20 replies to this topic

[Ampa-omega]

M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation.

http://www.ncbi.nlm....pubmed/11392612

Mesopontine cholinergic neurons (Ch5 and Ch6 cell groups) activate the cerebral cortex via thalamic projections, and activate locomotion and reward via dopamine neurons in the substantia nigra and ventral tegmental area (VTA). Nicotinic receptors in VTA activate dopamine neurons quickly, and are needed for the stimulant and rewarding effects of nicotine in rats. Muscarinic receptors in VTA activate dopamine neurons slowly, and are needed for the rewarding effects of hypothalamic stimulation, but do not increase locomotion. Antisense oligonucleotides targetting M5 mRNA, when infused into the VTA, inhibited M5 receptor binding and rewarding hypothalamic stimulation. Mutant mice with truncated M5 muscarinic receptor genes drank more water than wild-type controls. Spontaneous locomotion and locomotor responses to amphetamine and scopolamine were unchanged. Electrical stimulation near Ch6 induced dopamine release in the nucleus accumbens in two phases, an early phase (0-2 min after stimulation) dependent on nicotinic and gluatamatergic receptors in VTA, and a late phase (8-50 min after stimulation) dependent on muscarinic receptors in VTA. The late phase was lost in M5 mutant mice, while the early phase was unchanged. M5 muscarinic receptors bind slowly to muscarinic ligands, and appear to mediate slow secretions.


There are lots of people with motivational problems, especially perhaps related to a lack of a reward response in the brain.

I thought it would be a good thing to share this study to get some feedback about it, if anyone knows anything about the M5 muscarinic receptors in connection to reward response and motivation, and if there are any natural herbals or nootropics that can take advantage of this effect.

also as we likely know there is a connection between choline, nicotine, dopamine,

Edited by Ampa-omega, 28 November 2011 - 11:20 PM.

[ElusiveMind]

Interesting find Ampa-omega. So according to wiki (which isn't a great source but a source to start a search), the ventral tegmental area (VTA) is a hotbed of dopaminergic neurons and GABAergic neurons. The GABAergic neurons regulate the flow of dopaminerigic neurons to the prefrontal cortex, the nucleus accumbens, and the locus coeruleus.

While, what seems like upregulation from M5 receptors (to me anyways, correct me if wrong), the amount of dopamine to the various areas in the brain which help with cognition and concentration may be a benefit, that VTA also deals with fear-conditioning and avoidance (according to wiki). So would that increase or decrease the avoidance and fear-conditioning?
With an increase of dopamine, I would think it would decrease the two areas, but this is why I am asking... anyone?

Thanks.

Pce,
ElusiveMind

Source for Wiki claims: https://en.wikipedia..._tegmental_area

[Ampa-omega]

good catch, yes, it's a hotbed of dopamine and gaba activity, fear condition and avoidance is directly related to motivation by reward response. I don't exactly know, I'm guessing muscarinic receptor agonism would increase dopamine indirectly and reduce task avoidance.

Edited by Ampa-omega, 29 November 2011 - 02:07 AM.

[medievil]

Most muscarinic receptors have anti dopamine property's, wich is why they give antimuscarinics for example to parkinson patients, acetylcholine can induce depression because of this, and scopalamine has been shown to be a potent antidepressant.
Simultamious antagonism of the muscarinics causes a increase in dopamine, wich makes me think the role of M5 isnt that important when other receptors are antagonized too.

[medievil]

I beleive glutamate and mu receptors cause reward and not dopamine wich most likely just induces wanting. Dopamine does corrolate with reward.

[Ampa-omega]

thanks medievil, so glutamate receptors?

yeah the inverse correlation between choline and dopamine seems to ring true with parkinsons but the m5 receptors show increases in dopamine in quite a few studies, perhaps selective agonism of m5 is what is actually necessary,

I looked into m5 recetptors as an alternative option instead of opioids, i think people may have been overlooking the m5 receptors, and anyway how exactly does glutamate increase motivation, how could we do that safely? racetams, then should have some obvious effect on motivation right? or does it require glutamate agonist?

Edited by Ampa-omega, 29 November 2011 - 03:54 AM.

[medievil]

Artane and increasing acetylcholine should show synergy with regards to increasing dopamine, artane blocks M1 and M4 blockade of both is the most important to increase dopamine, the antagonism will cause more M5 and nicotinic agonism tough, altough cognitive impairment probably is an issue because of artane.

