Phasic Dopamine Signaling During Ingestion: Modulation Across the Need-to-Satiety Arc

Maintaining body homeostasis is essential for survival, and deviations from physiological balance trigger goal-directed behaviors aimed at consuming the needed stimulus. The mesolimbic dopamine system plays a key role in driving and reinforcing such behaviors. While it is well established that physiological need states potentiate dopamine responses to relevant stimuli, less is known about how ongoing ingestion and the transition to satiety influence the mesolimbic dopamine system. To address this gap, I investigated how dopamine signaling is modulated as rats transition from need to satiety across three distinct conditions: sodium appetite, thirst, and hunger. Using in vivo fiber photometry, I measured dopamine release in the nucleus accumbens lateral shell during intraoral delivery of sodium chloride, water, or sucrose. Behavioral reactivity was tracked using deep learning-based pose estimation. Sodium and water evoked greater dopamine release in sodium deplete and water deprived rats, respectively, compared to ad lib controls. Dopamine release declined across trials, suggesting that negative feedback from ongoing ingestion dynamically modulates mesolimbic signaling. This feedback was further supported in sodium deplete rats, where a lower concentration of sodium resulted in a shallower decline in dopamine. In contrast, food restriction only moderately increased dopamine responses to sucrose, which remained relatively stable throughout ingestion despite a main effect of physiological state. Moreover, I applied different manipulations to evaluate their influence on slope of decline during ingestion. Systemic administration of nociceptin receptor antagonist, shown to influence the breakpoint in reward behavior, didn’t affect dopamine responses to water. In contrast, systemic treatment with GLP-1 receptors agonists, known to promote satiety, differentially modulated dopamine responses to sucrose. Exendin-4, but not Semaglutide, significantly suppressed dopamine release without influencing slope of decline, indicating a reduction in overall dopamine activity. This difference may be due to pharmacokinetics properties, as Exendin-4 crosses the blood-brain barrier, whereas Semaglutide does not. Together, these findings suggest that the mesolimbic dopamine system acts as a dynamic integrator of physiological signals, modulating motivational drive as ingestion progresses. These results provide insights into neural mechanisms underlying the transition from need to satiety and have implications for understanding and treating disorders of overconsumption, such as obesity.