# In Vivo Characterization of 5-HT7 Modulators in Rat Models of Cocaine Use Disorder

> **NIH NIH R44** · PRAEVENTIX, LLC · 2022 · $320,000

## Abstract

Cocaine is one of the most commonly abused illicit drugs, and the negative impact of this drug is apparent
in the 2011 Drug Abuse Warning Network (DAWN) report which revealed that >500,000 patients required
hospital emergency department services as a result of cocaine use. Despite the clear and compelling need,
there are no FDA approved medications for the treatment of cocaine use disorder (CUD). Cocaine produces
euphoria via the mesocorticolimbic dopamine (MCL-DA) system, also known as the reward system. Dopamine
release and transport systems within the MCL-DA are altered by both acute and chronic exposure to cocaine.
Over time and continued use, cocaine will produce adaptations in additional neural circuits resulting in impaired
executive function and decision-making processes and causing negative emotional affect for users. It has been
previously demonstrated that there is substantial interplay between MCL-DA activity and serotonergic neurons
that extend into this region of the brain. In addition, several studies have demonstrated that serotonin (5-HT)
releasing serotonergic neurons regulate the activity of dopaminergic neurons in these regions of the MCL-DA
system under both normal conditions and in the presence of cocaine. A link between DA and 5-HT7 signaling
suggests that modulating 5-HT7 signaling may be a viable and novel approach to CUD.
 In addition to the potential of 5-HT7 antagonism to regulate the MCL-DA system, our strategy in this program
stems from extensive literature demonstrating the role of 5-HT7 receptors in improving attentional set shifting,
reversal learning, and extinction in preclinical assays. By improving cognitive flexibility and facilitating extinction
learning in addition to modulating reward in the MCL-DA, we propose that selective 5-HT7 receptor antagonists
are the pharmacotherapy strategy needed in the treatment of CUD. We have identified a series of novel, drug-
like 5-HT7 receptor antagonists which reduced cocaine reinstatement in a well-established rat model of relapse
in our preliminary studies. We propose to test escalating doses of our first-generation lead in this cocaine
reinstatement model to achieve a full dose-response. Once achieved, we will build on our understanding of the
SAR for our 5-HT7 antagonists to identify novel, orally bioavailable, BBB penetrant lead compounds optimized
for advanced in vivo efficacy studies. We will test the effectiveness of our compounds to reduce ongoing cocaine
responding as a potential maintenance therapeutic and to identify behaviorally active doses to be advanced for
evaluation in a panel of cocaine reinstatement models including cocaine-, cue- and stress-induced reinstatement.
We hypothesize that our compounds will accelerate or augment extinction learning and reduce reinstatement of
cocaine responding whether produced by a noncontingent injection of cocaine, associated cues, or stress-
induced by injection of yohimbine. Leads identified in these in vivo screens w...

## Key facts

- **NIH application ID:** 10483526
- **Project number:** 1R44DA055443-01A1
- **Recipient organization:** PRAEVENTIX, LLC
- **Principal Investigator:** Benjamin Blass
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $320,000
- **Award type:** 1
- **Project period:** 2022-06-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10483526

## Citation

> US National Institutes of Health, RePORTER application 10483526, In Vivo Characterization of 5-HT7 Modulators in Rat Models of Cocaine Use Disorder (1R44DA055443-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10483526. Licensed CC0.

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