Neurotransmitters and Drugs

[pharmapsyche]

Neurotransmitters and Drugs

First I'll define what exactly neurotransmitters are and give you a example of a few:
First of all, the primary monoamine neurotransmitters are Dopamine, Norepinephine, and Serotonin.

Neurotransmitters are the chemicals which account for the transmission of singnals from one neuron to the next across the synapses within the brain. They are also found at the axon endings of motor neurons, which is where they simulate the muscle fibers to conctract.

Neurotransmitters:

Acetylcholine- Acetylcholine is imporant to know, becuase it was the first neurotransmitter to ever be discovered. It was first isolated in 1921 by the German biologist, Otto Loewi. Otto Lewoi actually later won the Nobel Prize for his discovery and hard work. Acetylcholine has many different functions such as, it is responsible for much of the stimulation of muscules, including the muscles of the gastro-intestinal system. It is also found in the sensory neurons and in the autonomic nervous system, and has a part in the schedule of REM sleep.

Norepinephrine- Norepinephrine was discovered in 1946 by the Swedish biologist Ulf Von Euler, who also won a Nobel Prize for his work. Norepinphrine is strongly associated with bringing our nervous system into a 'high-alert'. It is prevalent in the sympathetic nervous system and it also increases our blood pressure along with our heart rate. Our adernal glands release it into our blood stream, along with it's colse relative adernalin. Norepinephrine is very important when it comes to forming memories. Amphetamines work by causing the release of Norepinephrine.

Dopamine- Dopamine was discovered by the Swedish biologist Arvid Carlsson. It is an inhibitory neurotransmitter which means that when it finds its way to it's receptor sites, it then blocks the tendenct of that neuron to fire. Dopamine is strongly associated with the reward mechanisms in the brain. Drugs such as cocaine, opium, heroin,alcohol, and nicotine increase the levels of dopamine. Another thing to note is that schizophrenia has been shown to invlove excessive amounts of dopamine in the frontal lobes and drugs that block dopamine are used to help schizophrenics. But also, too little dopamine in the motor areas of the brain are the cause of the illness
Parkinson's disease.

Serotonin- Serotonin is mainly involved in emotion and mood. Too little serotonin has been shown to lead to depression, behavioral problems, obessive-compulsive disorder, and even suicide. Too little also leads to an increased appetite for carbohydrates and trouble sleeping. SSRI's, which are also known as Selective Serotonin Reuptake Inhibitors are drugs that help people with depression by preventing the neurons from taking up excess serotonin, so that there is more floating around in the synapses. An interesting fact is that a little warm mile before bedtime also increases the levels of serotonin. Serotonin also plays a role in perception. All hallucinogens, such as LSD-25 work by attaching to serotonin receptor sites.

Drugs work on Neurotransmitters in one or more of these ways:
1. Drugs can stop the chemical reactions that create neurotransmitters.
2. Drugs can empty neurotransmitters form the vesicles where they are normally stored and protected from breakdowns by enzymes.
3. Drugs can block neurotransmitters from entering or leaving vesicles.
4. Drugs can bind to receptors in place of neurotransmitters.
5. Drugs can prevent neurotransmitters from returning to their reuptake system
6. Drugs can interfere with second messengers, the chemical and electrical changes that take place in a receiving neuron.

[Chaote]

I was under the impression that there were two types of neuro transmitters, excitory and inhibitory and dopamine, seritonin.... were chemical sent to one of the types of neuro transmitters for the desired effect. Am I totally wrong?

[sands of time]

Chaote - I'm not sure exactly what you mean, but dopamine and serotonin are neurotransmitters, they bind with receptors by crossing the synapsis. That is how they work for the most part.

Nice info Pharma

[fatmanstan]

Here's a good slideshow from Dancesafe.org explaining the effects of ecstacy, showing how it, particularly, acts on the neurotransmitters in the brain.

http://www.dancesafe.org/slideshow/index.html

Many of you may have already seen this, but it is a very visual way of describing some of the actions mentioned above.

