Winning experiences curb drug-seeking behavior by reshaping the brain's dopamine system

In a study published in Nature Neuroscience on May 12, a research team led by Prof. ZHU Yingjie at the Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, has uncovered the neural mechanisms by which social rank influences vulnerability to drug addiction.

Drug addiction remains a major global public health challenge, with current treatments offering only limited efficacy. While clinical observations have long suggested that social rank plays a significant role in addiction susceptibility, the underlying neural mechanisms have remained poorly understood—until now.

To investigate this link, the researchers employed a suite of cutting-edge neuroscience tools, including fiber photometry, fast-scan cyclic voltammetry (FSCV), optogenetic modulation, and VISoR imaging, to examine how the dopamine system differs functionally and structurally among male rodents of different social ranks.

The findings revealed that social dominance alters the balance between two key dopamine pathways: the mesolimbic pathway, which delivers dopamine to the nucleus accumbens (NAc) and promotes reward-seeking behavior, whereas the mesocortical pathway, which projects to the medial prefrontal cortex (mPFC) and supports executive control, helping suppress compulsive drug use.

"Low-ranking mice exhibit a stronger 'reward' circuit and a weaker 'control' circuit—like a high-powered car with faulty brakes—making them more prone to drug-seeking. In contrast, high-ranking mice have a more balanced system, with effective 'brakes' that help them resist addiction," explained Prof. ZHU.

To test this causal link, the researchers used pharmacological and optogenetic approaches to manipulate dopamine signaling. Reducing dopamine-related proteins in the NAc of low-ranking male mice led to decreased methamphetamine (METH) intake. Conversely, disrupting dopamine fibers in the mPFC of high-ranking mice increased their drug-seeking behavior. Most strikingly, optogenetic activation of the mesocortical pathway not only increased social dominance but also significantly suppressed subsequent METH-seeking.

Notably, the study also found that these effects were sex-specific: Female mice exhibited METH-seeking behavior regardless of social rank, suggesting different neurobiological underpinning of addiction risk in male and females.

Moreover, when the team induced winning experiences in low-ranking mice, the animals not only climbed the social rank but also exhibited reduced drug-seeking behaviors. These behavioral changes were underpinned by functional and structural remodeling in both mesocortical and mesolimbic dopamine pathways.

This study introduces a novel neurobiological framework linking social status, dopamine circuit dynamics, and addiction vulnerability. "By boosting an individual's sense of social achievement or simulating successful experiences, it may be possible—at the neural level—to 'strengthen the brakes and ease off the accelerator,' thereby reducing addiction risk," said Prof. ZHU.

The findings also lay a scientific foundation for developing non-invasive neural stimulation therapies aimed at mitigating vulnerability to substance use disorders.