Brain cannabinoid CB₂ receptors modulate cocaine's actions in mice

Nat Neurosci. 2011 Jul 24;14(9):1160-6. doi: 10.1038/nn.2874.


The presence and function of cannabinoid CB(2) receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB(2) receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB(1) receptor knockout (CB(1)(-/-), also known as Cnr1(-/-)) mice, but not in CB(2)(-/-) (Cnr2(-/-)) mice. This inhibition was mimicked by GW405833, another CB(2) receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB(2) receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB(1)(-/-) mice, but not in CB(2)(-/-) mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB(2) receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.

Publication types

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

MeSH terms

  • Administration, Intranasal
  • Analysis of Variance
  • Animals
  • Brain / drug effects*
  • Brain / metabolism*
  • Cannabinoids / administration & dosage
  • Cocaine / administration & dosage*
  • Conditioning, Operant / drug effects
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Indoles / administration & dosage
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microdialysis
  • Motor Activity / drug effects
  • Receptor, Cannabinoid, CB1 / deficiency
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / deficiency
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Rotarod Performance Test / methods
  • Self Administration


  • Cannabinoids
  • Dopamine Uptake Inhibitors
  • Indoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Cocaine
  • 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
  • iodopravadoline