Serotonin - Dopamin - (mu)-Opioid - connections? Please help me to understand

[palmanita]

Probably it is a stupid question or one that can't be answered in a message board, but let me try to explain ... I'm trying to understand how my depression works, technically. It appears to be a puzzle with a difficulty far beyond of my brain's capacity.

I used to look / think about these neurotransmitter systems isolated, which was obviously wrong (that appears to be a somewhat common fault though). Thought I had tracked it down to something about NMDA and serotonin, that was after I realized that using plain NMDA antagonists is a dead end for me.

Now I'm realizing that moderate dose Codeine (85mg or so) + high dose Memantine (40-60mg) can do the same, or even better, without involving any direct action on serotonin (granted, memantine is a 5-HT3 antagonist, but I don't think that's the miracle point here for now). This feels so naturally serotonergic that I would bet there is some 5-HT disinhibition happening.

Always thought that benzos and opioids must have some similarities (as the same people often like them), but for me they are completely unlike each other. I don't like benzos at all. They take me down and bring relief, for which I am thankful from time to time, but I dislike how they feel and sedate / limit me, what opioids curiously don't do. They are stimulating. On my first try of a tiny bit of heroin I couldn't sleep the whole night. No nausea or itching though (and it was legit heroin).

Also memantine alone appears to do / mess something with the endorphin system. When I was on 40mg/d of memantine and accidentally got exposed to naloxone I got my first terrible taste of opioid withdrawal- without having tolerance to opioids, or even an active opioid in my system!

How are these systems interconnected, is there some stuff online you could recommend to help me understanding this?

 

[Cotcha Yankinov]

There are opoid receptors on GABA interneurons, when opoids bind there the GABA neuron is inhibited and you see increased activity downstream (nucleus accumbens?). I would expect benzos to have the opposite effect in regards to those GABA neurons with opoid receptors.

I think what's key to understand about depression (serotonin as an example) is that even though you may not have a serotonin deficit as the real cause of your depression, boosting serotonin may still help with depression. So just because decreasing or increasing something helps with your depression, it may not necessarily mean it's the real cause.

From what I understand there are different biological origins of depression, some may involve a serotonin deficit because of shifts in tryptophan metabolism, some may have a basis in reduction of neurogenesis because of chronic stress, others may have to do with BDNF over expression strangely. I bet you there are many many different causes of depression, some probably genetic in origin.

Have you ever tried SSRIs?

 

[palmanita]

Thanks for your answer, the point about GABA interneurons is very interesting!

I forgot to add that I also experienced the effect the other way round - moderately dosed DXM (maybe 150-225mg) feels like a dirty version of codeine, yet it lacks any significant mu affinity if I'm correct. Methoxetamine also shows kind of this effect, I know it is a disputed topic but for me there is a striking similarity in subjective quality of effects. So NMDA antagonism + SSRI activity can somehow disinhibit endorphins?

Yes, I have been put on paroxetine in my adolescence, which brought intolerable mood swings and insomnia so it was stopped after one or two weeks. At a later time I got citalopram (20mg) which had a positive and negative effect, it lifted the depression somewhat but exacerbates ADHD-like symptoms and anxiety. I was on it for some months nevertheless, then with additional lamotrigine tried which had next to no effect and thankfully no skin rash. Finally venlafaxine which was an odd one, appears to work instantly and straight on for two weeks or so, then the effects fade and with dosage increase the same side effects as with the other two set in.

 

[Cotcha Yankinov]

NMDA antagonists are weird because NMDA provides a lot of the input to inhibitory interneurons.

DXM is kind of a dirty drug and the NMDA antagonism doesn't really kick in until 250mg or so.

 

[crzydiamond]

In regards to your "trying a tiny bit of heroin and not being able to sleep the whole night"---

That is extremely common in novice opiate users. In the beginning opiates often give an energy--a relaxed yet energetic awake feel that is different from an amphetamine energy.

Generally as one become more experience with opiates that goes away and the person will feel the classic opiate effects such as drowsiness/nodding. Not always though as some like oxycodone are more naturally stimulating.





