Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction

Neuropharmacology. 2005 Jun;48(8):1105-16. doi: 10.1016/j.neuropharm.2005.03.016.


Substantial evidence suggests that all commonly abused drugs act upon the brain reward circuitry to ultimately increase extracellular concentrations of the neurotransmitter dopamine in the nucleus accumbens and other forebrain areas. Many drugs of abuse appear to increase dopamine levels by dramatically increase the firing and bursting rates of dopamine neurons located in the ventral mesencephalon. Recent clinical evidence in humans and behavioral evidence in animals indicate that cannabinoid receptor antagonists such as SR141716A (Rimonabant) can reduce the self-administration of, and craving for, several commonly addictive drugs. However, the mechanism of this potentially beneficial effect has not yet been identified. We propose, on the basis of recent studies in our laboratory and others, that these antagonists may act by blocking the effects of endogenously released cannabinoid molecules (endocannabinoids) that are released in an activity- and calcium-dependent manner from mesencephalic dopamine neurons. It is hypothesized that, through the antagonism of cannabinoid CB1 receptors located on inhibitory and excitatory axon terminals targeting the midbrain dopamine neurons, the effects of the endocannabinoids are occluded. The data from these studies therefore suggest that the endocannabinoid system and the CB1 receptors located in the ventral mesencephalon may play an important role in regulating drug reward processes, and that this substrate is recruited whenever dopamine neuron activity is increased.

Publication types

  • Review

MeSH terms

  • Animals
  • Cannabinoid Receptor Antagonists*
  • Cannabinoid Receptor Modulators / metabolism*
  • Cannabinoid Receptor Modulators / physiology*
  • Dopamine / metabolism*
  • Dronabinol / pharmacology
  • Endocannabinoids*
  • Humans
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism*
  • Neurons / metabolism*
  • Piperidines / therapeutic use*
  • Pyrazoles / therapeutic use*
  • Reward
  • Rimonabant
  • Signal Transduction
  • Substance-Related Disorders / drug therapy*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism


  • Cannabinoid Receptor Antagonists
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Piperidines
  • Pyrazoles
  • Dronabinol
  • Rimonabant
  • Dopamine