Il copy my post from mind and muscle here as it can cause an interesting discussion.

Alpha7 nicotinic agonists and GHB receptor agonists, according to a mate of me its only the glutamate and mu receptors able to cause reward, this goes in line with our inability to feel the reward of all drugs except amphetamine and GHB, he didnt try GHB tough but it induces reward because of both the glutamate system and opiate receptors, and suprise my response to GHB is about 50% blunted compard to other people.

Damned for some reason i can never copy full texts in this textthing, only posts a few lines, read this link:
http://www.mindandmu...35-post205.html

[medievil]

Interesting find Ampa-omega. So according to wiki (which isn't a great source but a source to start a search), the ventral tegmental area (VTA) is a hotbed of dopaminergic neurons and GABAergic neurons. The GABAergic neurons regulate the flow of dopaminerigic neurons to the prefrontal cortex, the nucleus accumbens, and the locus coeruleus.

While, what seems like upregulation from M5 receptors (to me anyways, correct me if wrong), the amount of dopamine to the various areas in the brain which help with cognition and concentration may be a benefit, that VTA also deals with fear-conditioning and avoidance (according to wiki). So would that increase or decrease the avoidance and fear-conditioning?
With an increase of dopamine, I would think it would decrease the two areas, but this is why I am asking... anyone?

Thanks.

Pce,
ElusiveMind

Source for Wiki claims: https://en.wikipedia..._tegmental_area

Dopamine, in particular D2 receptors cause this, acts as a NMDA antagonist in the prefrontal cortex wich can have negative effects on cognition, D1 and D4 cause positive effects tough.

D1 is extremely important for cognition togheter with the glutamate system.

[medievil]

Anti muscarinics increase VTA glutamate besides.

[Ampa-omega]

glad i came back to check, thanks for bringing over your post. m5 receptor is not really going to benefit overall motivation? i find it odd that m5 receptors increase dopamine and reward, do you think selective agonism just for the m5 receptor would be of any benefit for hedonic drive? So since you mention ghb and glutamate receptors for motivation, what do you suggest someone can take?

edit: ok so Artane would block M1 and M4 which will increase dopamine and agonize nicotine and m5 receptors, which would increase dopamine further, sounds viable as an option but cognitive impairment is not good unless it can be worked around somehow.

Edited by Ampa-omega, 29 November 2011 - 09:25 AM.

[ElusiveMind]

Most muscarinic receptors have anti dopamine property's, wich is why they give antimuscarinics for example to parkinson patients, acetylcholine can induce depression because of this, and scopalamine has been shown to be a potent antidepressant.
Simultamious antagonism of the muscarinics causes a increase in dopamine, wich makes me think the role of M5 isnt that important when other receptors are antagonized too.

I am assuming when you're talking about muscarinic receptors having anti dopamine property's, you are referring to the increase or decrease of acetylcholine that is cause from messing around with the muscarinic receptors.
I don't believe the muscarinic receptors can directly influence dopamine levels, only through acetylcholine or some other stepping stone can they achieve this. This sound correct?

Pce,
ElusiveMind

P.S. good to know D1 and D4 are more productive as nootropic target than D2 receptors

Edited by ElusiveMind, 29 November 2011 - 09:29 AM.

[medievil]

Thats a false asumpton, antimuscarinics as an example dont change the acetylcholine levels yet increase dopamine, trough the muscarinic receptors, here's an overview:
http://www.mindandmu...em-interactions

Especially this is interesting:

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.

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.

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).

Here's an excellent paper reviewing M5:

M5 mAChR kinetics
We have shown that LDT stimulation facilitates NAc dopamine
efflux in two distinct phases (Fig. 2A, Table 1). The first phase,
activated immediately with LDT stimulation and lasting 3 min,
is mediated by ionotropic glutamatergic and nicotinic cholinergic
receptors in the VTA (Forster and Blaha, 2000). The second,
activated 8 min after LDT stimulation and lasting 35 min on
average, is mediated entirely by a slow-activating metabotropic
M5 mAChR. M5 mAChRs have been found previously to mediate prolonged salivation (15– 60 min) in response to pilocarpine
administration in mice (Takeuchi et al., 2001). Also, N-methylscopolamine binding to M5 mAChRs in cultured cells has been
found to be the slowest of all mAChRs (association half-life of 6
min, dissociation half-life of 20.5 min) (Ferrari-Dileo et al., 1994).
Despite obvious methodological differences, these time constants
are strikingly similar to our own half-life rise (5.5 min) and decay
(16.5 min) estimates of the M5 mAChR-mediated component.
These results support our hypothesis that M5 mAChRs serve a
unique role in mediating prolonged excitatory effects on midbrain
dopamine neurons (Yeomans et al., 2001).

