# Modulation of Nac-DA Signaling by Learning, Motivational State and Peptides

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $354,155

## Abstract

Project Summary/Abstract
Combined, the preventable diseases of obesity and drug addiction impact an enormous number of people and
cost billions to treat. Physiological need (e.g. thirst, hunger), its hormonal signals and related central circuits,
modulate seeking for and consumption of both nutritive and drug stimuli and thus may serve as risk factors for
overeating and drug relapse. Ventral tegmental area (VTA) dopamine neurons and dopamine release in the
nucleus accumbens play critical roles in reinforcement. This mesolimbic system also integrates physiological
state with primary reward and environmental cues to tune approach and consumption. Indeed, the parent
grant of this competitive renewal determined that deviations from homeostasis potentiate phasic mesolimbic
signaling evoked by cues predictive of restorative stimuli. It also determined that gut hormones signaling
deviations from homeostasis act centrally to modulate phasic mesolimbic signaling in the context of both food
and drug reward. Peripheral signals act on central “first order” hypothalamic sites (e.g. subfornical nucleus
(SFO), arcuate nucleus (ARC)) that have a permeable blood-brain barrier. Modulation of discrete populations
of the SFO or ARC is sufficient to induce negative affect and modulate consummatory behavior for restorative
stimuli in a manner consistent with negative reinforcement. How first order hypothalamic neurons
communicate with the mesolimbic system for reinforcement and to bias approach and consummatory behavior
is unknown. We hypothesize that parallel circuits for thirst and hunger access the VTA via lateral hypothalamic
area (LHA) orexin neurons. As LHA orexin neurons are recruited during morphine withdrawal and orexin
receptor blockade reduces negative affect associated with morphine withdrawal, we also hypothesize that
aberrant activity in first order thirst and hunger circuits during morphine withdrawal are excellent targets for
the treatment of negative affect and to break the cycle of addiction. While hypothalamic signals clearly
modulate aspects of psychostimulant seeking and taking, their role in modulating responses to other classes of
drugs – chiefly opioids – has received little attention. In light of the obesity and opioid epidemics and their co-
morbidity, these are critical gaps in knowledge which will be addressed here. We will measure VTA dopamine
cell body activity or nucleus accumbens dopamine release using in vivo fiber photometry in behaving rats while
selectively modulating first and second order hypothalamic neurons. The aims of the proposal are: 1) to
determine the mechanism by which first order thirst neurons (SFO) modulate phasic mesolimbic signaling to
cues that predict water and drive approach; 2) to determine the mechanism by which first order hunger/satiety
neurons (ARC) modulate phasic mesolimbic signaling to cues that predict food and drive approach; and 3) to
intervene at the level of first order thirst and hunger neurons to mo...

## Key facts

- **NIH application ID:** 10050649
- **Project number:** 2R01DA025634-11A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** MITCHELL F ROITMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,155
- **Award type:** 2
- **Project period:** 2009-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050649

## Citation

> US National Institutes of Health, RePORTER application 10050649, Modulation of Nac-DA Signaling by Learning, Motivational State and Peptides (2R01DA025634-11A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10050649. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*