As we have seen, the neurotransmitter dopamine is far and away the most prominent prize the brain rewards itself with. “Those suffering from substance use disorders continue to self-administer to maintain dopamine levels within a satisfactory range.” Until, eventually, the satisfactory range becomes a long-distant memory, a mirage, a wispy apparition never to be seen again. If the relationship between user and substance has previously been untroubled, disturbing change will now occur.

About two years ago, a multi-authored paper explored dopaminylation (also known as H3R2me2a binding), which occurs in psychostimulant use disorder (also known as PSU.) The binding inhibitor Srcin1 is also more imaginatively called a “homeostatic brake” because it inhibits dopaminylation and,

[…] like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression.

In other words, Srcin1 is able to lessen the amount of reward that the user experiences, and consequently this would tend to reduce the “motivation to self-administer cocaine.” At some point in the future, Srcin1 might be a pharmaceutical product, like the several drugs that are currently prescribed to treat alcohol use disorder. They can block the opioid receptors and otherwise change the brain chemistry to make drinking less attractive. Just gulp down a few pills, or get an implant, and never again be tempted by cravings! Such ambitions ignite the gleam in a pharmaceutical executive’s eye.

And yet, that possibility might be unrealistic, because hard drug addicts are renowned for continuing to “chase the dragon” and attempt to duplicate their blissful earlier highs — no matter what a chore it might have recently become to get truly and irrevocably wasted.

Anyway, as R. Douglas Fields phrased it,

It looks as though dopaminylation […] may control drug-seeking behavior.

But wait, there is more. It seems that dopamine is not only a neurotransmitter, but an epigenetic regulator. Through dopaminylation, “It binds to chromatin, altering gene expression in brain cells and effectively rewiring the brain’s reward circuitry.” This spells both good and bad news:

Dopamine boosts mood, motivation, and attention, and helps regulate movement, learning, and emotional responses. Dopamine also enables us not only to see rewards but to take action to move toward them… Through the newfound mechanism of dopaminylation, dopamine may reinforce drug addiction behaviors.

(To be continued…)

Written by Pat Hartman. First published April 5, 2024.

Sources:

“Dopaminylation in Psychostimulant Use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression,” IngentaConnect.com, April 1, 2022.

“The Epigenetic Secrets Behind Dopamine, Drug Addiction and Depression,” Quanta Magazine, October 27, 2020.

“Cocaine Seeking Heightened by Dopamine’s Epigenetic Effects,” Genetic Engineering & Biotechnology News, April 10, 2020.

Image Copyright: Underway in Ireland/CC BY-SA 2.0 DEED