Liting Deng1, Katie Viray1, Simar Singh1, Ben Cravatt2, Nephi Stella1,3. 1. Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington, USA. 2. Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA. 3. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
Abstract
Introduction: Activation of cannabinoid 1 receptors (CB1Rs) by endocannabinoids (eCBs) is controlled by both eCB production and eCB inactivation. Accordingly, inhibition of eCB hydrolyzing enzymes, monoacylglycerol lipase (MAGL) and α/β-hydrolase domain containing 6 (ABHD6), enhances eCB accumulation and CB1R activation. It is known that inhibition of MAGL regulates select CB1R-dependent behaviors in mice, including locomotor behaviors and their modulation by psychostimulants, but much less is known about the effect of inhibiting ABHD6 activity on such behaviors. Methods: We report a new mouse line that carries a genetic deletion of Abhd6 and evaluated its effect on spontaneous locomotion measured in a home cage monitoring system, motor coordination measured on a Rotarod, and amphetamine-stimulated hyperlocomotion and amphetamine sensitization (AS) measured in an open-field chamber. Results: ABHD6 knockout (KO) mice reached adulthood without exhibiting overt behavioral impairment, and we measured only mild reduction in spontaneous locomotion and motor coordination in adult ABHD6 KO mice compared to wild-type (WT) mice. Significantly, amphetamine-stimulated hyperlocomotion was enhanced by twofold in ABHD6 KO mice compared to WT mice and yet ABHD6 KO mice expressed AS to the same extent as WT mice. A twofold increase in amphetamine-stimulated hyperlocomotion was also measured in ABHD6 heterozygote mice and in WT mice treated with the ABHD6 inhibitor KT-182. It is known that amphetamine-stimulated hyperlocomotion is not affected by the CB1R antagonist, SR141617, and we discovered that the enhanced amphetamine-stimulated hyperlocomotion resulting from ABHD6 inhibition is blocked by SR141617. Conclusions: Our study suggests that ABHD6 controls amphetamine-stimulated hyperlocomotion by a mechanistic switch to a CB1R-dependent mechanism.
Introduction: Activation of cannabinoid 1 receptors (CB1Rs) by endocannabinoids (eCBs) is controlled by both eCB production and eCB inactivation. Accordingly, inhibition of eCB hydrolyzing enzymes, monoacylglycerol lipase (MAGL) and α/β-hydrolase domain containing 6 (ABHD6), enhances eCB accumulation and CB1R activation. It is known that inhibition of MAGL regulates select CB1R-dependent behaviors in mice, including locomotor behaviors and their modulation by psychostimulants, but much less is known about the effect of inhibiting ABHD6 activity on such behaviors. Methods: We report a new mouse line that carries a genetic deletion of Abhd6 and evaluated its effect on spontaneous locomotion measured in a home cage monitoring system, motor coordination measured on a Rotarod, and amphetamine-stimulated hyperlocomotion and amphetamine sensitization (AS) measured in an open-field chamber. Results: ABHD6 knockout (KO) mice reached adulthood without exhibiting overt behavioral impairment, and we measured only mild reduction in spontaneous locomotion and motor coordination in adult ABHD6 KO mice compared to wild-type (WT) mice. Significantly, amphetamine-stimulated hyperlocomotion was enhanced by twofold in ABHD6 KO mice compared to WT mice and yet ABHD6 KO mice expressed AS to the same extent as WT mice. A twofold increase in amphetamine-stimulated hyperlocomotion was also measured in ABHD6 heterozygote mice and in WT mice treated with the ABHD6 inhibitor KT-182. It is known that amphetamine-stimulated hyperlocomotion is not affected by the CB1R antagonist, SR141617, and we discovered that the enhanced amphetamine-stimulated hyperlocomotion resulting from ABHD6 inhibition is blocked by SR141617. Conclusions: Our study suggests that ABHD6 controls amphetamine-stimulated hyperlocomotion by a mechanistic switch to a CB1R-dependent mechanism.
Authors: Agnieszka A Kaczor; Katarzyna M Targowska-Duda; Jayendra Z Patel; Tuomo Laitinen; Teija Parkkari; Yahaya Adams; Tapio J Nevalainen; Antti Poso Journal: J Mol Model Date: 2015-09-08 Impact factor: 1.810
Authors: Alipi V Bonm; Izaskun Elezgarai; Christina M Gremel; Katie Viray; Nigel S Bamford; Richard D Palmiter; Pedro Grandes; David M Lovinger; Nephi Stella Journal: Eur J Neurosci Date: 2021-07-13 Impact factor: 3.698