Cocaine seeking and consumption are oppositely regulated by mesolimbic dopamine in male rats

Lauren M. Burgeno, Ryan D. Farero, Nicole L. Murray, Marios C. Panayi, Jennifer S. Steger, Marta E. Soden, Scott B. Evans, Stefan G. Sandberg, Ingo Willuhn, Larry S. Zweifel and Paul E. M. Phillips ()
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Lauren M. Burgeno: University of Washington
Ryan D. Farero: University of Washington
Nicole L. Murray: University of Washington
Marios C. Panayi: National Institutes of Health
Jennifer S. Steger: University of Washington
Marta E. Soden: University of Washington
Scott B. Evans: University of Washington
Stefan G. Sandberg: University of Washington
Ingo Willuhn: University of Washington
Larry S. Zweifel: University of Washington
Paul E. M. Phillips: University of Washington

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Drug-associated stimuli (cues) can usurp potent control of behavior in individuals with substance use disorders; and these effects are often attributed to altered dopamine transmission. However, there is much debate over the way in which dopamine signaling changes over the course of chronic drug use. Here, we carried out longitudinal recording and manipulation of cue-evoked dopamine release in the core of the nucleus accumbens across phases of substance use in male rats. We show that, in a subset of individuals that exhibit increased cue reactivity and escalated drug consumption, this signaling undergoes diametrically opposed changes in amplitude, determined by the context in which the cue was presented. Dopamine evoked by non-contingent cue presentation (independent of the animal’s actions) increases over drug use, producing greater cue reactivity; whereas dopamine evoked by contingent cue presentation (dependent on the animal’s actions) decreases over drug use, producing escalation of drug consumption. Therefore, despite being in opposite directions, these dopamine trajectories each promote cardinal features of substance use disorders.

Date: 2025
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DOI: 10.1038/s41467-025-64885-y

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