Schizophrenia

Schizophrenia has been the most prominent target of antipsychotic medications for the last 75 years. Although these treatments are broadly considered anti-dopamine, the most effective agents seem to be more chemically similar to guanine than dopamine. (IMG dopamine, clozapine, guanine). 

At the same time, there are pro-dopamine medications that also mimic the chemical structure of guanine. (IMG apomorphine, bromocryptine, LSD)

Several pro-dopamine and anti-dopamine molecules mimic guanine, but the antipsychotics (and not the pro-dopamines) have evasive maneuvers: 

• clozapine, olanzapine, quetiapine, loxapine, and blonanserin (IMG) add a bulky ring to the guanine-identifying amine group

• Zotepine, chlorpromazine, fluphenazine, thioridazine, and xanomeline (IMG) retain the flexibility to move the guanine-identifying amine group out of the way, hide-and-seek style

• Paliperidone (IMG) uses an adjacent oxygen to make a carbon look close-but-not-quite like the expected nitrogen

When high-dopamine schizophrenia is treated, excessively high doses result in low-dopamine (Parkinsonian) symptoms.

When low-dopamine Parkinson's disease is treated, excessively high doses result in high-dopamine (psychotic) symptoms.

Dopamine excess and dopamine deficient disease states may extreme ends of the same biochemical pathway.

There is known purine-based modulation of dopamine: in Lesch-Nyhan disease, a single defective purine metabolism gene results in brains with abnormally low dopamine in the same area (SNpc) that schizophrenic patients have high dopamine.

Allopurinol is a purine-mimic who's accepted mechanism of action is changing purine metabolism. Allopurinol shows efficacy in treating schizophrenia.

Purine-based control of dopamine is echoed in a fascinating case report: newly diagnosed Parkinson's disease, when treated, resulted in new onset gout, which was treated with purine-mimic allopurinol, which resulted in increased Parkinsonian symptoms PMID 34062024.

Since LND is caused by a genetic change, it is possible to say that a cell or cell culture has LND. When LND cells are studied, they have undetectable guanine levels and show dramatically decreased production of dopamine-creating enzymes. These same enzymes are implicated in other low-dopamine conditions, including Parkinson's Disease.

Adding a high concentration of guanine-similar folate to LND cells dramatically reduces pathologic purine changes: a close folate mimic where the guanine-identifying nitrogen is replaced with a xanthine-identifying oxygen does not show improvement PMID 32430324. Unfortunately, dopamine production markers were not assessed. 

Low guanine is associated with low dopamine in the SNpc (LND gross histology) and low dopamine-production enzymes (induced LND cell cultures).
Adding a guanine-similar agent seems to reverse pathological purine metabolism patterns (LND cell culture); adding a xanthine-similar agent does not.
Clinical treatment of low-dopamine disease states include adding guanine-similar agents: used excessively, these may result in schizophrenia-similar symptoms.
Clinical treatment of high-dopamine disease states includes adding guanine-trickster agents: used excessively, these may result in Parkinsonian symptoms.

Do low-dopamine diseases share low-guanine?
Do high-dopamine states share high-guanine?
Is activating pro-dopamine guanine signaling an unrecognized mechanism of pro-dopamine agents?
Is blocking pro-dopamine guanine signaling an unrecognized mechanism of action of antipsychotics?