I was exactly like that way back when I first sniffed some heroin. Laid there in bed awake all night, but comfortable and not a toss/turn aggravated awake

 

[bingey]

^
For me the stimulant effect never went away, i do think serotonin is to blame as depressions most telltale symptom is usually unnatural fatigue (I also get a crash from opiates before WD if I take unreasonable doses for more than 1 day)

 

[Nagelfar]

That is extremely common in novice opiate users. In the beginning opiates often give an energy--a relaxed yet energetic awake feel that is different from an amphetamine energy.

As bingey said about, I think it's more about tolerance, as whenever I up my dosage even now, I become wakeful (i.e. sleep a half-hour, wake up feeling like I have a full night's rest) and I haven't been off of strong opioids (heroin, oxycodone, hydromorphone, etc.) for more than nine months in the past nine years.

 

[MeDieViL]

Probably it is a stupid question or one that can't be answered in a message board, but let me try to explain ... I'm trying to understand how my depression works, technically. It appears to be a puzzle with a difficulty far beyond of my brain's capacity.

I used to look / think about these neurotransmitter systems isolated, which was obviously wrong (that appears to be a somewhat common fault though). Thought I had tracked it down to something about NMDA and serotonin, that was after I realized that using plain NMDA antagonists is a dead end for me.

Now I'm realizing that moderate dose Codeine (85mg or so) + high dose Memantine (40-60mg) can do the same, or even better, without involving any direct action on serotonin (granted, memantine is a 5-HT3 antagonist, but I don't think that's the miracle point here for now). This feels so naturally serotonergic that I would bet there is some 5-HT disinhibition happening.

Always thought that benzos and opioids must have some similarities (as the same people often like them), but for me they are completely unlike each other. I don't like benzos at all. They take me down and bring relief, for which I am thankful from time to time, but I dislike how they feel and sedate / limit me, what opioids curiously don't do. They are stimulating. On my first try of a tiny bit of heroin I couldn't sleep the whole night. No nausea or itching though (and it was legit heroin).

Also memantine alone appears to do / mess something with the endorphin system. When I was on 40mg/d of memantine and accidentally got exposed to naloxone I got my first terrible taste of opioid withdrawal- without having tolerance to opioids, or even an active opioid in my system!

How are these systems interconnected, is there some stuff online you could recommend to help me understanding this?

I suffer from extreme anhedonia, social anxiety and other issues which every stimulant completely resolves, they also make me feel completely normal which is hard to explain.

 

[palmanita]

I suffer from extreme anhedonia, social anxiety and other issues which every stimulant completely resolves, they also make me feel completely normal which is hard to explain.

The same for me. Alpha-PVP was the best I've tried so far, but it's also a true stimulant in that I could stay up all night feeling just normal and awake, in full control. Ethyl-Hexedrone was pretty good too.

I'm on buprenorphine for some time now, and unfortunately it doesn't do what I hoped. Missing MXE like a close friend.. (low dose, there is a nice 'window' slightly above or even below threshold [takes one to two hours to unfold making me thinking about metabolites] but below where the dissociation becomes noticeable) Anyone else here who got into this side of it?

Yes, the stimulating opioids (codeine) give me a short crash too, odd as here is the first time I read that from somebody else.

 

[AlphaMethylPhenyl]

I suffer from extreme anhedonia, social anxiety and other issues which every stimulant completely resolves, they also make me feel completely normal which is hard to explain.

The anxiolytic and antidepressant effects of stimulants don't tend to last with chronic, use, unless one chases it by constantly upping the dose. Your experience of feeling "completely normal" on stimulants is typical of someone after they've become addicted to stimulants.

The same for me. Alpha-PVP was the best I've tried so far, but it's also a true stimulant in that I could stay up all night feeling just normal and awake, in full control. Ethyl-Hexedrone was pretty good too.

I'm on buprenorphine for some time now, and unfortunately it doesn't do what I hoped. Missing MXE like a close friend.. (low dose, there is a nice 'window' slightly above or even below threshold [takes one to two hours to unfold making me thinking about metabolites] but below where the dissociation becomes noticeable) Anyone else here who got into this side of it?

