How the chemical synpase really works?

[gman7104]

I am trying to understand how exactly the reuptake mechanism works in synapses. I understand that the neurotransmitter is released and then brought back into the storage vesicles, but what I am not sure about is whether or not the monaminine transporter is responsible for both putting the neurotransmitter into the synaptic cleft and then removing it, or if it is only responsible for reuptake of the neurotransmitter.

I used to think the monaminine transporter released the neurotransmitter from the storage vesicles into the synaptic cleft and then brought it back, which explained why reuptake inhibitors like cocaine and ritalin cause an intense rush and then a long, harsh crash, because it stops the transporter and therefore once the dopamine is gone in the synaptic cleft, the transporter is still blocked and therefore unable to release more dopamine.

However, from looking at pictures of the synapse, it seems that the neurotransmitter is released in one area and taken up in another area. Therefore, DRI's block the reuptake and drugs like amphetamine reverse the reuptake mechanism, causing dopamine to be released by both "gates", hence the reason you feel so good from it.

But if that's the case, why do you feel so shitty after using cocaine? If the reuptake mechanism is blocked and the dopamine is released from a different area, shouldnt you theoretically feel good all day?


Sorry if this is hard to understand I'm pretty stoned, but I'm trying to get a better understanding of the synapse and how drugs like amphetamine and cocaine affect it.

 

[3rd_I_blind]

Neurotransmitters are released from vesicles that fuse with the cell membrane of the releasing cell. They are taken up by transporters a small distance away from the synaptic cleft, to save resource (recycling) and to prevent them from reaching other neurons. The reason you feel shitty after using cocaine has nothing to do with the site of neurotransmitter release and reuptake, but with downregulation/adaptation and effects in other areas than the CNS (muscles, bloodstream, heart) and the metabolism of cocaine and dopamine (both inside the CNS and in the liver).

Perhaps you should not start threads in advanced drug discussion while stoned, although I must admit you did a fairly good job in the OP.

 

[gman7104]

Neurotransmitters are released from vesicles that fuse with the cell membrane of the releasing cell. They are taken up by transporters a small distance away from the synaptic cleft, to save resource (recycling) and to prevent them from reaching other neurons. The reason you feel shitty after using cocaine has nothing to do with the site of neurotransmitter release and reuptake, but with downregulation/adaptation and effects in other areas than the CNS (muscles, bloodstream, heart) and the metabolism of cocaine and dopamine (both inside the CNS and in the liver).

Perhaps you should not start threads in advanced drug discussion while stoned, although I must admit you did a fairly good job in the OP.

But if your brain adapts to the dopamine surge that quickly, why dosen't drugs like adderall and meth cause a similar reaction? wouldnt your brain adapt to them too?

 

[3rd_I_blind]

But if your brain adapts to the dopamine surge that quickly, why dosen't drugs like adderall and meth cause a similar reaction? wouldnt your brain adapt to them too?

Surely your brain adapts to those substances too; I am sure you are aware methamphetamine is notorious for causing bad hangovers as well? To me, the most obvious reasons why cocaine is even more prone to cause a bad hangover are:
- Short duration of effects, making you take more than with comparable compounds with a longer duration.
- It is an extremely effective dopamine, serotonin and norepinephrine reuptake inhibitor; especially the concurrent release of dopamine and serotonin are a recipe for disaster.
- Cocaine is also able to cross the blood-brain barrier extremely well, leading to even higher levels in the brain than with other compounds (relatively speaking, of course).

So in short:
- It works short, so you take more cocaine
- It works good, so you use up more neurotransmitters
- It also releases serotonin, so you fuck up both dopamine and serotonin
- It can reach the brain much faster

Perhaps I should have gone a bit deeper, as I have no doubt the above will be more or less corrected by someone else. But I do not have the time nor the motivation to do so, for now.

 

[sekio]

But if that's the case, why do you feel so shitty after using cocaine? If the reuptake mechanism is blocked and the dopamine is released from a different area, shouldnt you theoretically feel good all day?

The elevated concentration of dopamine caused by DAT block causes desensitization of the dopamine receptors and when DA levels fall because the cocaine has worn off, your system is even more deficient.

