title: Contribution of limbic norepinephrine to cannabinoid-induced aversion.
abstract: BACKGROUND
  The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects.
  
  
  OBJECTIVE
  In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats.
  
  
  METHODS
  An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze.
  
  
  RESULTS
  Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety.
  
  
  CONCLUSIONS
  These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.
authors.affiliation: Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA. arfranky@gmail.com
authors.forename: Ana Franky
authors.initials: AF
authors.lastname: Carvalho
authors.forename: Arith-Ruth S
authors.initials: AR
authors.lastname: Reyes
authors.forename: Robert C
authors.initials: RC
authors.lastname: Sterling
authors.forename: Ellen
authors.initials: E
authors.lastname: Unterwald
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Van Bockstaele
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced; D001362:Avoidance Learning / Q000187:drug effects; D048588:Benzoxazines / Q000633:toxicity; D002186:Cannabinoids / Q000633:toxicity*; D000922:Immunotoxins / Q000276:immunology; D008032:Limbic System / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009025:Morpholines / Q000633:toxicity; D009281:Naphthalenes / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D000922:Immunotoxins; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009638:Norepinephrine