title: Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure.
abstract: Chronic nicotine exposure (CNE) alters synaptic transmission in the ventral tegmental area (VTA) in a manner that enhances dopaminergic signaling and promotes nicotine use. The present experiments identify a correlation between enhanced production of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) and diminished release of the inhibitory neurotransmitter GABA in the VTA following CNE. To study the functional role of on-demand 2-AG signaling in GABAergic synapses, we used 1,2,3-triazole urea compounds to selectively inhibit 2-AG biosynthesis by diacylglycerol lipase (DAGL). The potency and selectivity of these inhibitors were established in rats in vitro (rat brain proteome), ex vivo (brain slices), and in vivo (intracerebroventricular administration) using activity-based protein profiling and targeted metabolomics analyses. Inhibition of DAGL (2-AG biosynthesis) rescues nicotine-induced VTA GABA signaling following CNE. Conversely, enhancement of 2-AG signaling in naïve rats by inhibiting 2-AG degradation recapitulates the loss of nicotine-induced GABA signaling evident following CNE. DAGL inhibition reduces nicotine self-administration without disrupting operant responding for a nondrug reinforcer or motor activity. Collectively, these findings provide a detailed characterization of selective inhibitors of rat brain DAGL and demonstrate that excessive 2-AG signaling contributes to a loss of inhibitory GABAergic constraint of VTA excitability following CNE.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Buczynski
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Herman
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Ku-Lung
authors.identifier: http://orcid.org/0000-0001-5620-3972
authors.initials: KL
authors.lastname: Hsu
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Luis A
authors.initials: LA
authors.lastname: Natividad
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Cristina
authors.initials: C
authors.lastname: Irimia
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Ilham Y
authors.initials: IY
authors.lastname: Polis
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Holly
authors.initials: H
authors.lastname: Pugh
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Niphakis
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037; lparsons@scripps.edu.
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D063388:Endocannabinoids / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D005989:Glycerides / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors*; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D005680:gamma-Aminobutyric Acid; D009538:Nicotine; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase
keywords: 2-arachidonoylglycerol; GABA; diacylglycerol lipase; nicotine; ventral tegmental area