# Phasic dopamine in negative reinforcement driven by internal state > **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $199,041 ## Abstract Project Summary/Abstract Combined, the preventable diseases of obesity and drug addiction affect an enormous number of people. In 2016, the World Health Organization estimated that over 1.9 billion people were overweight and at risk for obesity- associated diseases. It also estimated that 5.6% of the world population (between the ages of 15-64) used illicit drugs. Vulnerable individuals seek food and drug initially for positive reinforcement. However, with repeated cycles of use, abstinence and relapse, negative reinforcement mechanisms, where individuals consume (food, drug) to eliminate feelings of negative emotion, are thought to develop and dominate. The mesolimbic dopamine system has long been considered as a neural substrate for positive reinforcement but more recently it has been shown to play a role in negative reinforcement as well. Negative emotion generated by external stimuli (e.g. restraint stress, foot shock) modulates the mesolimbic dopamine system. Internal signals, and in particular, those arising from physiological need (e.g. hunger, thirst) also generate negative emotion, enhance drug reactivity and promote relapse to seeking in abstinent individuals. Thus physiological need is a risk factor for relapse via negative reinforcement. However, the mechanisms by which the signals and circuits activated by the negative reinforcing properties of physiological need modulates dopamine signaling remains unknown. Sodium depletion is a strong interoceptive signal that generates a sodium appetite – a natural motivated behavior that can be recapitulated in the laboratory using rodent models. Sodium depletion is an ideal foundation on which to determine how physiological need interacts with dopamine signaling through negative reinforcement because: 1) it causes a sign change in the value of hypertonic sodium solutions from aversive to rewarding, an effect reflected by phasic dopamine activity; 2) it can be recapitulated via activation of a select population of brainstem neurons in the pre-locus coeruleus expressing prodynorphin (Pre-LCPDYN); and 3) Pre-LC depletion-responsive neurons project directly to dopamine neurons. Here, we will use transgenic mice (PDYN-cre) to express light- sensitive opsins in Pre-LCPDYN neurons and determine, using brain slices and electrophysiology: a) if Pre-LCPDYN neurons project directly to dopamine cell bodies and b) the consequences of activation of Pre-LCPDYN terminals for dopamine cell body excitability. In awake and behaving mice, we will measure dopamine release in multiple dopamine terminal regions to determine if the activity of Pre-LCPDYN neurons is sufficient and necessary to recruit dopamine signaling to cues predictive of a hypertonic sodium solution. Finally, we will determine whether dopamine spikes are correlated with mice working to eliminate the activity of Pre-LCPDYN neurons. Collectively, these exploratory/developmental studies will determine if the satisfaction of physiological need drives do... ## Key facts - **NIH application ID:** 10142416 - **Project number:** 5R21DA050868-02 - **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO - **Principal Investigator:** MITCHELL F ROITMAN - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $199,041 - **Award type:** 5 - **Project period:** 2020-04-15 → 2024-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10142416 ## Citation > US National Institutes of Health, RePORTER application 10142416, Phasic dopamine in negative reinforcement driven by internal state (5R21DA050868-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10142416. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*