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, ?/?-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.

Public Health Relevance

Amphetamine is a potent brain stimulant often used for the treatment of select psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD); but repetitive use of high doses of amphetamine can lead to addiction, impaired cognitive function and psychosis. This grant is designed to establish how inhibition of a recently identified molecular component of endocannabinoid signaling, ABHD6, tightly controls amphetamine's stimulatory response and might represent a new combination therapy approach to help optimize the medical use of psychostimulants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA047626-01A1
Application #
9823414
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Rapaka, Rao
Project Start
2019-07-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195