Endocannabinoids produced upon action potential firing evoke a Cl current via type-2 cannabinoid receptors in the medial prefrontal cortex

Femke S. den Boon, Pascal Chameau, Kas Houthuijs, Simone Bolijn, Nicolina Mastrangelo, Chris G. Kruse, Mauro Maccarrone, Wytse J. Wadman, Taco R. Werkman

Research output: Contribution to journalArticlepeer-review


The functional presence of type-2 cannabinoid receptors (CB2Rs) in layer II/III pyramidal neurons of the rat medial prefrontal cortex (mPFC) was recently demonstrated. In the present study, we show that the application of the endocannabinoids (eCBs) 2-arachidonoylglycerol (2-AG) and methanandamide [a stable analog of the eCB anandamide (AEA)] can activate CB2Rs of mPFC layer II/III pyramidal neurons, which subsequently induces a Cl current. In addition, we show that action potential (AP) firing evoked by 20-Hz current injections results in an eCB-mediated opening of Cl channels via CB2R activation. This AP-evoked synthesis of eCBs is dependent on the Ca2+ influx through N-type voltage-gated calcium channels. Our results indicate that 2-AG is the main eCB involved in this process. Finally, we demonstrate that under physiologically relevant intracellular Cl conditions, 20-Hz AP firing leads to a CB2R-dependent reduction in neuronal excitability. Altogether, our data indicate that eCBs released upon action potential firing can modulate, through CB2R activation, neuronal activity in the mPFC. We discuss how this may be a mechanism to prevent excessive neuronal firing.

Original languageEnglish
Pages (from-to)2257-2268
Number of pages12
JournalPflugers Archiv European Journal of Physiology
Issue number12
Publication statusPublished - Nov 18 2014


  • 2-AG
  • AEA
  • Ca-activated Cl current
  • In vitro brain slice preparation
  • Whole-cell recording

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)
  • Medicine(all)

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