Dopamine Pathways Link Social Rank to Drug Vulnerability

A team led by researchers at the Shenzhen Institutes of Advanced Technology (SIAT), part of the Chinese Academy of Sciences, has identified a biological pathway by which social rank influences vulnerability to drug addiction. Their findings, published in Nature Neuroscience on May 12, describe how differences in dopamine signaling within the brain can account for rank-related disparities in addiction susceptibility among male rodents.

Addiction is a major public health concern, with few effective treatments. While social hierarchy is known to influence mental health and substance use outcomes, the neural basis for this association has remained unclear.

Dopamine pathway activity differs by social rank

The researchers used advanced techniques including fiber photometry, fast-scan cyclic voltammetry, optogenetics and volumetric imaging to examine the brains of male mice with established social ranks. These tools enabled real-time measurement of neural activity and chemical signaling, along with precise control and visualization of brain circuits.

They focused on two dopamine pathways: the mesolimbic pathway, which projects to the nucleus accumbens (NAc) and is associated with reward behavior, and the mesocortical pathway, which connects to the medial prefrontal cortex (mPFC) and is involved in executive control. Mice with low social rank showed increased activity in the mesolimbic system and reduced mesocortical activity – patterns linked to greater drug-seeking behavior. In contrast, high-ranking mice had stronger control-related signaling and reduced vulnerability to methamphetamine (METH) use.

Circuit manipulation influences addiction behavior

The team demonstrated causality by selectively altering dopamine signaling. When dopamine-associated proteins were reduced in the NAc of low-ranking mice, drug-seeking behavior declined. Similarly, damage to dopamine projections in the mPFC of high-ranking mice increased drug preference.

Optogenetic stimulation of the mesocortical pathway reduced both METH-seeking behavior and increased the likelihood that mice would win social competitions. These findings support a model in which strengthening executive control circuits in the brain not only alters behavior but also influences social status.

Sex-specific patterns and behavioral modulation

The study also identified sex-specific effects: Female mice exhibited METH-seeking behavior irrespective of social hierarchy. This result points to a different neurobiological basis for addiction risk in males and females.

The researchers further found that inducing experiences of social success in low-ranking males not only elevated their rank but also reduced drug-seeking in subsequent tests. These behavioral shifts were accompanied by changes in the structure and function of both dopamine pathways, suggesting a feedback loop between behavior, brain function and social environment.

Broader implications for addiction treatment

These findings suggest that targeting dopamine circuits – specifically by enhancing mesocortical function – may reduce addiction risk. Approaches that promote social achievement or simulate successful experiences could serve as behavioral interventions. The study also supports development of non-invasive neurostimulation strategies aimed at altering brain function associated with control and reward.

Reference: Deng X, Xu W, Liu Y, et al. Social rank modulates methamphetamine-seeking in dominant and subordinate male rodents via distinct dopaminergic pathways. Nat Neurosci. 2025. doi: 10.1038/s41593-025-01951-0

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