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Upregulation of D2 Receptors: Useful in stimulant tolerance?

TCMVegas

TCMVegas

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Nov 22, 2012
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This seems like a relatively unexplored, as well as interesting topic. Let's see what useful results we can come up with.


Dopamine receptors fall into two groups, in terms of functionality. D1-like and D2-like.

D1 agonism increases adenylyl cyclase, which in turn raises adenosine monophosphate (cAMP)
D2 agonism decreases adenylyl cyclase, which in turnlowers levels of adenosine monophosphate (cAMP)
Source: Wikipedia (unverified)

Since D1-like and D2-like receptors seem to have exactly opposite effects according to this, I'm not sure how to make sense of it. A hypothesis I have is that a postsynaptic cell gets to express these receptors at it's own ratio, so that the reaction to increased dopamine can be different in different cells.


The goal of this thread is to dive into the behavioral effects of selectively upregulating D2 receptors. This could be induced by antipsychotics, which I believe are all selective for D2.

Would upregulating D2 via antipsychotics maintain stimulant efficacy? Or is the seemingly-inevitable D1 downregulation going to singlehandedly be responsible for stimulant tolerance?
 
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EA, Tardive Dyskinesia is really only an issue in people with chronically lowered dopamine signalling, who experience huge receptor upregulation. By stimming sometimes, and DA-antagonizing sometimes, receptor levels should be relatively normal.

Here's what wikipedia seems to say about dopamine receptor subtypes and prefrontal cortex functionality:
In the frontal lobes, dopamine controls the flow of information from other areas of the brain. Dopamine disorders in this region of the brain can cause a decline in neurocognitive functions, especially memory, attention, and problem-solving. Reduced dopamine concentrations in the prefrontal cortex are thought to contribute to attention deficit disorder. It has been found that D1 receptors[30] as well as D4 receptors[31] are responsible for the cognitive-enhancing effects of dopamine, whereas D2 receptors are more specific for motor actions.
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I think this may be why D2 antagonists are given to people with schizophrenia, basically as a sedative to keep them from doing violent acts. It likely just decreases motivation to initiate behaviors. Dopamine is often seen as motivation to initiate behaviors. This makes me think that D2 upregulation might give you more motivation to do work, but might not be a receptor subtype that helps with information processing, working memory, etc.
 
I think this may be why D2 antagonists are given to people with schizophrenia, basically as a sedative to keep them from doing violent acts.
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Thats crap, increased cyclic amp, glutamate potentiation, and other downstream effects explain their antipsychotic effect, shizophrenics also arent really known to do vialent acts, maybe when psychotic but taking a ap then doesnt help, you cant reverse psychosis with them it may speed up the proces a bit tough but it will still take days to go away.

That said D2 antagonism isnt sedative, nor does it alter the motivational effects of stims for me.
 
As for this thread it wont work, the strong D2 blocker i just took only made the effects of my stims better as an example, and even if it would work after the ap your stim would work better for 3 days untill its downregulated again and you need to go back on the ap for a few days.

Good for people that love variaty, stimmed at some days and risperdalled at other days for a change.
 
MeDieViL said:
As for this thread it wont work, the strong D2 blocker i just took only made the effects of my stims better as an example, and even if it would work after the ap your stim would work better for 3 days untill its downregulated again and you need to go back on the ap for a few days.

Good for people that love variaty, stimmed at some days and risperdalled at other days for a change.
Click to expand...


Yeah that's the point, he's saying that they will help with tolerance and therefore INCREASE the effects of stimulants.

I think _Olon_ is trying to say that taking them together will even them out, which I know is true for Seroquel and Methamphetamine.
 
I wanted to say that normal people without schizophrenia aren't high all the time, too.
 
TCMVegas said:
EA, Tardive Dyskinesia is really only an issue in people with chronically lowered dopamine signalling, who experience huge receptor upregulation. By stimming sometimes, and DA-antagonizing sometimes, receptor levels should be relatively normal.

Here's what wikipedia seems to say about dopamine receptor subtypes and prefrontal cortex functionality:


I think this may be why D2 antagonists are given to people with schizophrenia, basically as a sedative to keep them from doing violent acts. It likely just decreases motivation to initiate behaviors. Dopamine is often seen as motivation to initiate behaviors. This makes me think that D2 upregulation might give you more motivation to do work, but might not be a receptor subtype that helps with information processing, working memory, etc.
Click to expand...

Straight upregulation of D2 by long term addition of an antagonist, and the accompanying epigenetic changes, will effect the PFC and the basal ganglia. I know I'm painting with a broad brush, but I just wanted to make a known side effect of this approach clear.

Stim tolerance is so beautifully multifaceted though, endorphins/enkelphalins, 5HT signalling, and epigenetic changes on top of various metabolic perturbations all play roles with various other mechanisms waiting to be discovered.

Man if I wasn't busy as hell I would be balls deep in the third installment of my thread.
 
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