Researchers unlock new paths toward treating stress-related psychiatric disorders

In a comprehensive Genomic Psychiatry review article published today, researchers from the University of Rochester Medical Center have synthesized decades of research on stress hormone systems in primate brains, potentially unlocking new paths toward treating stress-related psychiatric disorders. The article offers groundbreaking insights into how corticotropin releasing factor (CRF), a key stress hormone, interacts with dopamine neuron populations in ways that differ significantly between rodents and primates.

The stress-dopamine connection: More complex than previously understood

Stress affects every organism on Earth, from simple invertebrates to humans. At the center of this universal response is corticotropin releasing factor (CRF), an ancient neuropeptide that modulates brain systems during stress exposure. While CRF has been studied extensively in rodent models since its discovery over 40 years ago, translating these findings to human treatments has proven surprisingly difficult.

Our review highlights why higher animal models might be required to truly understand stress effects on the brain. There are subtle but critical differences in how CRF peptides and receptors are distributed in primate brains compared to rodents, which could explain the challenges we've faced in developing effective treatments for stress-related disorders."

Dr. Julie Fudge, corresponding author

The research team specifically focused on interactions between CRF and the midbrain dopamine system, which plays essential roles in motivation, reward processing, and stress responses. Their findings reveal that primates possess more expanded and complex dopamine neuron populations than rodents, particularly in brain regions that have been implicated in psychiatric disorders.

Anatomical differences may hold key to treatment failures

One of the most significant insights from this review is the identification of specific anatomical differences that may explain why treatments that work in rodent models often fail in human clinical trials. The review highlights how primate brains show a more diffuse distribution of CRF-containing cells and different receptor expression patterns compared to rodents.

These findings raise important questions: How do these species differences impact the stress response? Could they explain why pharmacological approaches targeting the CRF system have had limited success in human clinical trials?

"Understanding these species differences isn't just academic-it's potentially critical for developing the next generation of treatments for conditions like depression, anxiety, and addiction," notes Dr. Fudge. "Our laboratory has been particularly interested in mapping the neural architecture of how stress and dopamine systems interact in the primate brain because it offers a much closer model to humans."

New data reveals surprising complexity in neurotransmitter systems

The researchers also present preliminary findings suggesting that dopamine neurons in primates are far more complex than previously understood. Their data indicates that the majority of dopamine neurons in the primate brain contain multiple neurotransmitters, creating a highly sophisticated signaling system that could allow for more nuanced responses to stress.

This "multiplexed" neurotransmitter profile-where neurons can release combinations of dopamine, glutamate, and GABA-appears to be more prevalent in primates than in rodents. This raises the intriguing possibility that primates have evolved more complex stress-response systems to handle the more varied social and environmental challenges they face.

"We're finding that many neurons that were traditionally just classified as 'dopaminergic' are actually capable of releasing multiple neurotransmitters, creating a kind of chemical symphony that allows for incredibly nuanced responses to stress," explains Dr. Fudge. "Although multiple- transmitter dopamine neurons occur in rodents, the system is even diverse in the primate. This complexity may explain why simplistic approaches to treating stress disorders have fallen short."

Future directions point to personalized treatment approaches

The researchers outline several promising directions for future research, including a more comprehensive mapping of how age, sex, and individual differences influence the CRF-dopamine relationship. These factors may be critical for developing personalized approaches to treating stress-related disorders.

One particularly intriguing question is how early life stress might permanently alter these brain systems in primates. Studies have shown that stress during development can have lasting effects on mental health, but the precise neural mechanisms underlying these effects remain poorly understood.

Could different CRF receptor variants explain why some individuals are more resilient to stress while others are vulnerable to developing psychiatric disorders? How might hormonal differences between males and females affect the response of this system to stress? These questions represent frontier areas for research with significant implications for human health.

"What we're learning about these stress systems in primates is that context, timing, and individual differences matter tremendously," says Dr. Fudge. "The future of treatment likely lies in understanding the unique patterns of these systems in each patient rather than one-size-fits-all approaches."

The review synthesizes findings from laboratories worldwide and offers a roadmap for future investigations that could revolutionize our understanding of stress-related mental health conditions.

The article in Genomic Psychiatry titled "Translating stress systems: corticotropin releasing factor, its receptors, and the dopamine system in nonhuman primate models," is freely available via Open Access on 6 May 2025 in Genomic Psychiatry at the following hyperlink: https://doi.org/10.61373/gp025i.0038.