A review on alcohol: from the central action mechanism to chemical dependency (2015)

[neophyte]

A review on alcohol: from the central action mechanism to chemical dependency

Interesting study on what alcohol does in the brain and mechanism for dependency

[Ne/Neva Eva]

Thanks, Neo.



I thought the following quote was particularly interesting:

[T]he multiple actions of alcohol on the CNS result in a general effect of psychomotor depression, difficulties in information storage and logical reasoning and motor incoordination, in addition to stimulating the reward system, a fact that may explain the development of addiction.

It's important to note that depression, in the context of alcohol, does not mean the mental illness. It means it depresses the central nervous system functions of the body and brain. Meaning, it doesn't cause depression, the mental illness. It causes the brain to lack the ability to tell the body how to move, what to think and where to store that info.

[neophyte]

This section is interesting as it pertains to Baclofen and its supposed mechanism of action

Effects of alcohol on opioid and dopaminergic transmission

Alcohol also exerts effects on the reward system through the opioid and dopaminergic systems.26 This effect is mediated by the release of dopamine in the ventral tegmental area and in the nucleus accumbens of the limbic system.19,27-29 A large number of natural opioid receptors are found around these areas. There are three classes of opioid receptors involved in opioid dependence: mu, delta and kappa.26,29 Opioids activate the reward system in an indirect manner through two actions. The first consists of the binding of opioids to opioid receptors within the reward system.27,29 This binding triggers a signal to release the neurotransmitter dopamine into the synaptic cleft where it binds to D-1 and D-2 receptors of the nerve cell, activating the reward system in the CNS.19,29,30 The second action would be through the GABA system, which inhibits the release of dopamine. However, opioids block the action of this system. As a consequence, the effects of dopamine become more potent and long lasting.31 Within this context, alcohol acts directly on these opioid receptors, with the description of a positive effect on mu opioid receptors, which is related to the feeling of pleasure and stimulation of dopamine release, and a negative effect on delta receptors, increasing alcohol addiction. Studies also report that alcohol can increase the number of beta opioid receptors, which stimulate the release of dopamine. Therefore, the opioid system acts directly on the reward system and is associated with the development of addiction.29

Baclofen hypothetical mechanism of action

It has been demonstrated that baclofen suppresses alcohol-stimulated dopamine release in the shell of the Nucleus accumbens (NAc or NAcc) of rats. Different lines of experimental evidence suggest that mesolimbic dopamine neurons are invovled in the mediation of alcohol intake and reinforcement. interestingly, GABA-b receptors are located in the ventral tegmental area, both on the cell body of dopamine neurons and on the terminals of glutamatengic afferent neurons. Their activation by the GABA-b receptor agonists may exert an inhibitory action on the dopamine neurons. The possible mechanism through which baclofen suppresses alcohol stimulated dopamine release and in turn, dopamine mediated, alcohol reinforced and motivated behaviors

[Otter]

This section is interesting as it pertains to Baclofen and its supposed mechanism of action



Baclofen hypothetical mechanism of action

Hi Neo, I am interested in baclofen's connection with dopamine. Can you simplify what you have posted for us? Not sure I understand it

Thanks.

[Mentium]

Reading the link, the study they refer to concerns low dosage baclofen, i.e. 30 MG a day, whereas the treatment Ameisen developed was for high dosage - in his case up to 300 MG. In any case baclofen seems pretty conclusively to reduce cravings and overall consumption of alcohol.

Hi Neo, I am interested in baclofen's connection with dopamine. Can you simplify what you have posted for us? Not sure I understand it

Thanks.

[terryk]

Hi Neo, I am interested in baclofen's connection with dopamine. Can you simplify what you have posted for us? Not sure I understand it

Thanks.

Otter - As I have been saying for sometime, baclofen's anti-craving mechanism most probably relies on it's modulation (most likely suppression) of dopamine in the mesolimbic reward system. Dopamine is not exactly a "feel good" neurotransmitter as many here have described it, it serves as a tool in our animal brains to reinforce behaviors that are necessary for survival - that is, necessary for survival in a world of scarce resources with no surplus of food, drugs, and alcohol to get obese with, hopped up on, and addicted to.

Here's something that kronkcarr posted a while ago that I found interesting, from http://www.hamsnetwork.org/dopamine.pdf:

Moreover, the experimental evidence suggests that alcohol does not cause the increase in dopamine directly. Rather, it appears that alcohol directly affects the GABA system and the endorphin system.