(not sure if I can post links yet, just copy and paste the URL into the address bar)

This Slideshow was created by Emanuel Sferios. Feel free to reproduce any or all of it at will. All we ask is that you credit Emanuel and DanceSafe. Emanuel can be contacted at at: emanuelsferios@dancesafe.org (emanuelsferios@dancesafe.org)

Mods: hope this isn't against the rules. I have read them, and I'm pretty sure it isn't. However, please feel free to delete if necessary.

[pharmapsyche]

Chaote, you're right-on when you say there are two types of neurotransmitters: excitatory and inhibitory. Basically, a neurotransmitter can either cause a neuron to "fire" (cause depolarization inside of the neuron) or block a neuron from "firing" (cause hyperpolarization inside of the neuron.)

Dopamine is a unique neurotransmitter because it is considered inhibitory yet causes depolarization in some instances... or something like that

[psyche]

Quite nice... I still feel it would've needed introduction of GABA. Gamma-aminobutyric acid is major inhibitory neurotransmitter wich functions almost everywhere on the brain. GABA-receptors are affected by alcohol, benzos and barbiturates for example. And Muscimol also, active ingredient in delerian Fly Agaric.

[Forthesevenlakes]

in response to chaote, most neurotransmitters fall under the categories of either inhibitory or excitatory. GABA I think should have been introduced as well, understanding the shape of the gaba receptor and how it functions allows one to see immediately why, say, mixing alcohol and benzos can be dangerous. Perhaps glutamate should have been introduced too, I cant think of many drugs offhand that affect glutamate levels, but I do know that DXM binds a type of glutamate receptor, among a few other things.

[sands of time]

Chaote, you're right-on when you say there are two types of neurotransmitters: excitatory and inhibitory. Basically, a neurotransmitter can either cause a neuron to "fire" (cause depolarization inside of the neuron) or block a neuron from "firing" (cause hyperpolarization inside of the neuron.)

Dopamine is a unique neurotransmitter because it is considered inhibitory yet causes depolarization in some instances... or something like that

Acetylcholine behaves the same way.

[psyche]

I think it would be good to have own section for neuropharmakology and brain.

[Richard_smoker]

Glutamate is pretty damn important as well.

It is THE excitatory neurotransmitter inside the brain. Why isn't it mentioned??? It's GABA's opposite.

[sands of time]

Glutamate is pretty damn important as well.

It is THE excitatory neurotransmitter inside the brain. Why isn't it mentioned??? It's GABA's opposite.

Glutamate is also the most abundently found neurotransmitter in the brain. Other than that, I don't know much about it actually. I'm assuming it's not given much attention here because it's not one of the primary pleasure neurotransmitters hehe.

[Richard_smoker]

Yeah, you're right about being abundant. It's the primary activating NT in the brain; like GABA is the primary de-activating--or, maybe I should reword-->GABA decreases likelihood of axon transmission, slowing down the circuit, making you feel sedated, etc.

But don't underestimate the power of glutamate. It is the end-result of activation by many drugs including amphetamine, cocaine, etc. Glutamate is the chemical which causes neurotoxicity from overload. It is also the mechanism by which benzo/alcohol withdrawal causes over-excitation neurotoxicity (brain-damage).

By the way, Sandsoftime, I don't remember if I included this as a well recognized form of brain damage or not. Remember? In my 265 pg long reply to your question about drugs and brain damage??

Well, regardless of whether or not i remembered to include it, glutamate toxicity is a well-known cause of withdrawal seizures, and worse--of a type of toxicity that can be thought of as a nerve cell self-destruction cascade. When 1 nerve dies, it loses its glutamate (and DNA and everything else) to its environment. Then that loose glutamate causes chaos in the neighboring cells, leading to toxicity and cell death, which causes more glutamate dumping from dead neurons, etc. Not a very pretty picture.

[Richard_smoker]

Oh yeah! I totally forgot something REALLY important about Glutamate and NMDA receptors!

Remember our old discussions about piracetam, nootropics, and other 'smart drugs'??

