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bioRxiv · 10.1101/2025.10.04.680105

Incentive Salience, not Psychomotor Sensitization or Tolerance, Drives Escalation of Cocaine Self-Administration in Heterogeneous Stock Rats

Ramborger, J.·Mosquera, J.·Brennan, M.·Sichel, B.·Othman, D.·Plasil, S.·Sneddon, E. A.·Bonnet Zahedi, S.·Morgan, A.·Chonwattanagul, S.·Bai, K.·China, L.·La, T.·Maturin, L.·Carrette, L. L. G.·George, O.
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Abstract

Sensitization and tolerance are two phenomena often studied independently despite overlapping neurobiological substrates. Each has extensive research showing their influence on the development and maintenance of addiction, but the degree to which they drive escalation in cocaine self-administration is poorly understood. Using self-administration, intravenous noncontingent infusions, and pose-estimation machine vision, we find that incentive salience, not psychomotor sensitization or tolerance, drives the escalation of cocaine self-administration in heterogenous stock rats. Individual differences in psychomotor sensitization or tolerance were found to have no effect on cocaine intake. Incentive salience as measured by locomotion and active lever entrances per meter traveled occurring before the self-administration session began (pre-lever activity measures) during Short Access (2-hours) was found to predict intake during Long Access (6-hours). Both pre-lever locomotion and active lever entrances per meter were found to increase during Long Access and after two-to-three days of abstinence. Critically, rats with low pre-lever activity during Short Access escalated both their intake and pre-lever measures by the end of Long Access to levels comparable with high pre-lever activity rats who maintained their elevated responding. These findings support the notion that incentive salience during Short Access is a catalyst to escalated use and an early marker of addiction vulnerability. Moreover, they suggest that individuals initially resistant to incentive salience can, with sufficient exposure, become sensitized and escalate cocaine use to the same level as more susceptible individuals. Analysis of pre-lever activity offers a novel longitudinal behavioral marker to predict vulnerability and provides a framework for understanding individual trajectories of addiction.

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Ramborger, J., Mosquera, J., Brennan, M., Sichel, B., Othman, D., Plasil, S., Sneddon, E. A., Bonnet Zahedi, S., Morgan, A., Chonwattanagul, S., Bai, K., China, L., La, T., Maturin, L., Carrette, L. L. G., George, O.. 2025-10-06. Incentive Salience, not Psychomotor Sensitization or Tolerance, Drives Escalation of Cocaine Self-Administration in Heterogeneous Stock Rats. https://doi.org/10.1101/2025.10.04.680105

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