Neurons from the GABA system extend into the reward pathway and when alcohol affects the GABA system these neurons release dopamine into the reward pathway. Likewise, neurons extend from the endorphin system into the reward pathway and these also release
dopamine into the reward pathway when alcohol directly stimulates the endorphin system (Boileau et al, 2003).

All things which give us pleasure, from a symphony to food to sex to drugs and alcohol, cause a release of dopamine in the reward pathway as well as triggering a number of other events in the brain including endorphin release and activation of the orbitofrontal region of the prefrontal cortex.

Researchers from the 1950s who implanted electrodes into the reward pathway thought that they had discovered the pleasure center of the brain (Olds, 1956). However, research since then has demonstrated that pleasure is a far more complex phenomenon which involves many parts of the brain. Contemporary researchers believe that pleasure has several components such as "liking," "wanting," "learning (pavlovian conditioning)," "reward," and "valuation" (Berridge and Kringelbach, 2008).

Many researchers currently believe that dopamine in the reward pathway is involved in the phenomena of "wanting," "learning," and "reward," but that it is not involved "liking" or "valuation." In other words, the dopamine in the reward pathway may make you crave drugs or alcohol or sex or a symphony, and it may also reinforce habitual drug use, sex, or symphony listening, but it is not responsible for the pleasure you get from these activities .

The pleasure which we get from these things seems to involve neurotransmitters called endorphins and to involve hedonic hot spots. Researchers identify the hedonic hot spots as existing in the Nucleus Accumbens, Ventral Pallidum, and Parabrachial Nucleus.

You may recall that the Nucleus Accumbens is also a part of the reward pathway; this tells us that part of the Nucleus Accumbens is involved in "liking" and part of it is involved in "wanting." The orbitofrontal area of the prefrontal cortex is largely involved in the "valuation" of pleasurable stimuli.

-tk

[Otter]

Thanks, Tk.

So how does this relate to the fact of baclofen being a Gaba b agonist as opposed to a Gaba a agonist, because this is Ameisen's theory, that it works because it is a Gaba b agonist?

From what you have posted, it seems to me, and I'll put this in my own "baby talk" as it were, the drugs which work on Gaba a receptors are doing something with the "pleasure " receptors, whereas baclofen works on Gaba b, which has to do with the underlying "need" but not the actual "pleasure" you might get out of something.

This seems to make some sense because baclofen doesn't give one a sense of euphoria or any pleasurable "high". So, does Gabab have to do with "want" and "need" while Gaba a has to do with "pleasure" ???

[terryk]

bump

[Ne/Neva Eva]

I don't think I read this in it's entirety when it was posted, but it's really interesting. I'm definitely going to have to figure out a way to bump this until I can get back to it and read the whole thing.

Otter - As I have been saying for sometime, baclofen's anti-craving mechanism most probably relies on it's modulation (most likely suppression) of dopamine in the mesolimbic reward system. Dopamine is not exactly a "feel good" neurotransmitter as many here have described it, it serves as a tool in our animal brains to reinforce behaviors that are necessary for survival - that is, necessary for survival in a world of scarce resources with no surplus of food, drugs, and alcohol to get obese with, hopped up on, and addicted to.



Here's something that kronkcarr posted a while ago that I found interesting, from http://www.hamsnetwork.org/dopamine.pdf:

-tk

Here's the info that Kronkcarr posted:

Moreover, the experimental evidence suggests that alcohol does not cause the increase in

dopamine directly. Rather, it appears that alcohol directly affects the GABA system and the

endorphin system. Neurons from the GABA system extend into the reward pathway and when

alcohol affects the GABA system these neurons release dopamine into the reward pathway.

Likewise, neurons extend from the endorphin system into the reward pathway and these also

release dopamine into the reward pathway when alcohol directly stimulates the endorphin

system (Boileau et al, 2003).

All things which give us pleasure, from a symphony to food to sex to drugs and alcohol, cause a

release of dopamine in the reward pathway as well as triggering a number of other events in

the brain including endorphin release and activation of the orbitofrontal region of the

prefrontal cortex. Researchers from the 1950s who implanted electrodes into the reward pathway

thought that they had discovered the pleasure center of the brain (Olds, 1956). However, research

since then has demonstrated that pleasure is a far more complex phenomenon which involves

many parts of the brain. Contemporary researchers believe that pleasure has several components

such as "liking," "wanting," "learning (pavlovian conditioning)," "reward," and "valuation"

(Berridge and Kringelbach, 2008).

