# Brain-wide circuit mapping to delineate therapeutic strategies for amphetamine abuse

> **NIH NIH P50** · STANFORD UNIVERSITY · 2023 · $325,235

## Abstract

PROJECT SUMMARY (Project 3)
 MDMA, an amphetamine derivative known both as an ‘empathogen’ and the recreational drug ‘ecstasy’,
may soon be approved for treating Post-Traumatic Stress Disorder. MDMA’s therapeutic efficacy is linked to its
unique ability to foster feelings of social connection and trust. However, MDMA‘s well-known abuse potential,
and associated cardiovascular and neuropsychiatric toxicity, present a major public health risk. The
psychological and behavioral effects of MDMA in human subjects contrast strongly with the closely related
psychostimulant, methamphetamine (MA). While MDMA and MA share chemical and pharmacological
similarities, MA has an even higher abuse liability and, accordingly, a more devastating societal impact. We
hypothesize that the unique prosocial properties of MDMA are mechanistically linked to its comparatively lower
abuse potential. A deeper understanding of how MDMA’s unique prosocial effect mitigates abuse of
amphetamine-class compounds may lead to entirely new therapeutic strategies for amphetamine use
disorders.
 We exploit the contrasting behavioral effects of MDMA and MA to probe brain-wide patterns of neural
activity corresponding to these drugs’ differential regulation of natural reward sensitivity as well as their shared
abuse potential. We propose a rigorous, systematic screening process to identify and test novel neural circuits
that differentiate these behavioral properties of MA and MDMA. Using simple, reproducible behavior assays
that parallel human imaging experiments in Project 4, we identify, validate and characterize these novel circuits
in three broad steps. First, we use a whole-brain imaging and mapping process to identify candidate brain
regions where neural activity is differentially regulated by MDMA, MA, or a drug-by-behavioral context
interaction. Second, we perform loss-of-function experiments to define the contribution of these identified
regional ensembles to specific MA and MDMA-induced behaviors using a transgenic mouse line that allows for
capture-and-control of drug-activated ensembles. Third, we focus on the drug-induced temporal structure of
ensemble activity within those identified brain regions, collaborating across Projects to perform detailed
recordings of cellular activity in vivo. Developing effective, scalable therapies for existing and emerging
amphetamine-derivative abuse disorders requires approaches that build upon, and transcend, simple
preclinical models of ligand-receptor interference. To our knowledge, no other research group has proposed or
executed a circuit-based approach that leverages parallel mouse-human behavior and imaging modalities so
directly.

## Key facts

- **NIH application ID:** 10494007
- **Project number:** 2P50DA042012-06
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** ROBERT C MALENKA
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $325,235
- **Award type:** 2
- **Project period:** 2017-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10494007

## Citation

> US National Institutes of Health, RePORTER application 10494007, Brain-wide circuit mapping to delineate therapeutic strategies for amphetamine abuse (2P50DA042012-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10494007. Licensed CC0.

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