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CB1 cannabinoid receptors and on-demand defense against excitotoxicity

Giovanni Marsicano1, Sharon Goodenough, Krisztina Monory

  • 1Molecular Genetics of Behaviour, Max-Planck-Institute of Psychiatry, Kraepelinstrabetae 2-10, 80804 Munich, Germany.

Science (New York, N.Y.)
|October 4, 2003
PubMed

Insights

The endogenous cannabinoid system protects central nervous system neurons from damage caused by excessive activity. This system, involving cannabinoid receptor type 1, provides on-demand protection against excitotoxicity.

Area of Science:

  • Neuroscience
  • Neuropharmacology
  • Cellular Signaling

Background:

  • Abnormal neuronal firing can lead to neuronal damage.
  • The existence of protective signaling systems against such activity has been hypothesized.

Purpose of the Study:

  • To investigate the role of the endogenous cannabinoid system in protecting forebrain neurons from excitotoxicity.
  • To determine if cannabinoid receptor type 1 (CB1) signaling is essential for neuroprotection.

Main Methods:

  • Generated conditional mutant mice lacking CB1 in principal forebrain neurons.
  • Administered kainic acid (KA) to induce seizures and excitotoxicity in vivo and in vitro.
  • Measured neuronal excitation thresholds and hippocampal anandamide levels.

Main Results:

  • Mutant mice exhibited excessive seizures and a reduced excitation threshold following KA administration.
  • KA rapidly increased hippocampal anandamide levels in wild-type mice.
  • KA-induced protective mechanisms were absent in mutant mice, indicating a failure in CB1-mediated signaling.

Conclusions:

  • The endogenous cannabinoid system, via CB1 receptors, provides crucial on-demand neuroprotection against acute excitotoxicity.
  • Targeting the cannabinoid system may offer therapeutic strategies for conditions involving neuronal hyperexcitability and damage.

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