Neurochemical evidence that stimulation of CB1 cannabinoid receptors on GABAergic nerve terminals activates the dopaminergic reward system by increasing dopamine release in the rat nucleus accumbens

Neurochem Int. 2009 Jun;54(7):452-7. doi: 10.1016/j.neuint.2009.01.017. Epub 2009 Feb 6.


We examined the effect of cannabinoid receptor activation on basal and electrical field simulation-evoked (25 V, 2 Hz, 240 shocks) [(3)H]dopamine efflux in the isolated rat nucleus accumbens in a preparation, in which any effect on the dendrites or somata of ventral tegmental projection neurons was excluded. The cannabinoid agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212-2, 100 nM) significantly enhanced stimulation-evoked [(3)H]dopamine release in the presence of the selective dopamine transporter inhibitor 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR12909, 100 nM). GBR12909 (100 nM-1 microM), when added alone, increased the evoked [(3)H]dopamine efflux in a concentration-dependent manner. The stimulatory effect of WIN55,212-2 on the evoked tritium efflux was inhibited by the selective CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, 100 nM) and by the GABA(A) receptor antagonist bicuculline (10 microM). Repeated application of N-methyl-d aspartate (1 mM) under Mg(2+)-free conditions, which directly acts on dopaminergic terminals, reversibly increased the tritium efflux, but WIN55,212-2 did not affect N-methyl-d aspartate-evoked [(3)H]dopamine efflux, indicating that WIN55,212-2 has no direct action on dopaminergic nerve terminals. AM251 (100 nM) alone also did not have an effect on electrical stimulation-evoked [(3)H]dopamine efflux. Likewise, the selective CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630, 0.3 microM) and the anandamide transport inhibitor (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (VDM11, 10 microM) had no significant effect on electrically evoked [(3)H]dopamine release. This is the first neurochemical evidence that the activation of CB1 cannabinoid receptors leads to the augmentation of [(3)H]dopamine efflux via a local GABA(A) receptor-mediated disinhibitory mechanism in the rat nucleus accumbens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazines / pharmacology
  • Bicuculline / pharmacology
  • Dopamine / metabolism*
  • Dopamine / physiology*
  • Electric Stimulation
  • GABA Antagonists / pharmacology
  • GABA-A Receptor Antagonists
  • Male
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Nerve Endings / drug effects*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / agonists*
  • Reward*
  • gamma-Aminobutyric Acid / physiology*


  • Benzoxazines
  • GABA Antagonists
  • GABA-A Receptor Antagonists
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • AM 251
  • gamma-Aminobutyric Acid
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Dopamine
  • Bicuculline