing feelng of calm like had never, ever felt before. The dead feelng of the Anhedonia was still there though. My whole life, whenever I'd stop eating or eat a lot less and low fat, and those times were few and far between, I'd start feelng sooooo much more alive and pleasure and motivated. That was the Only thing that over made me feel good. I think the fasting increased the number of or sensitized my dopamine receptors, I'm tryng to figure out which. As per the science daily artcle I read, "Calorie restrcton in rats increases dopamne receptor density" Crazymed, I think you said ibogaine is the best treatment for this?? I also heard somone in another forum say uridine is the best way to go, it increases dopamine receptors. I have a bottle of cdp choline by me that I take when I can remember, which has only been 3 times in 3 weeks. I also have an eating disorder, insomnia and ptsd but the Anhedonia and total lack of motivation are the worst. I have tried many natural treatments and been to several different doctors including 3 natural alternatve doctors and nobody knows any thing about this. I am in a grave situatiion. I am ready for it to be over... one way or the other. Please help.


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## stellium n scorpio (Aug 23, 2011)

*Ibogaine for Anhedonia?*

To clarify, I said not eating makes me feel better, I meant before the anhedonia hit full force. Now nothing makes a dent. I guess I will try ibogaine first. I have looked but I cannot seem to find dosing information. Can someone give me a heads up on this and what is a good source to buy from?

Also what you you guys think of ayahuasca?


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## istayhome (Apr 4, 2012)

stellium n scorpio said:


> To clarify, I said not eating makes me feel better, I meant before the anhedonia hit full force. Now nothing makes a dent. I guess I will try ibogaine first. I have looked but I cannot seem to find dosing information. Can someone give me a heads up on this and what is a good source to buy from?
> 
> Also what you you guys think of ayahuasca?


Ibogaine:
http://www.erowid.org/chemicals/ibogaine/ibogaine.shtml

There are many threads on this forum regarding Ayahuasca, just use the search function on this forum.

As for buying illegal drugs - we can't discuss that topic on this forum. Use your head.


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## istayhome (Apr 4, 2012)

stellium n scorpio said:


> Hi everyone. I have had anhedonia for 5 years and to say it is hell might be an understatement. Can you guys please give me your suggestions on the best treatment? I did some saliva tests and my dopamine level is fine, just a little above average. My 5hiaa was really low, pea was low and a and cortisol was low, but isocort gave me the worst fatigue I've ever experienced. It's supposed to do the opposite right. Even fish oil worsens my symptoms x10, as does tryptophan which in the beginning for a day or two gave me an amazing feelng of calm like had never, ever felt before. The dead feelng of the Anhedonia was still there though. My whole life, whenever I'd stop eating or eat a lot less and low fat, and those times were few and far between, I'd start feelng sooooo much more alive and pleasure and motivated. That was the Only thing that over made me feel good. I think the fasting increased the number of or sensitized my dopamine receptors, I'm tryng to figure out which. As per the science daily artcle I read, "Calorie restrcton in rats increases dopamne receptor density" Crazymed, I think you said ibogaine is the best treatment for this?? I also heard somone in another forum say uridine is the best way to go, it increases dopamine receptors. I have a bottle of cdp choline by me that I take when I can remember, which has only been 3 times in 3 weeks. I also have an eating disorder, insomnia and ptsd but the Anhedonia and total lack of motivation are the worst. I have tried many natural treatments and been to several different doctors including 3 natural alternatve doctors and nobody knows any thing about this. I am in a grave situatiion. I am ready for it to be over... one way or the other. Please help.


Are you being treated by a doctor and/or psychiatrist for all of this? It sounds like things are really rough for you and trying to fix it all on your own isn't working; see the professionals man.

I have don't all that bs to re-sensitize dopamine receptors. It's not going to work for you right now unless you start living like an ultra-marathon runner today (and doing the non-stop cardio for real). It sounds like you don't have the motivation to do so, so see a doctor.


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