# ABHD6 and amphetamine stimulated locomotion

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2020 · $223,713

## Abstract

Summary
Recent evidence shows that the potent brain stimulatory effects of amphetamine are controlled by the
endocannabinoid (eCB) signaling system. Our laboratory established that the enzyme, α/β-hydrolase domain 6
(ABHD6), represent a novel molecular component of the eCB signaling system. Indeed, this post-synaptic
enzyme controls the activity-dependent production of 2-arachidonoylglycerol (2-AG, the most abundant eCB in
the brain), and as such controls the levels and efficacy of 2-AG at cannabinoid CB1 receptors (CB1R).
 We recently evaluated the involvement of ABHD6 in the locomotor responses stimulated by amphetamine
in mice and found that its pharmacological inhibition and genetic deletion exerts a profound enhancing effect
on the acute amphetamine-stimulated locomotor activity through a CB1R-dependent mechanism. In this R21
grant, we propose to identify brain regions involved in the ABHD6-dependent control of psychostimulants using
several recently developed tools, including a brain-penetrant selective inhibitor of ABHD6 (KT-182 and
MJN193), a Cre-dependent ABHD6 mouse line (ABHD6lox/lox), a specific antibody for ABHD6, and a
CRISPR/Cas9 Slc6a3 (DAT) knockout model of hyperactivity. There are two main questions that will be
addressed by this proposal. First, where in the brain is the interaction between ABHD6 and amphetamine
occurring? Second, does ABHD6 alone, or in combination with low dose amphetamine, result in paradoxical
calming response measured in a mouse model of attention deficit hyperactivity disorder (ADHD)-like
phenotypes. Our aims are:
1: Identify brain regions involved in the ABHD6-dependent control of psychostimulants.
2: Establish the dose-dependent effects of ABHD6 inhibition on the paradoxical calming effects of
psychostimulants in an animal model of hyperactivity.
The completion of these studies will provide foundational results on the molecular mechanism by which
ABHD6 regulates psychostimulant behavior in mice. A better understanding of this novel molecular interaction
should help optimize the therapeutic use of psychostimulants while reducing their addiction and toxicity profile.

## Key facts

- **NIH application ID:** 9964747
- **Project number:** 5R21DA047626-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Nephi Stella
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $223,713
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964747

## Citation

> US National Institutes of Health, RePORTER application 9964747, ABHD6 and amphetamine stimulated locomotion (5R21DA047626-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964747. Licensed CC0.

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