Paranoia caused by dopamine reuptake inhibitors

[MeDieViL]

MDPV and ritalin both cause severe paranoia when i take them (low and high doses) as i understand they are specific dopamine inhibitors (and its like impossible to inhibit with benzo's, no matter how many i take...)
while amphetamine doesnt give me any problems at all while its supposed to raise noradrenaline wich is more often to cause paranoia

any idea's on this?

 

[MurphyClox]

ritalin...as i understand they are specific dopamine inhibitors

Then you understood it wrong. Methylphenidate ('Ritalin') is not specific in this respect, it inhibits norepinephrine reuptake as well.

Murphy

 

[MeDieViL]

i see, but has it less of an action on norepinephrine then amphetamines?

 

[MurphyClox]

The action is not 'less' but different. The one inhibits the reuptake of neurotransmitters into the presynaptic cell, while the other releases these neurotransmitters.
Both actions result in the same: Increased concentration of both D and 5HT in the synaptic cleft. But the mechanisms are different. Don't ask me about receptor subtypes here, that's not my best field.

The difference is, that the transmitter release is independent from the cell's signal, while the reuptake needs somehow longer to built up a comparable transmitter concentration. This agrees well with own observations: When considering the same route of application (e.g. intranasal), methylphenidate is always a bit slower than amphetamine.

Peace! Murphy

Edit: I just noticed that the last point can of course (!) have pharmacokinetic implications...silly me!

 

[MeDieViL]

any idea on what simularities there are when comparing ritalin and MDPV that doesnt happen with normal amphetamines (like adderall)

both ritalin and mdpv give me a weird feeling worrying about everything, like that my dad will be home in a few minutes when it really doesnt matter if he is coming home, just paranoia about everything >< this isnt only happening with abuse but also anything above the treshold dose

 

[LuxEtVeritas]

it may be in what areas of the brain the release and RI are predominant and your particular sensitivities

 

[negrogesic]

Amphetamines do not simply release catecholamines....

Based on an article I was reading the other day, reversal of transport may be the primary mechanism through which amphetamines may act. I think they arrived at this conclusion because amphetamine failed to release dopamine in DAT knockout mice...

Also, d-MPH is more selective in regards to the DAT.

Out of curiousity, do you get more paranoia with d-amphetamine versus d-meth?

 

[LuxEtVeritas]

all are releasers and DARIs but it is the ratios that make the amph class more selective to release and the others more selective to RI


meth is a mega-releaser, but amphs are still i think a good deal more selective for release as well

 

[Riemann Zeta]

Interestingly, there are a few studies on using various stimulants to treat the cognitive problems common in schizophrenics. The schizophrenics were already maintained on some form of antipsychotic, to which was added a low-ish dose of either dextroamphetamine or methylphenidate. The patients on dextroamphetamine were a lot less likely to experience an exacerbation of psychotic (paranoid/delusional) symptoms than those on methylphenidate.

In terms of Ki for uptake inhibition (strictly measuring inhibition of [3H]-monoamine uptake into recombinant hDAT or hNET cells, not "synaptosomes"), methylphenidate has a greater affinity for the DAT than the NET and d-amphetamine has similar affinities at both DAT and NET.

As an aside, I believe (although I would have to dig up a reference on this one) that methamphetamine is much more likely to cause psychotic-like symptoms than regular amphetamine.

 

[MurphyClox]

Amphetamines do not simply release catecholamines....

Based on an article I was reading the other day, reversal of transport may be the primary mechanism through which amphetamines may act. I think they arrived at this conclusion because amphetamine failed to release dopamine in DAT knockout mice...

I think that this IS actually the mechanism of release! I never really understood why a molecule that resembles similarity with an endogenous ligand would cause the release (and now talking about direct release, exocytosis) of exactly this ligand, e.g. dopamine. That would lead to a seriously dangerous signal amplification, depleting the cell of this transmitter extremely fast and effectively. This 'inverted' (reversed) transport looks more like a 'malfunction' to me, and thus, makes more sense.

Peace! Murphy

 

[djsim]

I think that this IS actually the mechanism of release! I never really understood why a molecule that resembles similarity with an endogenous ligand would cause the release (and now talking about direct release, exocytosis) of exactly this ligand, e.g. dopamine. That would lead to a seriously dangerous signal amplification, depleting the cell of this transmitter extremely fast and effectively. This 'inverted' (reversed) transport looks more like a 'malfunction' to me, and thus, makes more sense.

