Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure

Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):1086-91. doi: 10.1073/pnas.1522672113. Epub 2016 Jan 11.


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.

Keywords: 2-arachidonoylglycerol; GABA; diacylglycerol lipase; nicotine; ventral tegmental area.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arachidonic Acids / analysis
  • Arachidonic Acids / antagonists & inhibitors
  • Arachidonic Acids / physiology
  • Endocannabinoids / analysis
  • Endocannabinoids / antagonists & inhibitors
  • Endocannabinoids / physiology
  • Glycerides / analysis
  • Glycerides / antagonists & inhibitors
  • Glycerides / physiology
  • Lipoprotein Lipase / antagonists & inhibitors*
  • Male
  • Nicotine / pharmacology*
  • Rats
  • Rats, Wistar
  • Self Administration
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / physiology
  • gamma-Aminobutyric Acid / metabolism


  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • gamma-Aminobutyric Acid
  • Nicotine
  • glyceryl 2-arachidonate
  • Lipoprotein Lipase