Schizophrenia

Dopamine Regulation

Schizophrenia is widely understood as a dopamine excess, with the primary treatments thought of as blocking dopamine at the receptor.

What if we could decrease excess dopamine production, rather than simply block dopamine's effects? What if we could increase dopamine production in low-dopamine disorders including Parkinson's disease?

Clinical Continuum of Dopamine Disorders

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

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.

Purine-based Regulation of Dopamine in LND

Purine-based dopamine regulation is directly observed in Lesch-Nyhan disease, where dysfunction of a single purine metabolism enzyme dramatically reduces dopamine.

The difference is visible on autopsy. Melanin in a natural pigment formed from dopamine. In schizophrenia, the SNpc (a brain region) shows excess dopamine and excess TH expression and activity PMID 20089137. In LND and in low-dopamine Parkinson's Disease (PD), the SNpc has dramatically less melanin pigmentation and dopamine than normal PMID 23975452.

Purine Correlates in Parkinson's Disease

Although this correlation suggesting purine-based regulation of dopamine occurs in a rare low-dopamine disease, the more common Parkinson's disease also demonstrates purine correlations: low uric acid (the only purine for which a clinical test is readily available) is strongly associated with rapid decline PMID 35208569. Proteomics in Parkinson's patients suggests changes in purine metabolism over the course of illness PMID 25597950: these changes are expected to decrease adenosine derivatives and increase oxopurines. There is also evidence that the shift away from adenosine-derivatives during symptomatic progression is reversed by effective treatment, using SAM-e as a marker for adenosine-derivatives PMID 16340382. However, substrate supplementation in the form of inosine is not sufficient to improve PD outcomes PMID 34519802.

An alternative hypothesis is that low adenosine could increase COMT activity, increasing dopamine breakdown: SAM-e is the primary physiologic methyl-donor, and low-SAM-e levels could indicate excess utilization of this COMT co-factor. However, decreased TH expression suggests a dopamine synthesis pathophysiology, rather than a dopamine breakdown pathophysiology.

Purine Modulation of Dopamine in Therapy

Purine-based treatment of schizophrenia is demonstrated with allopurinol, a purine-mimic whose accepted mechanism of action is changing purine metabolism. Allopurinol shows efficacy in treating schizophrenia PMID 15694232. Allopurinol is converted by the body into allopurinol riboside, which inhibits the sole enzyme producing guanine PMID 121041.

Allopurinol's effect is echoed in a low-dopamine context in a fascinating case report: newly diagnosed Parkinson's disease, when treated, resulted in new onset gout, which was treated with allopurinol, which resulted in increased Parkinsonian symptoms PMID 34062024. Purine metabolism suggests alternative targets to increase guanine without increasing uric acid, providing an alternative to the back-and-forth in this case.

Allopurinol's conversion to PNP-inhibiting allopurinol riboside is dependent on functioning hgPRT, consistent with allopurinol's limited benefit for LND patients.

Single-cell LND Findings

Since LND is caused by a genetic change, it is possible to say that a single cell or cell culture has LND. When SNpc dopaminergic neurons are studied, they have undetectable guanine levels PMID 23859490 and show dramatically decreased production of dopamine-creating and transporting enzymes PMID 18313225. These same enzymes are implicated in (low-dopamine) PD.

Lacking an important purine recycling enzyme, LND is characterized by excess from-scratch purine production. When high levels of guanine-similar folate are present, this excess purine production resolves. If the folate is replaced by methotrexate, a non-guanine-similar folate analogue, the pathologic excess purine production continues PMID 32430324.

Learning from Therapeutics

Some pro-dopamine medications mimic the chemical structure of guanine. The size of the rings don't seem to be as important as the location of the guanine-identifying nitrogen in comparison to two mostly-flat rings.

Most of these compounds don't mimic dopamine very closely: dopamine has only one ring, with a flexible nitrogen tail.

Antipsychotic Tricks

Several anti-dopamine molecules also mimic guanine, but have evasive maneuvers at the guanine-identifying location:

clozapine, olanzapine, quetiapine, loxapine, and blonanserin add a bulky ring to the guanine-identifying nitrogen

Antipsychotic Tricks (cont'd)

chlorpromazine and zotepine retain the flexibility to move the guanine-identifying nitrogen out of the way, hide-and-seek style, while xanomeline, thioridazine, and fluphenazine combine hide-and-seek with a bulky ring

Antipsychotic Tricks (cont'd)

the primary risperidone metabolite, paliperidone, uses an adjacent oxygen to make a carbon look close-but-not-quite-like the expected nitrogen, combined with a bulky ring

Noticing Similarities

Notice that the antipsychotics above consistently have a guanine-similar, dopamine-dissimilar nitrogen or, as in zotepine, xanomeline, or thiothixine (not pictured here), a mimic.

Add a nitrogen-mimic in the corresponding position to amphetamine and the result is cathinone (street-named bath salts): the pro-dopamine effect is magnified.

It may be that guanine-similarity is more important than dopamine-similarity in predicting therapeutic effects of both antipsychotic and pro-psychotic drugs.

Summary so far...

Low dopamine in the SNpc (in LND gross histology) is assoiciated with low dopamine-production enzymes and low guanine (in LND cell cultures).
Adding high-dose guanine-similar folate seems to reverse pathological purine metabolism patterns in a low-dopamine disease state (in LND cell culture).
Clinical treatment of low-dopamine disease states include adding guanine-similar pro-dopamine agents: at excessive doses, these guanine-similar agents can produce schizophrenia-similar symptoms.
Clinical treatment of high-dopamine disease states includes adding guanine-trickster agents: used excessively, these may result in low-dopamine (Parkinsonian) symptoms.

Hypothesis

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?

If so, this could cause a clinical paradigm shift where temporary excess dopamine production is targeted for symptomatic control, rather than assumed chronic treatment.

Another guanine-analogue

Acute dystonia/ Parkinsonian side-effects are treated with antihistamines, which may temporarily dislodge guanine-similar histamine from receptors. Without addressing long-term histamine regulation, these have limited efficacy in subacute or chronic symptoms.

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