Slow changes in the functional mass of hypothalamic-pituitary-adrenal (HPA) glands, which plays a role in alcohol addiction, may be a target for intervention in the addiction, according to a study recently published in iScience.

The researchers analyzed the dynamics of the secretion of β-endorphin after HPA axis activation after acute and repeated alcohol intake using a model that they had developed of the HPA axis on the timescale of weeks to study addiction. They added 2 new equations for the dynamics of β-endorphin: 1 for secretion from pituitary corticotrophs into the bloodstream and the other for secretion of the β-endorphin from POMC neurons in the hypothalamus into the cerebrospinal fluid (CSF).

The study authors proposed that the opponent process was structural change of the HPA glands, including the change of the total cell mass due to cell proliferation and growth. When the adrenal cortex grows due to chronic activation of the HPA axis, cortisol secretion increases and suppresses β-endorphin secretion.

They used the model to analyze fold-change detection (FCD) for β-endorphin dynamics in response to the alcohol and found that FCD circuits that control subjective reward maintain sensitivity to reward at higher levels of alcohol intake. The benefits for this control include the ability to learn across several orders of magnitude of rewards and its use of potential-based reward shaping.


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Limitations of the study included the mathematical model’s reliance on experimental testing to establish its validity.

“The gland masses thus provide an opponent process, explaining data on b-endorphin and HPA hormones during alcohol addiction and withdrawal, as well as the effect of adrenalectomy and cortisol replacement on alcohol preference in rodents,” the study authors wrote. “The main message of this study is thus that a weeks-scale feedback loop in which HPA gland masses change over time provides an opponent process.”

The researchers said that this opponent process may also apply to other addictive drugs, such as cocaine and nicotine that activate the HPA axis.

References

Karin O, Raz M, Alon U. An opponent process for alcohol addiction based on changes in endocrine gland mass. iScience. Published online February 2, 2021. doi: 10.1016/j.isci.2021.102127