Is treatment of Schizophrenia with ACh agonists paradoxical?

[Lightning-Nl]

After doing a ton of research - I've come to the conclusion that the reduction in psychotic symptoms seen in individuals with Schizophrenia that is mediated by Acetylcholine agonists is paradoxical. Why? Because our current model of Schizophrenia is excessive monoamine neurotransmission in central nervous system and (while there's no solid evidence to back this part up) impaired GABA neurotransmission - Specifically in the Prefrontal Cortex, Basal Ganglia, and Locus Coeruleus.

ACh receptor agonism (both muscarinic and nicotinic) greatly upramp Dopaminergic neurotransmission all over the central nervous system. If Schizophrenia is caused by excessive amounts of Dopamine, then why do ACh agonist help when they cause a pretty massive release of Dopamine?! It seems that the reduction of Psychotic symptoms seen by these types of drugs is rather paradoxical in that sense.

So what's going on here? Does anyone actually know at this point in time? Lemme know what you think.

 

[Lightning-Nl]

Of forgot to mention. This huge increase in Dopamine is mediated by the neuroopeptide Gherlin. This link of cholinergic and dopaminergic activity is responsible for the huge increase of Acetylcholine that is caused by Amphetamine and it's also responsible for the huge increase in Dopamine caused by Nicotine. This system is know as the cholinergic-dopaminergic link.

http://www.sciencedirect.com/science/article/pii/S0303720711001547

 

[angeleyes]

Hey Swampfox,

I might not know as much as the other guys in here but I'd like to talk about this with you if possible! Real important issue for me.

How did you find your initial research? This is crazy stuff, I may not be a neuroscientist but I found this article which may be worthwhile for some related reading:


Schizophrenia and the alpha7 nicotinic acetylcholine receptor.

AuthorsMartin LF, et al. Show all Journal
Int Rev Neurobiol. 2007;78:225-46.

Affiliation
Research Service, VA Eastern Colorado Health Care System, Denver, Colorado 80220, USA.

Abstract:
In addition to the devastating symptoms of psychosis, many people with schizophrenia also suffer from cognitive impairment. These cognitive symptoms lead to marked dysfunction and can impact employability, treatment adherence, and social skills.


Deficits in P50 auditory gating are associated with attentional impairment and may contribute to cognitive symptoms and perceptual disturbances. This nicotinic cholinergic-mediated inhibitory process represents a potential new target for therapeutic intervention in schizophrenia. This chapter will review evidence implicating the nicotinic cholinergic, and specifically, the alpha7 nicotinic receptor system in the pathology of schizophrenia. Impaired auditory sensory gating has been linked to the alpha7 nicotinic receptor gene on the chromosome 15q14 locus. A majority of persons with schizophrenia are heavy smokers.


Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. The alpha7 nicotinic agonist 3-(2,4 dimethoxy)benzylidene-anabaseine (DMXBA) can also enhance auditory sensory gating in animal models.

DMXBA is well tolerated in humans and a new study in persons with schizophrenia has found that DMXBA enhances both P50 auditory gating and cognition. alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia.


Sorry this is 7am and I'm seriously not awake, but is this telling me that nicotine reduces the effects but only temporary due to the receptor desensitisation?


Have a good day either way.

 

[Lightning-Nl]

Sorry this is 7am and I'm seriously not awake, but is this telling me that nicotine reduces the effects but only temporary due to the receptor desensitisation?

I suppose it is. I doubt that all therapeutic effects are gone after receptor desensitization. However, they're greatly dulled I'm sure.

Anyways, does anyone have any insight on this? I'm still quite interested in the subject

 

[Lightning-Nl]

If you have ever seen someone on deliriants like dph or datura, which are Acetylcholine antagonists, you would think they are senile or schizophrenic. It doesn't seems so crazy to me that an ACh agonist might have a good therapeutic response from schizophrenic patients. What you say about dopamine is really interesting.

My question was not asking if they worked or not. But rather why they work. I'm well aware of the delirium inducing effects of anticholinergics, but the mechanism that causes this is totally different than what increased ACh firing does. Also, Schizophrenia is linked directly to an incredibly inbalance of the Monoamine neurotransmitters. Specifically, Dopamine is way too abundant.

This huge increased amount of Dopamine in Schizophrenics causes immense over timulation of the frontal lobe, but also the limbic system. It also directly suppress motor activity which is why psychomotor retardation almost always comorbid with Schizophrenia.

It doesn't seem crazy to you because you don't know how these drugs work. Technically, no one knows completely how drugs work. We can't monitor it since we can't see inside someones brain without killing them. However, increasing nAChR firing causes massive Dopamine release. Since Dopamine levels are already too high in people with Psychotic disorders; the fact that nAChR firing causes a decrease in the psychotic symptoms of Schizophrenics seems very paradoxical.

I'm not saying using an nAChR agonist is crazy for treating psychotic illness. They obviously increase the functionability of the unfortunate souls who have to endure such a serious psychotic illness. However, from a pharmacological stand point - it doesn't seem like it would be a good idea.

 

[Lightning-Nl]

Anyone else have input on this? I'm curios to hear other suggestions.