# Orexin/hypocretin as a common mediator of stress and reward behavior in cocaine addiction

> **NIH NIH K99** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2020 · $193,796

## Abstract

Project Summary/Abstract
Addicts often report the emergence of negative emotional states during withdrawal, including stress and
anxiety, and it is thought that these states can drive future drug taking through negative reinforcement
processes. Hypothalamic orexin (also known as hypocretin) neurons are unique as they mediate both reward
and stress behaviors, making these cells a promising target for pharmacotherapies designed to treat the
multifaceted symptomology of addiction. However, our understanding of how these neurons modulate both
reward and stress behaviors in addiction is currently limited. In the current proposal, I seek to receive training
in several sophisticated neuroscience techniques to test my hypothesis that orexin neurons innervate discrete
subpopulations of dopamine neurons in ventral tegmental area (VTA) with projections to nucleus accumbens
shell (NAcSh) and medial prefrontal cortex (mPFC), to mediate reward and stress behaviors, respectively.
These experiments will yield highly novel data that will inform the development of more effective therapeutics
for addiction. In addition, the training and mentorship that I receive under this award will be invaluable in
assisting my transition to a career as an independent scientist.
 During the mentored phased of this application, I will use a combination of optogenetic and behavioral
electrophysiology approaches to interrogate the orexin reward system in addiction. I will record from
dopaminergic VTA neurons that project to NAcSh and receive input from LH orexin neurons, and predict that
both tonic and phasic activity of these neurons will be enhanced in animals exposed to a novel cocaine self-
administration paradigm (intermittent access; IntA) that promotes highly-motivated drug seeking behavior. In a
second set of experiments, I will use a chemogenetic approach to downregulate activity within this circuit,
which I predict will normalize drug-seeking behaviors in these animals.
 During the independent phase, I will use the techniques that I learned during the K99 portion to
investigate the orexin stress system in addiction. I have previously shown that IntA self-administration model is
associated with exacerbated anxiety-like behavior during acute withdrawal, and in these experiments, I will
record from VTA neurons that innervate mPFC and receive input from DMH/PF orexin neurons. I predict that
the activity of these cells will be augmented during withdrawal in these animals, and that downregulation of this
circuit during withdrawal (using a chemogenetic approach) will reduce anxiety-like behavior. In my final
experiment, I will use a chemogenetic stimulation approach test the hypothesis that chronic activation of the
orexin stress system produces plasticity at the level of the VTA that subsequently augments activity of the
orexin reward system. These data will point to an integration of orexin stress and reward systems in addiction,
and will form the basis of my first R01 applicat...

## Key facts

- **NIH application ID:** 9883768
- **Project number:** 5K99DA045765-02
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Morgan H. James
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,796
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883768

## Citation

> US National Institutes of Health, RePORTER application 9883768, Orexin/hypocretin as a common mediator of stress and reward behavior in cocaine addiction (5K99DA045765-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9883768. Licensed CC0.

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