A single In Vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens

Lawrence Fourgeaud, Susana Mato, Delphine Bouchet, Agnès Hémar, Paul F. Worley, Olivier J. Manzoni

Research output: Contribution to journalArticlepeer-review

160 Scopus citations


In the nucleus accumbens (NAc), a key structure to the effects of all addictive drugs, presynaptic cannabinoid CB1 receptors (CB1Rs) and postsynaptic metabotropic glutamate 5 receptors (mGluR5s) are the principal effectors of endocannabinoid (eCB)-mediated retrograde long-term depression (LTD) (eCB-LTD) at the prefrontal cortex-NAc synapses. Both CB1R and mGluR5 are involved in cocaine-related behaviors; however, the impact of in vivo cocaine exposure on eCB-mediated retrograde synaptic plasticity remains unknown. Electrophysiological and biochemical approaches were used, and we report that a single in vivo cocaine administration abolishes eCB-LTD. This effect of cocaine was not present in D1 dopamine receptor (D1R) -/- mice and was prevented when cocaine was coadministered with the selective D1R antagonist 8-chloro-2,3,4,5-tetrahydro-3-5-1h-3-benzazepin-7-ol (0.5 mg/kg) or with the NMDA receptor (NMDAR) blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (1 mg/kg), suggesting the involvement of D1R and NMDAR. We found that the cocaine-induced blockade of retrograde signaling was correlated with enhanced expression levels of Homer scaffolding proteins containing the coiled-coil domain and accompanied by a strong reduction of mGluR5 surface expression. The results suggest that cocaine-induced loss of eCB retrograde signaling is caused by a reduction in the ability of mGluR5 to translate anterograde glutamate transmission into retrograde eCB signaling.

Original languageEnglish (US)
Pages (from-to)6939-6945
Number of pages7
JournalJournal of Neuroscience
Issue number31
StatePublished - Aug 4 2004


  • Accumbens
  • CB1
  • Cocaine
  • D
  • Drug abuse
  • Endocannabinoid
  • Long-term depression
  • NMDA
  • Synaptic plasticity
  • mGluR

ASJC Scopus subject areas

  • Neuroscience(all)


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