Misc Stimulant: I feel good and bad at the same time.

[Jabberwocky]

Hey,

May anyone please explain or give ideas on what is happening to the brain (neurotransmitters/Catecholamines) when you "come down" / "drug wears off" etc.

How:
In the past 3 hours I have noticed it changing in a serve way.
EG: In the past 3 hours and now I feel good and bad. Like I feel good and fine on one side, but on the other side I feel bad (tired,drained,etc).

Now, what's happening with the Catecholamines please?.

Please, your ideas please.

waiting for your idea/opinion/etc.
thank you.

 

[lalune]

Catecholamines (substituted) are a large class of compounds so im gonna just be more specific and talk about dopamine agonists. however catecholamines also include epinephrine, norepinephrine which are involved in fight or flight response so that can also give you more idea on physical fx on the body, especially things like vasoconstriction and increased anxiety. when youre talking about stimulants (im going to just refer to example of amphetamine and its dopamine activating fx) in terms of its biochemical (more specifically neurochemical) processes, amphetamine works by increasing the amount of dopamine in the synaptic cleft of a neuron by inhibiting the reuptake of it and then the post synaptic activation occurs (thus making it stay longer at higher amounts) increases the cytosolic (intracellular) concentration in the presynaptic nerve terminal (basically moving it out of the vesicles its SUPPOSED to be in into the cytoplasm more dopamine =more high.) also reverse transport is involved meaning your body is regularly supposed to terminate DA signaling but with amphetamine the dat (dopamine transporter is blocked) so the DA will not be removed. amphetamines are more than just dopaminergic, they also have effect on serotonin and nor-epinephrine, the precursor to adrenaline.

in other words amphetamine displaces catecholamines from storage vesicles and blocks catecholamine reuptake.

like any drug, it doesnt stay in your blood long. as time passes by, its concentration decreases. concentration decreases, high starts to fade. this is when the comedown hits. because ur nervous system was "enjoying" a nice dopamine/adrenaline feast (which causes euphoria fast talking increased sociability) these things decrease and your body responds accordingly. you will become tired and maybe even a little depressed/irritable (theoretically dopamine is seen as a part of the reward system ((which is still being research)), euphoria) no more happiness from exogenous ligand for you pretty much. i havent read much on this stuff in awhile (a month) so my info may be not the most detailed or might be incorrect. if im wrong some1 feel free to correct me since im not an expert

 

[MrSpeedyG]

Aiir what drug are you on? I am assuming it is either amphetamine or methamphetamine... What you are experiencing is the start of a comedown where the euphora wears thin and anxiety comes through and there will be a stage where you will feel both before your just left with anxiety/dysphoria aka the comedown.

Get some rest and sleep, try get some food into you aswell.

 

[Grand Touring]

Catecholamines (substituted) are a large class of compounds so im gonna just be more specific and talk about dopamine agonists. however catecholamines also include epinephrine, norepinephrine which are involved in fight or flight response so that can also give you more idea on physical fx on the body, especially things like vasoconstriction and increased anxiety. when youre talking about stimulants (im going to just refer to example of amphetamine and its dopamine activating fx) in terms of its biochemical (more specifically neurochemical) processes, amphetamine works by increasing the amount of dopamine in the synaptic cleft of a neuron by inhibiting the reuptake of it and then the post synaptic activation occurs (thus making it stay longer at higher amounts) increases the cytosolic (intracellular) concentration in the presynaptic nerve terminal (basically moving it out of the vesicles its SUPPOSED to be in into the cytoplasm more dopamine =more high.) also reverse transport is involved meaning your body is regularly supposed to terminate DA signaling but with amphetamine the dat (dopamine transporter is blocked) so the DA will not be removed. amphetamines are more than just dopaminergic, they also have effect on serotonin and nor-epinephrine, the precursor to adrenaline.

in other words amphetamine displaces catecholamines from storage vesicles and blocks catecholamine reuptake.

like any drug, it doesnt stay in your blood long. as time passes by, its concentration decreases. concentration decreases, high starts to fade. this is when the comedown hits. because ur nervous system was "enjoying" a nice dopamine/adrenaline feast (which causes euphoria fast talking increased sociability) these things decrease and your body responds accordingly. you will become tired and maybe even a little depressed/irritable (theoretically dopamine is seen as a part of the reward system ((which is still being research)), euphoria) no more happiness from exogenous ligand for you pretty much. i havent read much on this stuff in awhile (a month) so my info may be not the most detailed or might be incorrect. if im wrong some1 feel free to correct me since im not an expert

I feel that your example of an amphetamine inhibiting the reuptake is incorrect. Dextro is a pure agonist which down-regulates the D receptors. Now something like methylphenidate will effect the D reuptake, as it is a DNRI. And also like your case, I could be wrong, but this is just what I have gathered.

