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Endogenous intoxicants in metabolic disorders

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In a medical condition called idiopathic recurrent stupor, patients have episodes of drowsiness, ataxia and unresponsiveness, that can be temporarily treated with flumazenil, a benzo antagonist. The disease is thought to be caused by accumulation of endozepine-4, an endogenous BZD agonist in the blood...

Another similar condition is the succinic semialdehyde dehydrogenase deficiency, which leads to accumulation of gamma-hydroxybutyrate in the body.

Are there any other examples of diseases where endogenous intoxicants accumulate? Everyone knows the age-old hypothesis that schizophrenia is caused by excessive endogenous DMT, but that doesn't seem to be true...

The enzyme succinic semialdehyde dehydrogenase can be inhibited with compounds like n-formylglycine and p-hydroxybenzoate, do these only work in vitro, or would they cause GHB accumulation when administered orally?
 
As far as I know, you don't want to play with succinic semialdehyde dehydrogenase because inhibition would lead to massive GHB blood levels. (and coma etc)

I don't think that there's an orally active inhibitor for SSAD though. Those compounds look to me like they'd be in vitro agents.

Monoamine accumulation has been pretty much ruled out as a cause of schizophrenia.
 
sekio said:
As far as I know, you don't want to play with succinic semialdehyde dehydrogenase because inhibition would lead to massive GHB blood levels. (and coma etc)

I don't think that there's an orally active inhibitor for SSAD though. Those compounds look to me like they'd be in vitro agents.

Monoamine accumulation has been pretty much ruled out as a cause of schizophrenia.
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Really? Isn't the dopamine hypothesis still the most widely accepted one?
 
There's a whole rainbow of hypotheses, too much dopamine activity is only one of them.

As far as I know the idea that schizos made more monoamines than "normal" people was debunked because they don't exhibit higher levels of the metabolites.
 
At this point, I'm on board with the glutamate hypothesis of schizophrenia, in which neurons undergo some detrimental changes near the end of their maturation due to DNA copying errors, including losing the ability to manufacture NMDA and AMPA receptors. Thus it's like entering a permanent ketamine trip -- you don't have long term potentiation anymore, and any mental processes that depend on long term potentiation are severely and permanently hindered.

OP, you might want to look into cortisol secreting tumors and hyperthyroidism. Both have mental components that in some ways mirror toxidromes.

People with a pheochromocytoma will get sudden attacks that feel like a speed rush, including tachycardia, racing thoughts, and often panic attacks or rage. What it actually is is a tumor that secretes bursts of catecholamines into the bloodstream.

People with carcinoid syndrome have a series of tumors in their gut lining that release serotonin. They can present with a set of signs and symptoms that are hard to distinguish from serotonin syndrome, though effects are usually more peripheral than central.
 
The reason I think the dopamine hypothesis makes the most sense is mainly because 1. I've experienced psychosis, which is basically temporary paranoid schizophrenia, from overuse of amphetamines, which release crap-tons of dopamine in addition to sleep deprivation also being theorized to increase dopamine each day. and 2. d2 antagonists treat it successfully and all antipsychotics block d2 receptors.
 
cannibalsnail said:
Incorrect. The receptor target for modern antipsychotics is primarily 5HT2A.
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All atypical antipsychotics block d2 and 5-ht2a. They're not any more effective than typical selective d2 antagonist antipsychotics, they just cause less side effects. ALL antipsychotics block d2, except abilify, which blocks more dopamine receptors than any other antipsychotic but activates them weakly.

Find me one efficacious antipsychotic that doesn't block d2 and I shall award you a gold star.
 
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