The volitional nature of nicotine exposure alters anandamide and oleoylethanolamide levels in the ventral tegmental area

Neuropsychopharmacology. 2013 Mar;38(4):574-84. doi: 10.1038/npp.2012.210. Epub 2012 Nov 21.


Cannabinoid-1 receptors (CB(1)) have an important role in nicotine reward and their function is disrupted by chronic nicotine exposure, suggesting nicotine-induced alterations in endocannabinoid (eCB) signaling. However, the effects of nicotine on brain eCB levels have not been rigorously evaluated. Volitional intake of nicotine produces physiological and behavioral effects distinct from forced drug administration, although the mechanisms underlying these effects are not known. This study compared the effects of volitional nicotine self-administration (SA) and forced nicotine exposure (yoked administration (YA)) on levels of eCBs and related neuroactive lipids in the ventral tegmental area (VTA) and other brain regions. Brain lipid levels were indexed both by in vivo microdialysis in the VTA and lipid extractions from brain tissues. Nicotine SA, but not YA, reduced baseline VTA dialysate oleoylethanolamide (OEA) levels relative to nicotine-naïve controls, and increased anandamide (AEA) release during nicotine intake. In contrast, all nicotine exposure paradigms increased VTA dialysate 2-arachidonoyl glycerol (2-AG) levels. Thus, nicotine differentially modulates brain lipid (2-AG, AEA, and OEA) signaling, and these modulations are influenced by the volitional nature of the drug exposure. Corresponding bulk tissue analysis failed to identify these lipid changes. Nicotine exposure had no effect on fatty acid amide hydrolase activity in the VTA, suggesting that changes in AEA and OEA signaling result from alterations in their nicotine-induced biosynthesis. Both CB(1) (by AEA and 2-AG) and non-CB(1) (by OEA) targets can alter the excitability and activity of the dopaminergic neurons in the VTA. Collectively, these findings implicate disrupted lipid signaling in the motivational effects of nicotine.

Publication types

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

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism*
  • Choice Behavior / drug effects
  • Choice Behavior / physiology*
  • Endocannabinoids / metabolism*
  • Male
  • Nicotine / administration & dosage*
  • Oleic Acids / metabolism*
  • Polyunsaturated Alkamides / metabolism*
  • Rats
  • Rats, Wistar
  • Self Administration
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*


  • Arachidonic Acids
  • Endocannabinoids
  • Oleic Acids
  • Polyunsaturated Alkamides
  • oleoylethanolamide
  • Nicotine
  • anandamide