M5 mAChRs may serve to maintain these dopamine-dependent
behaviors. This hypothesis is consistent with the recent finding
that M5 mAChRs in the VTA are necessary for brain-stimulation
reward (Yeomans et al., 2000).
The majority of studies examining the role of mesopontine
nuclei in incentive-driven behaviors have focused on an anatomically adjacent cholinergic nucleus, the pedunculopontine tegmental nucleus (PPT). It is thought that the PPT is involved in
making associations between environmental stimuli and rewards
by mediating arousal or attentional mechanisms (Garcia-Rill,
1991; Inglis and Winn, 1995). In light of the present data, it is
likely that the LDT serves a similar f unction in incentive behaviors via activation of M5 mAChRs in the VTA.
In addition to their potential significance in motivational behaviors, the role of the PPT in Parkinson’s disease and the role of
the PPT and LDT in schizophrenia are being actively explored
(Zweig et al., 1989; Garcia-Rill et al., 1995; Yeomans, 1995;
Pahapill and Lozano, 2000). Postmortem analyses of brain tissue
from Parkinson’s patients indicate a significant loss of cholinergic
cells in the PPT, which is correlated with dopaminergic cell loss
in the substantia nigra (Jellinger, 1988; Zweig et al., 1989). Conversely, postmortem analyses of certain populations of schizophrenic patients show increased cholinergic cell numbers in the
pons (Karson et al., 1991; Garcia-Rill et al., 1995). Thus, midbrain
M5 mAChR regulation of prolonged dopaminergic activity in the
basal forebrain may represent a new target for pharmaceutical
intervention in cases in which dopaminergic hypoexcitation or
hyperexcitation is apparent. The observations that other receptor
types in the VTA are not affected by transient or permanent
inactivation of M5 mAChRs emphasize the feasibility of using
agents selective to the M5 mAChRs to regulate midbrain dopaminergic cell activity in vivo.

http://www.jneurosci.../RC190.full.pdf

Edited by medievil, 29 November 2011 - 09:51 AM.

[medievil]

glad i came back to check, thanks for bringing over your post. m5 receptor is not really going to benefit overall motivation? i find it odd that m5 receptors increase dopamine and reward, do you think selective agonism just for the m5 receptor would be of any benefit for hedonic drive? So since you mention ghb and glutamate receptors for motivation, what do you suggest someone can take?

edit: ok so Artane would block M1 and M4 which will increase dopamine and agonize nicotine and m5 receptors, which would increase dopamine further, sounds viable as an option but cognitive impairment is not good unless it can be worked around somehow.

Hard to say as no realy selective ligands are available whatever ppl say increases motivation, as examples amphetamine, nicotine, some racetams, cerebrolysin, semax and more things.

I sometimes take artane as it increases avolution and social reward in shizophrenics a disorder i beleive i was developping for various things.

Amisulpiride is interesting too as it works for dysthimia, motivation, social anxiety and also for negative symptons in shizoprhrenia wich is why its sometimes added to classic atypical psychotics, unfortionally it causes a massive increase in prolacting and has tolerance issues.

Some serotonine receptors like 5HT6 improve anhedonia too.

[medievil]

P.S. good to know D1 and D4 are more productive as nootropic target than D2 receptors

D2 and D3 are implicated in efford related decission making tough, and are the dopamine receptors that are the key players in the vta. Those receptors are also implicated in social behavor and hypofunctioning of them can cause social avoidance.

[ElusiveMind]

P.S. good to know D1 and D4 are more productive as nootropic target than D2 receptors

D2 and D3 are implicated in efford related decission making tough, and are the dopamine receptors that are the key players in the vta. Those receptors are also implicated in social behavor and hypofunctioning of them can cause social avoidance.

Good point. So each dopamine subtypes would have to be dealt with differently.... more or less.

Thanks for the link above, looks like a good read and cant wait to dive in. Not the greatest at neurobiology or neurochemistry but always like to learn.

Just as a side note, does anyone know if dopamine and acetylcholine levels effect each other directly or indirectly... or even at all? I have heard that they do effect each other but not quite sure.