Glutamate (and one of it's receptor: NMDA) is very important in memory circuits and it's what is affected by Piracetam, Ibogaine, and DXM. Here's a quote from my latest research into DXM as an Ibogaine replacement (posted under addiction and recovery)
THE GLUTAMANIERGIC PATHWAY:
DXM: is an NMDA ANTAGONIST.
IBOGAINE: is an NMDA ANTAGONIST.

The glutamatergic pathway is implicated in drug abuse and addiction, specifically N-methyl D-aspartate (NDMA) channel receptors.

NMDA antagonists interfere with sensitization, tolerance, and dependence related to stimulant, alcohol, benzodiazepine, barbiturate, and opiate use (Trujillo and Akil, 1991; Wolf and Khansa, 1991; Khanna, Kalant, Shah, and Chau, 1993; File and Fernandez, 1994; Popik and Skolnik, 1996).

NMDA antagonists act by occupying a binding site within a calcium channel, which is normally gated by glutamate, the brain’s principle excitatory neurotransmitter (Helsley, Rabin, and Winter, 2001).

Hope this helps. I'm afraid that all this information is going to do is end up re-affirming how fucking complicated that the human brain actually is! Sorry if I've confused anyone. I can clarify if anyone wants. -RS

[sands of time]

So when one comes off extensive use of almost any drug, glutamate concentrations go through the roof? Many resources claim that opiate use is not neurotoxic, but what your saying conflicts with that. This does sound pretty ugly indeed. Could high glutamate levels result in symptoms such as anxiety?

Another thing... Many doctors believe that Alzheimer's disease is caused, in part, from high levels of glutamate. Some medications work as NMDA antagonists, thus combating the effects of having such high levels of glutamate. As you have said, glutamate inflicts a great deal of damage to the brain in high amounts. It would be interesting to see how the damage caused by drug abuse compares to that of Alzheimers disease. It's also scary to see how Alzheimers disease is so sneaky.

[Richard_smoker]

Could high glutamate levels result in symptoms such as anxiety? YES! This is probably the NUMBER 1 symptom!

Many doctors believe that Alzheimer's disease is caused, in part, from high levels of glutamate. Some medications work as NMDA antagonists, thus combating the effects of having such high levels of glutamate. As you have said, glutamate inflicts a great deal of damage to the brain in high amounts. It would be interesting to see how the damage caused by drug abuse compares to that of Alzheimers disease. It's also scary to see how Alzheimers disease is so sneaky.

Here's a recent article about this very debate/question.

Neuronal Receptor Response May Help Explain Alzheimer's Memory Loss

Georgetown University Medical Center; Science Daily. February 10, 2006

Based on laboratory research, scientists at Georgetown University Medical Center have a new theory as to why people with Alzheimer's disease have trouble performing even the simplest memory tasks, such as remembering a family member’s name.

That’s because they discovered a physical link between apolipoprotein E (APOE), the transport molecules known to play a role in development of the disease, and glutamate, a brain chemical necessary for establishing human memory.

In a study published in the Journal of Biological Chemistry, the research team specifically found that receptors on the outside of brain nerve cells (neurons) that bind on to APOE and glutamate are connected on the surface of neurons, separated from each other by only a small protein.

While the researchers don’t know why these receptors are linked together, they say inefficient or higher-than-average levels of APOE in the brain could possibly be clogging these binding sites, preventing glutamate from activating the processes necessary to form memories.

“We have found out that two receptors previously thought to have nothing to do with each other do, in fact, interact, leading us to conclude that APOE affects the NMDA glutamate channel that is important in memory,” says the study’s senior author, G. William Rebeck, PhD, associate professor of neuroscience in Georgetown’s Biomedical Graduate Research Organization.

The researchers also hypothesize that this interaction might have something to do with development of Alzheimer’s disease, although they stress that at this early stage of research, this is impossible to prove.
Rebeck and first author Hyang-Sook Hoe, PhD, also of Georgetown, say that laboratory work now underway is attempting to unravel the relationship between APOE and NMDA receptors.