Yes, the stimulating opioids (codeine) give me a short crash too, odd as here is the first time I read that from somebody else.

MXE in also a DRI, as I recall.

 

[Cotcha Yankinov]

I suffer from extreme anhedonia, social anxiety and other issues which every stimulant completely resolves, they also make me feel completely normal which is hard to explain.

I would be curious if we could isolate this improvement to increased catecholamines in the PFC rather than limbic system and such. I would try atomoxetine (might have fucked up spelling) it is a selective NRI and will increase dopamine selectively in the PFC. These effects will probably be a lot more sustainable than from normal stimulants.

 

[palmanita]

The anxiolytic and antidepressant effects of stimulants don't tend to last with chronic, use, unless one chases it by constantly upping the dose. Your experience of feeling "completely normal" on stimulants is typical of someone after they've become addicted to stimulants.

In that one feels even more anxious and depressed when skipping doses, yes. But at this point it is really just consuming for baseline, no more good effects unless the dose is upped, and it isn't sustainable for long, as you've said. This is (for me personally) different from the beneficial effects, there is an overall dirty feeling when running into tolerance as the NRI effects seem to have a different tolerance curve and one gets physical stimulation, tachycardia and potentially anxiety again. Was one of the reasons that I went on memantine. While I was on it, the anti-tolerance and even almost withdrawal preventing [to opioids] as well as general mood stabilizing [as in slower and less mood swings, not anti-depressive] effects lasted.

MXE in also a DRI, as I recall.

Has this been proven in the meantime? Just thought that only NMDA and SERT have been found so far, with the DRI / 5-HT(2a) / mu statement coming from a paper, where it is based on another paper basically just saying "arylcyclohexylamines are also ...", not directly related to MXE which didn't exist to the date of the latter paper.

I've asked here some time ago about MXE and 3-MeO-PCE asking for the effects, will look for the thread. If I remember it correctly, the NMDA antagonism alone leads to increased release of monoamines.

Ketamine is more and less comfortably stimulating for me, insomnia long after the effects have worn off. Know people reported this w/ MXE too in higher dosages.

 

[AlphaMethylPhenyl]

It would depend on the stimulant. Amphetamine and cathinone derived stimulants tend to work more as releasing agents, as I seem to recall, be virtue of facilitated exchange diffusion. Cocaine and ritalin mainly produce effects through reuptake inhibition. And yet chronic abuse (but also in use, oftentimes) of both general categories produce a dirty-feeling, agitated, stimulating effect. I wonder if it somehow has to do with increased activity of the enzyme (I used to know it, brain fart) that catalyzes the metabolism of dopamine into norepinpehrine, and also that which turns norepinephrine into epinephrine. It's an interesting hypothesis.

Also, despite what some say, it's probably true that the longer a drug is used, the more regions of the brain it begins to affect, which makes sense from the rational standpoint that the brain isn't a vacuum. So perhaps dopaminergic action is constant, which gels well with the idea that though chronic stimulant use produces dysphoric stimulation, there is usually also a component of grandiosity there, which can spiral into outright paranoia, the idea of being very important. Maybe when the drug has infiltrated various regions of the brain stem, and/or the amygdala, to some non-specific extent, the dopaminergic action there somehow outweighs the dopamienrgic action in the nucleus accumbens. Just another hypothesis.

The glutamaterigc system is pretty complicated. It involves all kinds of strange things, like metabolism via astrocytes, co-activation by glycine, metabotropic and ionotropic receptors, Mg activation of receptors, and widespread brain plasticity. I would venture to say that NMDA antagonism does different things in different parts of the brain, partly because NMDA antagonists simulate both positive and negative symptoms of schizophrenia, but I'm not too studied up on it. That said, it doesn't make much sense to me that blocking the main excitatory neurotransmitter in the CNS from working would lead to the release of monoamine neurotransmitters, two of which are excitatory (nor/epinephrine), and two of which are usually excitatory (dopamine and serotonin).