Many researchers currently believe that dopamine in the reward pathway is involved in the

phenomena of "wanting," "learning," and "reward," but that it is not involved "liking" or

"valuation." In other words, the dopamine in the reward pathway may make you crave drugs or

alcohol or sex or a symphony, and it may also reinforce habitual drug use, sex, or symphony

listening, but it is not responsible for the pleasure you get from these activities. The pleasure

which we get from these things seems to involve neurotransmitters called endorphins and to

involve hedonic hot spots. Researchers identify the hedonic hot spots as existing in the Nucleus

Accumbens, Ventral Pallidum, and Parabrachial Nucleus as illustrated in Figure 2 (Berridge and

Kringelbach, 2008). You may recall that the Nucleus Accumbens is also a part of the reward pathway; this tells us that part of the Nucleus Accumbens is involved in "liking" and part of it is

involved in "wanting." The orbitofrontal area of the prefrontal cortex is largely involved in the

"valuation" of pleasurable stimuli.

[neophyte]

It's been my understanding also that alcohol's addictive properties stem from increasing dopamine in the Nucleus Accumbens and then down regulation of dopamine receptors there from repeated exposure to alcohol which leads to cravings.

Dopamine is not directly increasing by alcohol but via gaba modulation as kron mentioned, he seems to be very knowledgeable in this area based on his post.

There was a very technical pharmacological discussion in a video about this and the exact mechanism which went over my head but i figured out enough that this is basically how things play out in the brain. Can't remember what the video was called but it was 5 people discussing this, its posted on this forum somewhere, goes for about an hour.

When it comes to Baclofen it works by suppressing this dopamine release.

[Otter]

Very useful, thanks, Neo.

[Otter]

I don't think I read this in it's entirety when it was posted, but it's really interesting. I'm definitely going to have to figure out a way to bump this until I can get back to it and read the whole thing.



Here's the info that Kronkcarr posted:

Moreover, the experimental evidence suggests that alcohol does not cause the increase in
dopamine directly. Rather, it appears that alcohol directly affects the GABA system and the
endorphin system. Neurons from the GABA system extend into the reward pathway and when
alcohol affects the GABA system these neurons release dopamine into the reward pathway.
Likewise, neurons extend from the endorphin system into the reward pathway and these also
release dopamine into the reward pathway when alcohol directly stimulates the endorphin
system (Boileau et al, 2003).
All things which give us pleasure, from a symphony to food to sex to drugs and alcohol, cause a
release of dopamine in the reward pathway as well as triggering a number of other events in
the brain including endorphin release and activation of the orbitofrontal region of the
prefrontal cortex. Researchers from the 1950s who implanted electrodes into the reward pathway
thought that they had discovered the pleasure center of the brain (Olds, 1956). However, research
since then has demonstrated that pleasure is a far more complex phenomenon which involves
many parts of the brain. Contemporary researchers believe that pleasure has several components
such as "liking," "wanting," "learning (pavlovian conditioning)," "reward," and "valuation"
(Berridge and Kringelbach, 2008).
Many researchers currently believe that dopamine in the reward pathway is involved in the
phenomena of "wanting," "learning," and "reward," but that it is not involved "liking" or
"valuation." In other words, the dopamine in the reward pathway may make you crave drugs or
alcohol or sex or a symphony, and it may also reinforce habitual drug use, sex, or symphony
listening, but it is not responsible for the pleasure you get from these activities. The pleasure
which we get from these things seems to involve neurotransmitters called endorphins and to
involve hedonic hot spots. Researchers identify the hedonic hot spots as existing in the Nucleus
Accumbens, Ventral Pallidum, and Parabrachial Nucleus as illustrated in Figure 2 (Berridge and
Kringelbach, 2008). You may recall that the Nucleus Accumbens is also a part of the reward pathway; this tells us that part of the Nucleus Accumbens is involved in "liking" and part of it is
involved in "wanting." The orbitofrontal area of the prefrontal cortex is largely involved in the
"valuation" of pleasurable stimuli.

I'm not sure why TerryK is saying he has been telling me this for a long time. This is what Ameisen says in his book, which I read back in 2009 and is what I have been supporting for seven years now. It's at about page 220 of his book and I've never said anything to the contrary.