Dopamine

Themes In Disparate Disorders

Contrasting conditions Lesch-Nyhan Disease and Parkinson's Disease (LND and PD) are associated with low dopamine in the basal ganglia and have significant purine correlations. In both cases, low-dopamine pathophysiology has been attributed to the collection of energy failure, oxidative stress, proteosome dysfunction, and impaired arborization. However, LND disease models progressively demonstrate a direct purine-based downregulation of enzymes throughout the dopamine lifecycle: TH, VMAT, MAOB, COMT, and DAT. By considering the purine cycle in the context of these low-dopamine disorders, one neurodevelopmental and the other neurodegenerative, we arrive at a surprisingly simplistic model of dopaminergic dysfunction with clear treatment implications.

Other purine cycle charts

LND and g deficit

In LND, ineffective hgPRT results in dopamine depletion. Although lack of this purine metabolism enzyme results in many purine changes (excess hypoxanthine is recommended screening PMID XXXX), the low-dopamine symptom dystonia is most strongly correlated, not with excess in ZMP, i, or u, but low g (guanine) recycling PMID XXXX. This leads to g deficit PMID XXXX. Of note, the purine changes in LND seem to reverse themselves in the context of large amounts of g-similar folate: fill the deficit, and pathophysiology corrects.

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.

Reserpine Dopamine Depletion Mechanism

Reserpine can be used to deplete dopamine in animal models of low-dopamine disorders. Although increased PNP activity is not directly mentioned, reserpine dramatically increases g and lowers Go PMID XXXX. This flash of excess g likely overwhelms gPRT activity, resulting in g wasting and subsequent deficit.

Purine Correlates in Parkinson's Disease

In PD disease models, increased XOR activity worsens dopamine deficit, consistent with g-wasting via XOR. Removal of the XOR gene improves dopamine deficit, possibly by decreasing XOR-based g-wasting. PMID XXXX.

Limited PNP activity in PD?

Note that limited PNP activity, resulting in g deficit could explain the difference between high-urate, low-dopamine LND and low-urate, low-dopamine PD. L-DOPA may have a mild but similar effect to reserpine, increasing PNP activity to ameliorate low-g in PD.

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

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 Modulation of Dopamine in Therapy

Rather than attempt to treat PD and gout by alternatively activating (L-DOPA) and inhibiting (allopurinol riboside) PNP, it might be helpful to target GMP reductase. By inhibiting the return to IMP, inhibiting GMP reductase should increase G-derivatives. ONdansetron shows improvement when used to treat PD disease models PMID XXXX. A catatonia (dystonia) case report PMID XXXX and unpublished patient experience suggests that ondansetron may inhibit GMP reductase. In cases where an I-derivative deficit may be problematic, dietary supplementation with SAMe may ameliorate side-effects of ondansetron by increasing available purine substrate.

Purine Modulation of Dopamine in Therapy

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.

Page updated

Google Sites

Report abuse