Cannabinoid receptor activation shifts temporally engendered patterns of dopamine release

Neuropsychopharmacology. 2014 May;39(6):1441-52. doi: 10.1038/npp.2013.340. Epub 2013 Dec 18.


The ability to discern temporally pertinent environmental events is essential for the generation of adaptive behavior in conventional tasks, and our overall survival. Cannabinoids are thought to disrupt temporally controlled behaviors by interfering with dedicated brain timing networks. Cannabinoids also increase dopamine release within the mesolimbic system, a neural pathway generally implicated in timing behavior. Timing can be assessed using fixed-interval (FI) schedules, which reinforce behavior on the basis of time. To date, it remains unknown how cannabinoids modulate dopamine release when responding under FI conditions, and for that matter, how subsecond dopamine release is related to time in these tasks. In the present study, we hypothesized that cannabinoids would accelerate timing behavior in an FI task while concurrently augmenting a temporally relevant pattern of dopamine release. To assess this possibility, we measured subsecond dopamine concentrations in the nucleus accumbens while mice responded for food under the influence of the cannabinoid agonist WIN 55,212-2 in an FI task. Our data reveal that accumbal dopamine concentrations decrease proportionally to interval duration--suggesting that dopamine encodes time in FI tasks. We further demonstrate that WIN 55,212-2 dose-dependently increases dopamine release and accelerates a temporal behavioral response pattern in a CB1 receptor-dependent manner--suggesting that cannabinoid receptor activation modifies timing behavior, in part, by augmenting time-engendered patterns of dopamine release. Additional investigation uncovered a specific role for endogenous cannabinoid tone in timing behavior, as elevations in 2-arachidonoylglycerol, but not anandamide, significantly accelerated the temporal response pattern in a manner akin to WIN 55,212-2.

Publication types

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

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism
  • Benzoxazines / pharmacology*
  • Biological Clocks / drug effects*
  • Biological Clocks / physiology
  • Cannabinoid Receptor Agonists / pharmacology*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Endocannabinoids / metabolism
  • Glycerides / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Neuropsychological Tests
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism*
  • Polyunsaturated Alkamides / metabolism
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Reinforcement Schedule
  • Task Performance and Analysis
  • Time Factors


  • Arachidonic Acids
  • Benzoxazines
  • Cannabinoid Receptor Agonists
  • Endocannabinoids
  • Glycerides
  • Morpholines
  • Naphthalenes
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • glyceryl 2-arachidonate
  • anandamide
  • Dopamine