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Aversion-induced dopamine reductions predict drug-taking and escape behaviors

Neuropsychopharmacology volume 50, pages 1376–1384 (2025)Cite this article

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Abstract

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured during an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted the performance of escape behavior. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and is generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.

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Fig. 1: Presentation of intense white noise promoted cocaine intake.
Fig. 2: Intense white noise reduced dopamine and promoted drug-taking behavior.
Fig. 3: Intense, but not mild, white noise maintained negatively reinforced behavior.
Fig. 4: Operant responses for positive and negative reinforcement increased dopamine concentration.
Fig. 5: Onset of intense, but not mild, white noise reduced NAc dopamine on the first day of exposure and predicted subsequent escape behavior.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Vaibhav Konanur, Matthew Gelin, Peter Lamberton, Kara Zimolzak and Mitch Roitman for technical assistance.

Funding

This work was supported by the Charles E. Kubly Mental Health Research Center and the National Institutes of Health (DA048280 to RAW, MCH, and JRM).

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Authors and Affiliations

  1. Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA

    Elaine M. Grafelman, Bridgitte E. Côté, Lisa Vlach, Ella Geise, G. Nino Padula, Daniel S. Wheeler, Matthew C. Hearing & Robert A. Wheeler

  2. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    John R. Mantsch

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Contributions

EMG, DSW, JRM, MCH, and RAW designed the experiments. EMG, BEC, EG, LV, and DSW performed the surgeries, conducted the experiments, and analyzed the data. EMG, DSW, and RAW wrote the manuscript. BEC, JRM, MCH, LV, NP and DSW provided critical feedback on the manuscript.

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Correspondence to Robert A. Wheeler.

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Grafelman, E.M., Côté, B.E., Vlach, L. et al. Aversion-induced dopamine reductions predict drug-taking and escape behaviors. Neuropsychopharmacol. 50, 1376–1384 (2025). https://doi.org/10.1038/s41386-025-02101-7

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