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bioRxiv · 10.1101/2025.09.23.678075

Convergent and divergent neural and behavioral responses to chronic cocaine use in macaques

Manea, A. M. G.·Erickson, T.·Delgado Salazar, G.·Zilverstand, A.·Heilbronner, S. R.·Zimmermann, J.
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Abstract

Chronic cocaine use leads to physical dependence, psychological addiction, and various health problems such as cardiovascular issues and cognitive impairments. This condition continues to be extremely difficult to treat, as we grapple with its neural and behavioral complexities. What we are missing is a comprehensive account on how naive brains react to occasional and chronic cocaine use, abstinence and re-exposure within subject. We tracked naive macaques using precision functional mapping before, during and after chronic cocaine self-administration over a period of nine months. We analyzed the entire brain to illustrate the pervasive impact of chronic cocaine use on overall function. Although we set out to map the "addiction" connectome, we found that the neural correlates of chronic drug use and recovery are more complex that can be captured by a singular, canonical connectome. We provide a preclinical model that maps the progression of the macaque functional connectome from a naive state through chronic cocaine use, recovery and re-exposure. We demonstrate that the "addiction" connectome is dynamic and is characterized by the interaction of subject by drug by time. Occasional cocaine use, whether initial or re-exposure, overrides individual differences, leading to a strong homogenous effect across subjects, or convergence. However, the brains response to prolonged cocaine use becomes more individualized, resulting in the divergence of effects across subjects. This can be explained by heterogeneity in cocaine-induced effects and in their associated timescales. Abstinence-induced neural alterations converged across subjects after 1-month, but by 2 months, individual trajectories revealed heterogeneity, possibly indicating differences in recovery.

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Manea, A. M. G., Erickson, T., Delgado Salazar, G., Zilverstand, A., Heilbronner, S. R., Zimmermann, J.. 2025-09-25. Convergent and divergent neural and behavioral responses to chronic cocaine use in macaques. https://doi.org/10.1101/2025.09.23.678075

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