PET scans reveal key molecular driver of stress and addiction in people with alcohol use disorder

Preliminary findings suggested that individuals with AUD have higher [Hydroxysteroid dehydrogenase type 1 (beta-11 HSD1)] availability than healthy individuals, in brain regions specific to the ‘dark side of addiction.'

For the first time, PET scans have revealed what may be a key molecular driver of stress and addiction in people with alcohol use disorder, according to the researchers.

The group of researchers at Yale University in New Haven, CT, used PET imaging to visualize levels of a brain enzyme that generates cortisol in response to stress in people with AUD and compared findings to healthy controls; the results established a foundation for new research.

Regions specific to the dark side of addiction include d the hypothalamic-pituitary-adrenal (HPA) axis, a system that regulates the body's stress response. Preclinical studies have shown that exposure to chronic alcohol increases levels of brain cortisol, for instance, and that this hyperreactivity may blunt the ability of the HPA axis to respond to stress, the research group noted.

Results from this preliminary research have been mixed, and in 2019 researchers developed a PET radiotracer that binds to an enzyme involved in cortisol activity (beta-11 HSD1); in the study, Terril L. Verplaetse, Yale School of Medicine, New Haven, CT, USA, and colleagues used the tracer to visualize this enzyme activity for the first time in humans.

For this purpose, the group imaged nine individuals with moderate to severe AUD (four women, five men; mean age = 38 years) and 12 healthy controls (four women, eight men; mean age = 29 years).

People with AUD consumed 52.4 drinks per week with 5.8 drinking days per week, while healthy controls consumed 2.8 drinks per week with 1.3 drinking days per week.

Key findings:

• PET scans revealed 41.7% higher overall beta-11 HSD1 activity in the prefrontal-limbic circuit in the AUD group compared to the healthy control group.
• The mean F-18 AS2471907 radiotracer values were higher in the AUD group by 47% in the amygdala, 36% in the caudate, 52% in the anterior cingulate cortex, 39% in the hippocampus, and 36% in the ventromedial prefrontal cortex (vmPFC).
• Higher brain availability of the cortisol-regenerating enzyme beta-11 HSD1 in people with AUD and higher vmPFC beta-11 HSD1 availability is related to greater alcohol consumption. The researchers hypothesized that this higher beta-11 HSD1 availability in the brain may drive a blunted response to stress in individuals with AUD, which leads to increased vulnerability to excessive use.

The researchers noted the findings in this study are “first-in-kind” and that there will be a need for future studies to elucidate these mechanisms.

“These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population,” the researchers concluded.

Reference:

Verplaetse, T. L., Hillmer, A. T., Bhatt, S., Rusowicz, A., Li, S., Nabulsi, N., Matuskey, D., Huang, Y., McKee, S. A., & Cosgrove, K. P. (2024). Imaging a putative marker of brain cortisol regulation in alcohol use disorder. Neurobiology of Stress, 100609. https://doi.org/10.1016/j.ynstr.2024.100609