APOE is a protein that helps shuttle cholesterol and other non-soluble lipid particles around the body, moving these substances to where they are needed. All cells have receptors that bind on to APOE so that they can use lipids as needed, such as for quick energy, to store as fat for later use, or to repair wounds.

But researchers now know that APOE does more than distribute lipids, especially in the brain. About a decade ago, scientists linked APOE4, one of the three common forms of APOE, to development of Alzheimer’s disease, although the biological link between the protein and neurodegenerative diseases such as Alzheimer’s is not clear.

Based on recent research, Rebeck and others suspect that, in the brain, APOE also acts as a transporter, picking up lipids and perhaps other material that result from normal brain tissue wear and tear, or from trauma, and moving it to where it can be used or can be cleared away from the brain. Work in Rebeck’s lab found that APOE receptor 2 (ApoEr2), one of the eight different APOE receptor types, is crucial to both the development and operation of a normal brain.

Glutamate is a substance released at the synapse of neurons ? the junction between one nerve cell and the next through which chemical messages are transmitted. Glutamate increases the strength of a synaptic response following stimulation. The NMDA glutamate receptor binds on to the drug NMDA, and also on to glutamate, an excitatory neurotransmitter that also stimulates nerve cell activity. Researchers know that the NMDA receptor is needed to produce the long-lasting synaptic response that is necessary in order to establish, or “lay down,” memory, Rebeck says. “The molecular basis of memory depends on NMDA receptor.”

In work leading up to this study, Rebeck and the research team found that adding APOE to neurons in laboratory culture blocked NMDA receptors. In this study, they confirmed through a series of experiments that the receptors for APOE and NMDA interacted, and that the protein that linked the two was PSD95, often found in neural synaptic junctions. Together, they form a multiprotein complex that could presumably be activated by either APOE, NMDA or glutamate.

Rebeck suspects that the APOE4 variant — the one linked to Alzheimer’s disease — is less efficient at removing lipid debris in the brain than is APOE2 or APOE3, and because of this, brain cells secrete more of the faulty protein to do the job. If too much APOE ends up binding to the APOE/NMDA receptor, one of two things could possibly happen, Rebeck says. In one scenario, the receptor becomes over-stimulated due to the accumulating presence of APOE, which could trigger a process called excitotoxicity that results in death of the neruons. Or, in the presence of damage and secreted APOE, the receptor “turns down” its activity — thus, hampering memory formation — until the brain is repaired. “Having damage around tells the brain not to think too much for awhile,” Rebeck says. But if APOE4 cannot clear up accumulating damage, the ability to make new memories, and use old ones, may be increasingly lost.

“This is, of course, speculation, but now we have new avenues in which we can explore the molecular basis of memory and possibly Alzheimer’s disease,” Rebeck says.

The study was funded by the NIH. Co-authors include Ana Pocivavsek and Geetaanjali Chakraborty also of the Department of Neuroscience, Zhanyan Fu, PhD, and Stefano Vicini, PhD, of the Department of Physiology and Biophysics at Georgetown University Medical Center, and Michael D. Ehlers, PhD, of Duke University Medical Center.
Basically, this goes back to the finding that alzheimer's patients have plaques accumulated in their brains. This article is insinuating that the plaques are brought on by having faulty apo-E lipoproteins--much like the cholesterol plaques on arteries of people with atherosclerosis from high cholesterol.

There is some confusion, however, because it seems that NMDA receptors are vital to forming memories. So, I don't understand why an NMDA inhibitor would help with azheimer's disease...

Just trying to clear this up, I found that
Piracetam increases the number of specific NMDA receptors in senile rat brains. The receptors involved appear to be part of the memory process.
If I recall, Piracetam works mostly on another type of glutamate receptor: the AMPA receptor.