As for the OP, the sympathomimetic nature of the drug is purely an excitatory response, so when the levels of amp titrate down, you'll have that dual feeling of coming down but yet still under the influence.

 

[MrSpeedyG]

^^ to above poster, amphetamine does not directly agonise DA receptors, it is an indirect dopamine agonist working via how it is described by lalune (reversing dopamine transport and displacing dopamine from storage vesicles into the synaptic cleft thus causing supra physiological levels of dopamine in the synapse and activation receptor).

It is not so much that the concentration of amphetamine is becoming lower in the blood, rather short term tolerance build up. Amphetamine has a long half life, 12-13 hours.

 

[Jabberwocky]

Hi,

Thank You for the posts. It was not a amphetamine. The stimulant only blocks the reuptake of dopamine and noraderline.

 

[jeeves]

There seems to be a misconception that dopamine is strictly a feel-good neurotransmitter. Dopamine itself will not make you feel good, it depends on the dopaminergic pathway effected. Stimulants effect every dopaminergic pathway to a greater or lesser extent, the pathway responsible for feelings of pleasure is the mesolimbic pathway, when a stimulant effects this pathway that is what creates the euphoria that is so desirable. Conversely, stimulants also effect the mesocorital pathway, which makes you feel anxious, depressed or if you take enough of a stimulant creates psychosis. The reason you get shaky and twitchy on stimulants is due to its effect on the nigrostrital pathway, the part of the pathway responsible for motor control. If stimulants just effected the mesolimbic, pleasure related, pathway there would be no comedown or anxiety. Theres the answer to your question.

 

[tweex]

Excellent post jeeves, this is also probably the explanation as to why modafinil (provigil) heavily negates amphetamine comedowns: http://www.ncbi.nlm.nih.gov/pubmed/1347270

 

[Jabberwocky]

ahhh great post guys, learned so much thank you.

(comedown this night) -> feel like total total crap, don't care about anything extremely/ can't move/extreme lack of energy/ nothing is motivating/my body aches and is very slow/i overall feel slow slow slow3/ brain feels have asleep/no care/nothing is awarding(food/games/etc, EVEN stimulants do not seem rewarding(don't want them), Its so funny that now I don't want them what so ever but lets say another night and I had no comedown I would be there craving the stimulant (but it was all about preparing to take it and taking it was the best/better than the drug effects itself

any ideas here please?thank you very much. so what is happening to me right now in the brain (brain areas,dopamine receptors or what????. please please thank you ...

 

[MrSpeedyG]

Aiir what was the stimulant in question? Cocaine?

 

[lalune]

There seems to be a misconception that dopamine is strictly a feel-good neurotransmitter. Dopamine itself will not make you feel good, it depends on the dopaminergic pathway effected. Stimulants effect every dopaminergic pathway to a greater or lesser extent, the pathway responsible for feelings of pleasure is the mesolimbic pathway, when a stimulant effects this pathway that is what creates the euphoria that is so desirable. Conversely, stimulants also effect the mesocorital pathway, which makes you feel anxious, depressed or if you take enough of a stimulant creates psychosis. The reason you get shaky and twitchy on stimulants is due to its effect on the nigrostrital pathway, the part of the pathway responsible for motor control. If stimulants just effected the mesolimbic, pleasure related, pathway there would be no comedown or anxiety. Theres the answer to your question.

Im actually aware of your first since I like to read a lot on movement disorders, however in all the biochemistry (pharm too) texts I have read, its only referenced in its effects on it as a reward/euphoria booster (in terms of drug of abuse which makes sense that they only focus on that part) Thank you for this comment I just got educated on multiple things at once

I feel that your example of an amphetamine inhibiting the reuptake is incorrect. Dextro is a pure agonist which down-regulates the D receptors. Now something like methylphenidate will effect the D reuptake, as it is a DNRI. And also like your case, I could be wrong, but this is just what I have gathered.

As for the OP, the sympathomimetic nature of the drug is purely an excitatory response, so when the levels of amp titrate down, you'll have that dual feeling of coming down but yet still under the influence.

Oh okay, Idk to much about dextro. I was speaking of only amphetamine (as its the only drug that came in my mind atm) to avoid any confusion considering so many stimulants have varying pharmacologies and MOAs