Peace! Murphy

OK, so am I right saying...
* cocaine is a large, relatuvely bulky molecule which blocks the mechnism of the DAT
* amphetamine does 2 things:
1. gets inside presynaptic neuron, and displaces DA from vesicles
2. reverses DAT (the amphetamine binds with a receptor and/or transmembrane gprotein, which then (perhaps indirectly) phosphorylates the DAT, causing inversion relative to the membrane, thus causing reversal
EDIT: according to Wikipedia the phosphorylation of DAT is done by MAPK/PKC

 

[fastandbulbous]

The action is not 'less' but different. The one inhibits the reuptake of neurotransmitters into the presynaptic cell, while the other releases these neurotransmitters.
Both actions result in the same: Increased concentration of both D and 5HT in the synaptic cleft. But the mechanisms are different. Don't ask me about receptor subtypes here, that's not my best field.

The difference is, that the transmitter release is independent from the cell's signal, while the reuptake needs somehow longer to built up a comparable transmitter concentration. This agrees well with own observations: When considering the same route of application (e.g. intranasal), methylphenidate is always a bit slower than amphetamine.

Peace! Murphy

5HT? Don't you mean NA (refuse to use NE - it's noradrenaline! ). Amphetamine has negligable 5HT effects - that's why it's much less neurotoxic than methamphetamine

 

[MurphyClox]

OH SHIT!! yes, of course...I meant NE/NA of course! Thx for correction.

 

[MeDieViL]

i never tried meth so i wouldnt know

cocaine also doesnt cause any paranoia while its supposed to be simular to ritalin, makes me confused lol
MDMA doesnt cause any problems either

thx for replies allready

 

[MeDieViL]

i may want to add that this paranoia is impossible to inhibit with benzo's or alcohol, you gotta take like 20 xanax pills or something so you can fall asleep, zero effect on the weird toughts, alcohol doesnt work either!
GBL and opiates fail to inhibit either

 

[lenses]

Me and my friends stopped doing coke because I convinced them it had a shitty method of action versus speed. LAWLZ we're cool.

More on this later.

 

[negrogesic]

^^^^I used to prefer the pure reuptake inhibitors to the amphetamines, like cocaine/MDPV and even d-MPH.

I think that this IS actually the mechanism of release! I never really understood why a molecule that resembles similarity with an endogenous ligand would cause the release (and now talking about direct release, exocytosis) of exactly this ligand, e.g. dopamine. That would lead to a seriously dangerous signal amplification, depleting the cell of this transmitter extremely fast and effectively. This 'inverted' (reversed) transport looks more like a 'malfunction' to me, and thus, makes more sense.

Peace! Murphy

I think you are right...

Anyone ever had pyrovalerone? I think it is C-V....

 

[Riemann Zeta]

Me and my friends stopped doing coke because I convinced them it had a shitty method of action versus speed.

I've never done, nor ever intend to take coke--but I was offered it before...the individual offering it was a little surprised to hear me say that it would simply cancel out the effects of my usual speed by blocking the DAT and preventing those nice little amphetamine molecules from getting in to the presynaptic neurons (and preventing dopamine from moving back out).

And, to address the above: I have never tried pyrovalerone (and I don't actually know anyone who has--it seems quite rare), but I have tried methylenedioxypyrovalerone (MDPV). It sucked. I consider it to be the worst stimulant that I have ever come across, side effect wise. So, if pyrovalerone is extremely similar in effect, it will probably be full of headaches, sweating, peripheral tweakage and general annoying creepy-crawlies.

 

[The Monkey Mantra]

I'm like the original poster and find MPH and cocaine *extremely* uncomfortable. MDPV, too. Strangely enough, I do fine with desoxypipradrol, but it's still quite icky compared to meth/amphetamines.

Negrogesic, you asked the OP, but... I find methamphetamine to be far more tolerable than plain amphetamine. I've always assumed this was due to the calming influence of the 5-HT release? The calming effect actually increases with dose until it reaches a plateau, which I almost never go past. Read that as: Low doses of meth freak me out, but if I bump it up a bit, I'm groovy. No desire to redose, either, unlike, say, MPH.

 

[Nagelfar]

I've never done, nor ever intend to take coke--but I was offered it before...the individual offering it was a little surprised to hear me say that it would simply cancel out the effects of my usual speed by blocking the DAT and preventing those nice little amphetamine molecules from getting in to the presynaptic neurons (and preventing dopamine from moving back out).

Cocaine isn't supposed to suppress the subjective effects of amp, just prevent the phosphorylation AFAIK and save your DA transporters longer so they don't internalize as quickly. Due to amphetamines longer half life, this should prolong your entire experience not nullify it, I'm thinking.