Glutamic acid (glutamate) is the chief excitatory neurotransmitter in the mammalian brain. Piracetam has little affinity for glutamate (glutamate) receptors, yet it does have various effects on glutamate neurotransmission. One subtype of glutamate receptor is the AMPA receptor. Micromolar amounts [levels which are achieved through oral Piracetam intake] of Piracetam enhances the efficacy of AMPA-induced calcium influx [which "excites" nerve cells to fire] in cerebeller cells. Piracetam also increases the maximal density of [AMPA glutamate receptors] in synaptic membranes from rat cortex due to the recruitment of a subset of AMPA receptors which do not normally contribute to synaptic transmission." (1 (http://www.piracetam.com/piracetam-1.htm)) Further support for involvement of the glutamate system in Piracetam's action is provided by a Chinese study which showed that the memory improving properties of Piracetam can be inhibited by ketamine, an NMDA (another major subtype of glutamate receptor) channel blocker. (1 (http://www.piracetam.com/piracetam-1.htm))

Furthermore, high dose injected Piracetam decreases mouse brain glutamate content and the glutamate/GABA ratio, indicating an increase in excitatory nerve activity (1 (http://www.piracetam.com/piracetam-1.htm))

At micrornolar levels, Piracetam potentiates potassium-induced release of glutamate from rat hippocampal nerves. (1 (http://www.piracetam.com/piracetam-1.htm))

Given that acetylcholine and glutamate are two of the most central "activating" neurotransmitters and the facilatory effects of acetylcholine/glutamate neural systems on alertness, focus, attention, memory and learning. Piracetam’s effects on acetylcholine/glutamate neurotransmission must he presumed to play a major role in its demonstrated ability to improve mental performance and memory. Although Piracetam is generally reported to have minimal or no side effects, it is interesting to note that[B] Piracetam’s occasionally reported side effects of anxiety, insomnia, agitation, irritability and tremor (18 (http://www.piracetam.com/piracetam/piracetam-concussion.htm)) are identical to the symptoms of excess acetylcholine/glutamate neuroactivity.

In spite of the many and diverse neurological/psychological effects Piracetam has shown in human, animal and cell studies, Piracetam is generally NOT considered to he a significant agonist (direct activator) or inhibitor of the synaptic action of most neurotransmitters. Thus, major nootropic researchers Pepeu and Spignoli report that "the pyrrolidinone derivatives [Piracetam and other racetams] show little or no affinity for central nervous system receptors for dopamine, glutamate; serotonin, GABA or benzodiazepine." (23) They also note however that "a number of investigations on the electrophysiological actions of nootropic drugs have been carried out. Taken together, these findings indicate that the nootropic drugs of the [Piracetam-type] enhance neuronal excitability [electrical activity] within specific neuronal pathways." (23)


I guess the verdict is still out on nootropics... One thing is for sure though: THIS SHIT IS CONFUSING AS HELL! ;) My favorites are the directly contradictory tidbits of information!! :)

[psyche]

Umm, isn't alzheimers disease caused by excess of dopamine in frontal lobes?

Binge-drinking causes memory loss. It's because of the alcohol agonizes the GABA receptors, causing more GABA to be released. Does GABA bind to NMDA receptors and thus cause memory loss...? This doesn't sound like a good hunch. Or is it just because of overall depressing effects on the CNS. On the other hand, I don't remember hearing opiates cause same kind of memory loss. Could you clarify this?

[sands of time]

Umm, isn't alzheimers disease caused by excess of dopamine in frontal lobes?

No, excess dopamine usually results in schizophrenia. A deficiency of dopamine can result in Parkinson's disease.


Binge-drinking causes memory loss. It's because of the alcohol agonizes the GABA receptors, causing more GABA to be released. Does GABA bind to NMDA receptors and thus cause memory loss...? This doesn't sound like a good hunch. Or is it just because of overall depressing effects on the CNS. On the other hand, I don't remember hearing opiates cause same kind of memory loss. Could you clarify this?