It's also important to note that DA is more of an expectation-of-reward chemical rather than a reward proper. If you keep doing stuff thyat produces the expectation of reward (DA release) without any actual payoff, your brain learns what's up pretty fast.

 

[nirvus]

you guys covered pretty much everything, but i'd like to note that blocking of a reuptake transporter can lead to up-regulation of said neurotransmitter. this is how SSRI's (supposedly) work. basically, when neurotransmitter is released, then get picked back up by reuptake transporter, the pre-synaptic (releasing) neuron does a quick check to see how much neurotransmitter was out there. so when transporter is blocked, even though there will be more neurotransmitter in the synapse (since it is not being taken up as fast), the pre-syaptic neuron will detect less (or none) of it and try to make/release more of it to compensate. this is a slower process than the initial rush caused by excessive neurotransmitter in synapse, but it can lead to a secondary wave of increased neurotransmission. this can take weeks for SSRI's, but anyone who has done good yayo (coke), admittedly much rarer this decade than ever b4, can tell you that after use, after crash, comes another wave of stimulation, much smoother and longer lasting. probably, after the crash, most just take it as 'return to normal' but it's better than normal IMHO. since DA is up-regulated (along with SE and NE, probably others) decision making ability can be affected, leading to increased risk taking for reward, and if you've recently used coke, can lead to the desire to use again the very next night, even though during the depth of the crash you may have sworn it off.

sorry for run-on-forever sentencing. and i'm no doctor so maybe others on here can corroborate/elaborate/shoot down this theoretical meandering.

 

[3rd_I_blind]

you guys covered pretty much everything, but i'd like to note that blocking of a reuptake transporter can lead to up-regulation of said neurotransmitter. this is how SSRI's (supposedly) work. basically, when neurotransmitter is released, then get picked back up by reuptake transporter, the pre-synaptic (releasing) neuron does a quick check to see how much neurotransmitter was out there. so when transporter is blocked, even though there will be more neurotransmitter in the synapse (since it is not being taken up as fast), the pre-syaptic neuron will detect less (or none) of it and try to make/release more of it to compensate. this is a slower process than the initial rush caused by excessive neurotransmitter in synapse, but it can lead to a secondary wave of increased neurotransmission.

I'm sorry, but it seems you got it backwards i.e. wrong. SSRIs lead to an increased concentration of serotonin in the synaptic cleft. This increased concentration also excessively activates the presynaptic serotonin autoreceptor (what you call the 'checking mechanism'). Flooding of this receptor leads to a strong decrease in serotonin production. The imbalance between perceived serotonin levels and actual serotonin release gradually causes downregulation of the presynaptic autoreceptor. The end result of this is increased release of serotonin, because the autoreceptor functions like a 'thermostat' and by downregulating the autoreceptor, the sensitivity of this thermostat is decreased. Please note that this is not proven to be the mechanism by which SSRIs exert their effect; there is still much debate on their actual mode of action.

Oh, and the correct abbreviation for serotonin is 5-HT and not SE.

 

[specialspack]

- It is an extremely effective dopamine, serotonin and norepinephrine reuptake inhibitor; especially the concurrent release of dopamine and serotonin are a recipe for disaster.

SNIP

- It also releases serotonin, so you fuck up both dopamine and serotonin

I thought cocaine was only a re-uptake inhibitor, not a releaser?

 

[3rd_I_blind]

I thought cocaine was only a re-uptake inhibitor, not a releaser?

Yes it is a reuptake inhibitor (see first sentence in quoted text ??). So what does it do? Increase the total amount of serotonin in the synaptic cleft i.e. the amount released. So while it is not a serotonin or dopamine releasing substance, it more or less has the same effect: causing an excessive extracellular build-up of neurotransmitter, likely leading to a shortage of said neurotransmitter at a later moment in time.

 

[specialspack]

Yes, thank you, I understand that. In the interests of clarity you might want to edit your post. "It also releases serotonin" implies that it's a serotonin releaser, when it's not. "The concurrent release of dopamine and serotonin are a recipe for disaster" seems like you're alluding to methamphetamine type neurotoxic effects..? Or do you mean something else?