Pelligrini-Giampietro et al, TiPS (2003) 24 461-470
POSSIBLE EXPLANATION FOR THE NEUROPROTECTIVE EFFECTS OF METABOTROPIC GLUTAMATE 1 RECEPTOR ANTAGONISTS
(1) Excessive activation of postsynaptic AMPA and NMDA receptors by glutamate produces a sustained depolarizing influx of Na+ and Ca2+, which eventually leads to neurodegeneration
(2) Activation of postsynaptique GABAA receptors produces an influcx of Cl-, hyperpolarization and neuroprotection
(3) GABA can also interact with presynaptic GABAB receptors that negatively control the release of glutamate, thus leading to reduced excitation of postsynaptic neurons
(4) The release of GABA is negatively-controlled by mGlu1 receptors and cannabinoid CB1 receptors, via suppression of Ca2+ currents through N-type channels or activation of K+ channels
Antagonists of mGlu1 receptors can lead to increased release of GABA and therefore to neuroprotective hyperpolarization • Direct blockade of presynaptic mGLU1 receptor on GABAergic terminals • Indirect inhibition of CB1 receptors located on GABAergic terminals  promted by mGlu1 receptors located postsynapically
(1)
(2)
(3)
(4)
(4)
(4)
FARM 2146 - 2003-2004