Yes, it is widely believed that alcohol mimics GABA's effect in the brain by having an agonistic effect on the receptor sites. GABA does not bind to NMDA receptor sites though. If NMDA receptor sites are activated for too long, GABA is released as a result. The memory loss you speak of is a result of alcohol mimicing GABA, which is an inhibitory neurotransmitter. This inhibitory effect reduces memory function. Opiates do not effect memory to this degree because opiates do not mimic or increase levels of GABA

[Richard_smoker]

Sands,
I really must apologize for that lengthy post from way back earlier where i tried to 'explain' some shit to you about NT's etc... Sorry. I didn't know that you had so much valuable info in yer membrane! I read her post earlier today, and for the life of me, i couldn't remember what the hell the correct answer was...
So, HELL YEA!! You're right on the money, senior~! ;) in both aspects.

[sands of time]

Sands,
I really must apologize for that lengthy post from way back earlier where i tried to 'explain' some shit to you about NT's etc... Sorry. I didn't know that you had so much valuable info in yer membrane! I read her post earlier today, and for the life of me, i couldn't remember what the hell the correct answer was...
So, HELL YEA!! You're right on the money, senior~! ;) in both aspects.

Hey, we all learn somethin every day. By sharing info, your providing many people with a source of info. Keep spillin your brains, someone will learn from it.

[psyche]

Oh yes I mixed up schizophrenia and Alzheimer. Lack of two enzymes synthesizing and degreding Acetylcholine, Acetyltransferase and and acetylcholinesterase, is also typical to the alzheimers disease. That's because basal forebrain nucleis are heavily dimnished by the disease.

I seem to have forget to mention that opiates don't target GABA. I just wanted to know if the GABA has furthermore some effect on NMDA, but on afterthougts I don't know what was I getting at by that.

[Forthesevenlakes]

GABA could potentially have some effect on NMDA down the line, not sure what it'd be, but bear in mind that (from what i've been told) alcohol has effects at both GABA and NMDA receptors, both of which contribute to a depressant effect. can anyone confirm or refute me on this please, i'd like to know if i'm correct in this opinion.

[sands of time]

Alcohol does bind to the NMDA receptors, but I believe it has an antagonistic effect. This would result in less glutamate binding there, thus more sedation (since glutamate is excitatory). In cases of chronic alcohol consumption, the NMDA receptors become overly sensitive to glutamate, which results in the nasty effects that Richard Smoker described.

Alcohol also binds to the acetylcholine and serotonin receptors.

[Richard_smoker]

One more comment about glutamate that just popped into my head last night while watching cartoons...

We talked about glutamate being the number 1 excitatory NT in the CNS. Here's a good example.

MSG (monosodium glutamate)--the infamous 'flavor-enhancer'... look no further than doritos, cheap asian food, etc. This stuff triggers your taste-buds and causes them to fire-off with a new taste sensation called umami. Prior to MSG, there was only a few known taste sensations: sweet, salty, sour, bitter (??) i might be wrong about these primary tastes, but MSG did bring about a whole new era in taste bud nerve-firing, including the introduction of the new taste discovery: umami.

The reason is quite simple: Glutamate. The #1 excitatory NT.

[prescription]

this question may seem dumb (since i dont know the nature of MAO-B inhibitors) but since the primary cause of MDMA neurotoxicity is due to MAO-B metabolizing the dopamine which then mixes with seratonin, isnt it possible to preload MAO-B inhibitors and then eliminate the MDMA neurotoxicity (as was done with rats in 1995).
Is it because the MAO-B inhibitors are rare, harmful or simply too expensive?
Any answers (even ones correcting this post) would be much appreciated

[psyche]

I think you are referring to this: http://www.springerlink.com/content/761330141328321m/

AFAIK the primary cause of MDMA neurotoxicity is the overload of free radicals born, and I guess they are born in a oxidative reaction with MAO-B(?). They cause oxidative stress by tearing sell structures apart, especially axons are damaged. So best cure for this would be antioxidants found in, for example blueberries, in high concentrations. MAOIs are commonly considered life-threatening with MDMA by, for example erowid. But I think it's the MAOI-A that prevents MAO-A from rendering indoleamines(?), including excessive serotonin, inactive that causes the danger of lethal serotonin syndrome.