Looking into visual hallucinations regarding to parkinson's disease and how treatment with dopamine agonists and levodopa increase the visual hallucinations while, paradoxically, people treated with anticholinergics didn't have as many visual hallucinations.
What strikes me as odd, now with new info on how the muscarinic receptors work, is that both treatments seem to increase dopamine levels, while one works better than another. (If Im following this correctly...)
This seems very strange as anticholinergics are known to cause vivid (and terrifying) hallucinations, but that treatment seems to work better....

Can anyone shed some light on the situation?

Thanks,

ElusiveMind

P.S. Sorry to be taking away from the original post if I am doing so...

Edited by ElusiveMind, 29 November 2011 - 11:03 PM.

[medievil]

Increasing acetylcholine lowers dopamine levels mainly because of M1 and M4 agonism, doing the opposite with antimuscarinics increases dopamine levels, except antagonism of M5 but thats of limited significant effects as the other receptors overpower the effects of that one.

The visuals are dose related, enough D2 agonism for parkinson release also causes psychosis related symptons, the dosage used of artane as an example for symptons relief is not enough to cause hallucinations.

[medievil]

D1 agonism interacts with a peptide wich connects D1 and Alpha7 wich both activate the glutaminergic system as downstream effect.

[medievil]

glad i came back to check, thanks for bringing over your post. m5 receptor is not really going to benefit overall motivation? i find it odd that m5 receptors increase dopamine and reward, do you think selective agonism just for the m5 receptor would be of any benefit for hedonic drive? So since you mention ghb and glutamate receptors for motivation, what do you suggest someone can take?

edit: ok so Artane would block M1 and M4 which will increase dopamine and agonize nicotine and m5 receptors, which would increase dopamine further, sounds viable as an option but cognitive impairment is not good unless it can be worked around somehow.

Hard to say as no realy selective ligands are available whatever ppl say increases motivation, as examples amphetamine, nicotine, some racetams, cerebrolysin, semax and more things.

Sulbutiamine is noted to increase motivation too, its interesting to note all those substances have cholinergic and glutaminergic activity.

[Ampa-omega]

glad i came back to check, thanks for bringing over your post. m5 receptor is not really going to benefit overall motivation? i find it odd that m5 receptors increase dopamine and reward, do you think selective agonism just for the m5 receptor would be of any benefit for hedonic drive? So since you mention ghb and glutamate receptors for motivation, what do you suggest someone can take?

edit: ok so Artane would block M1 and M4 which will increase dopamine and agonize nicotine and m5 receptors, which would increase dopamine further, sounds viable as an option but cognitive impairment is not good unless it can be worked around somehow.

Hard to say as no realy selective ligands are available whatever ppl say increases motivation, as examples amphetamine, nicotine, some racetams, cerebrolysin, semax and more things.

Sulbutiamine is noted to increase motivation too, its interesting to note all those substances have cholinergic and glutaminergic activity.

ok so i just got back, medievil thanks for contributing so much while i was away, anyway ok i get what you are saying, there are no specific ligands identified, although we just might be able to catch onto something, you would think that with so many substances being trialed by so many people online that there may be some definitive substance identified for motivation, adhedonia too although a bit different from depression, and motivation problems, fits in with being a origin of the problem, which may be perceived as a lack of motivation, so this can be a pretty wide spectrum to look into.

choline for the most part in general will lower dopamine, with the exception of m5 receptors but like you said that likely isn't a pronounceable effect, but again who really knows neuroscience is always discovering new things. I'm surprised that specific ligands for motivation arent really known,at least we have some leads to work on,i was looking into nicotine mechanisms on motivation so thats how i stumbled upon that m5 study, i did look into sulbutiamine, although i haven't yet tried it, heard some bad things, unless that can be expounded.

here is some discussion on sulbutiamine and dopamine transport system:
http://www.drugs-for...ad.php?t=101487
http://www.longecity...iamine-worries/

i find it interesting that nicotine and glutamate show areas where this is strong stimulative addiction potential, and they both rely on the choline neurotransmitter a lot as well, so perhaps that could be a good place of where to look. I'll get back to your comments when you are online again.

Edited by Ampa-omega, 30 November 2011 - 02:02 AM.

[medievil]

That link contains a load of bullshit, it decreases dopamine in the prefrontal cortex and this guy is talking shit about it increasing dopamine like stimulants.

Il contribute more later.

[Ampa-omega]

that was a alarming thread, thats why i was a bit worried, but some people did post about negative symptoms from subultiamine, so there may be some type of merit to it.