I don't know much about MXE, so you could very well be right.

 

[Cotcha Yankinov]

Just thought I'd say I think some of the reports of D2 agonism in NMDA antagonists from I think Seeman are probably innacurate

 

[Cotcha Yankinov]

Also thought I'd comment on NMDA antagonists ability to increase dopamine and induce DeltaFosB - it appears that NMDA is providing a lot of input to inhibitory interneurons that inhibit the nucleus accumbens.

Selective DRIs seem very disappointing and even dysphoric to some. Also cocaine is probably a DAT inverse agonist, and methylphenidate is also possibly a DAT inverse agonist.

Ho, regarding the enzyme, are you thinking of COMT or MAO-B?

 

[serotonin2A]

The monoamines are neuromodulators and can produce both excitatory and inhibitory effects on cell activity.

NMDA-R are an important source of excitatory drive to inhibitory interneurons, which normally acts to suppress the firing if monoamine neurons. So NMDA-R antagonists can increase monoamine release because they disinhibit monoamine neurons.

 

[Cotcha Yankinov]

Hey serotonin, any comment on why DRIs vary in subjective effects from DRAs? Something to do with the expression of DATs in different cell types?

 

[serotonin2A]

Do you mean why do cocaine and amphetamine differ subjectively?
1. Even if they had exactly the same selectivity for DA/NE/5-HT, the MOA of amphetamine means that it has greater max "efficacy". But there are differences in selectivity.
2. Cocaine is a local anesthetic, which is another mechanism through which cocaine produces effects in the brain.
3. Pharmacokinetics can markedly alter how stimulant effects are perceived.
4. Don't forget about the possibility that other interactions can modify their effects. For example, sigma-1 and TAAR1.

But they are not completely different. Sometimes people have some difficulty differentiating them (not accounting for time-course differences):
http://archpsyc.jamanetwork.com/article.aspx?articleid=491586

 

[Cotcha Yankinov]

Hmmmm interesting... Are you of the opinion that cocaine is a DAT inverse agonist? It sounds like different DRIs can induce different confirmations, the whole "open to out" thing and stuff - I think somebody on here suggested that a pure DRI (topamaril?) was dissaponting in subjective effects and was wondering if you had a pure DRA and a pure DRI if they would be similar if the dosages were somewhat similar, though I understand even if you inhibit all of the transporters you might not be able to reach synaptic concentrations of dopamine like you see with DRAs (Is this your first point?)

 

[AlphaMethylPhenyl]

Also thought I'd comment on NMDA antagonists ability to increase dopamine and induce DeltaFosB - it appears that NMDA is providing a lot of input to inhibitory interneurons that inhibit the nucleus accumbens.

Selective DRIs seem very disappointing and even dysphoric to some. Also cocaine is probably a DAT inverse agonist, and methylphenidate is also possibly a DAT inverse agonist.

Ho, regarding the enzyme, are you thinking of COMT or MAO-B?

Yeah, I guess if the whole "dopamine is pleasure" reductivism were true, levodopa would be a controlled substance.

I was thinking of DBH and PNMT, in terms of conversion to norepinephrine, then epinephrine. COMT metabolizes dopamine too into what I guess can be considered a trace amine, and then into an inactive chemical by MAO. MAO can also directly metabolize dopamine too. But it's DBH and PNMT which turn it into norepinephrine, then epinephrine.

The monoamines are neuromodulators and can produce both excitatory and inhibitory effects on cell activity.

NMDA-R are an important source of excitatory drive to inhibitory interneurons, which normally acts to suppress the firing if monoamine neurons. So NMDA-R antagonists can increase monoamine release because they disinhibit monoamine neurons.

And yet it's only when autoreceptors begin to fill up that nor/adrenaline have inhibitory effects, which was presupposed. Dopaminergic activity is not generally associated with inhibitory action. Serotonin has seven subtypes, two of which are inhibitory, if that means anything (it might not, as number of the various subtypes in the brain would determine better, but a five to two is pretty stiff odds).

As stated, I don't know much about the amino acid system.