# Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Reinforcement

> **NIH NIH R01** · DREXEL UNIVERSITY · 2020 · $370,613

## Abstract

Project Summary:
Psychostimulant addiction is a chronic disease and currently no approved pharmacotherapies exist for its
treatment. Among the greatest challenges in the treatment of addiction is the prevention of relapse to drug use.
In animals, periods of abstinence following drug use intensifies craving and motivation for drug, which has
been associated with increased propensity for relapse. Recent advances suggest that alterations in mesolimbic
dopamine systems during abstinent periods may be a critical component of the intensification of drug craving
effect. Unfortunately, dopamine-based therapies are often ineffective or intolerable and may have abuse
potential themselves. The hypocretins/orexins (HCRT) are hypothalamic neuropeptides that participate in the
regulation of arousal, locomotor activity, and a variety of motivated behaviors. Over the past decade, the HCRT
system has also been shown to influence drug reinforcement via actions in the dopamine-rich ventral
tegmental area. For example, we have shown that disrupting HCRT neurotransmission within the ventral
tegmental area reduces the reinforcing effects of cocaine and attenuates cocaine-induced elevations in
dopamine within the nucleus accumbens. Recently we discovered a novel effect of acute HCRT disruption that
causes long-lasting alterations in dopamine terminal sensitivity to cocaine and prevents increased motivation
for cocaine following drug abstinence. To further examine the extent to which the HCRT system regulates
dopamine signaling and cocaine reinforcement, the proposed research will employ a multidisciplinary approach
using sophisticated behavioral, neurochemical, and genetic manipulation techniques. Studies will examine the
utility of acute HCRT receptor 1 blockade on the development of intensified behavioral and dopaminergic
responses to cocaine following a period of abstinence and whether these effects are dependent on dopamine
neurons of the ventral tegmental area. Completion of this work will offer insight into the neural mechanisms
underlying the addiction process and will provide the basis for a novel pharmacotherapy to treat cocaine
addiction.

## Key facts

- **NIH application ID:** 9933875
- **Project number:** 5R01DA031900-08
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Rodrigo A. España
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,613
- **Award type:** 5
- **Project period:** 2013-01-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933875

## Citation

> US National Institutes of Health, RePORTER application 9933875, Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Reinforcement (5R01DA031900-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933875. Licensed CC0.

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