Pharmacodynamic paradoxes, Types of Hallucinations, Dynorphin

[airsh0w]

There are many apparent paradoxes in the current sciences of pharmacology and this is a place to discuss them and hopefully clarify some. For Example, NMDA antagonism has been deemed the cause of the dream-like dissociation of Ketamine, DXM, and PCP and this seems to make sense until you see that Ethanol, Methadone, and many other non-dissociative like drugs. Perhaps this is due to the arrogance of people who have never even done a dissociative. But it may be due to potency and dose you might think. So theoretically if you could take enough methadone and not die you would have a dissociative experience of dream-like hallucinations. But what about Ethanol? It is an uncompetitive NMDA antagonist just like DXM and PCP. Since I haven't ever been able to find a Ki on the affinity of its NMDA antagonism (to know how well it sticks to those sites) I can't fully discount the possible explanation that it is due to the dose. But I have to admit that people can drink a lot of alcohol and feel nothing like DXM/DXO. This also brings me to the the Glutamate theory on schizophrenia which was derived from the fact that PCP somewhat mimics psychosis to someone looking from the outside at least. But I also know that PCP is a partial D2 agonist which is quite a miserable receptor and that is likely why they think that. So I subscribe the dopamine hypothesis but I wouldn't doubt that glutamate is mediated or something less direct. But a partial agonist often lower receptor activity like a weak antagonist...so why wouldn't this be true in this situation? If you can think of more paradoxes I would like to see them and I would like see someone make sense of this.

Of course every drug is different in a few ways but can we classify hallucination types? For the people who have more hands on experience this might be easier. But the three I can think of are Deliriant (ACH antagonism and K-opioid agonism), Dissociative (NMDA uncompetitive/noncompetitive antagonism...sometimes) , and psychedelic (Serotonin agonism [5-HT2A]). Two more could be schizophrenic delirium (haven't experienced) (DA agonism...a combination?), and the DMT (haven't experienced) may be either a combination of psychedelic, with the energy of A1, A2 and sigma receptors or D1 affinity but this one I have pretty much no idea other than its obvious 5-HT2A agonism.

Dynorphins are implicated in addiction in two paradoxical ways unless I am wrong.They are important in the negative feelings felt by craving addicts causing them to want the drug more but also anti-addictive in that they (perhaps by up-regulate mu-opioid receptors at the Kappa-opioid sites or inhibiting the release of dopamine) but can they do both or do they not do both?

I also want to note "The most potent (and hence probably most important) actions of ethanol are potentiation of GABA-A receptor actions, inhibition of NMDA receptors, inhibition of voltage gated calcium channels and possibley potentiation of Nicotinic receptors." which is interesting because all three of the classical dissociative block the Nicotinic receptors (albeit weakly) so this may be a synergistic effect. Which could account for nicotine's alleged antipsychotic effects.

[That quote is ostensibly unsourced from Bluelights bliz0r in this interesting post http://www.bluelight.ru/vb/threads/166687-Erowid-BlueLight-Neuropharmacology-Text/page2)

 

[cannibalsnail]

Aren't there also GABA mediated visuals aka Muscimol/Ibotenic acid?

 

[23536]

tianeptine having efficacy as an antidepressant even though its mechanism of action is opposite to that of SSRIs

 

[airsh0w]

That is interesting. Yes there is. Alchohol is a positive allosteric modulator where as muscimol is a direct agonist. So where as ethanol makes the natural ligands of GABA A more potent, muscimol attaches to the receptor and perhaps causes downregulation and autoreceptor interference. It also is a partial agonist at the GABAA-rho (retina) receptor which could reduce activity mediating the visual neural networks to causing the brain to fill it in with hallucinations which makes some sense because the positive allosteric modulators ( i.e. Ethanol, Benzodiazepines, Barbiturates) don't modulate GABAA-rho receptor. Ibotenic acid is substantially less potent and used to cause excitotoxic lesions and its effects glutamatergic effects are probably attenuated by the GABA A agonist effects of muscimol...I would say the GABA A agonism causes (indirectly perhaps) hallucinations as evident in the drugs Zopidem, and the highly selective GABA A agonist experimental drug CL-218,872. [both cause hallucinations]

But it is a deliriant which is even more confusing considering its weak Musarinic agonist properties which should fight against that. But the word deliriant has been abused, and stretched out to ridiculous limits. Considering the erowid report. I would consider the effects to make more sense from GABA A agonism. It is similar to alcohol in its reward chemical mediation but along with the hallucinations of the GABA A.

REF:

http://www.erowid.org/plants/amanitas/amanitas_effects.shtml

 

[airsh0w]

The SRI, SRA. That is a classical pharmacodynamic paradox and I'm glad you mentioned it. There are important facts to state before this question can even be addressed.

SRI's never work instantly. They take time to change the receptors in the brain. Often they are unpleasant at first and then may make someone feel better but not without killing a persons sex drive. What is important to address is the autoreceptors which are being slowly up-regulated by the SRI/SSRI and the post-synaptic receptors which could down-regulate in response to this higher amount of serotonin. But the brain isn't perfect and that may account for the anti-depressant effects of these but it isn't very difficult to see how an SRI could actually lower serotonin receptor actions and not all serotonin receptors are plesant. This truth is exploited by atypical antipsychotics which block a significant portion of these and stabilize miserable moods. Infact only around 3 of the 13 of them have been shown to have anti-depressant effects and many are known to cause misery.As this is all a very incomplete young science with so genetic variations, metabolic variations, up/down regulation variations, auto receptor variations, it is no wonder two people can take the same drug and feel quite differently but we do know there are some core similarity's and psychological (placebo effect/moods/expectations) factors that are yet to of been taken into account for the effect of a drug on emotions. There are actually genetic markers that can be used to predict whether or not an anti-depressant has a good chance of working. 5-HT2A receptors down regulate in response to SRI's etc etc

I think that explains the SRA/SRI paradox to some unsatisfying degree. But the truth probably lays somewhere in the land of up/down regulation of serotonin receptors, genes, and expectations.