In the CNS, CB1 is localized to presynaptic terminals of both GABAergic (Katona et al., 1999) and glutamatergic (Rodriguez et al., 2001) neurons, and activation of CB1 results in decreased neurotransmitter release from these terminals (Gerdeman and Lovinger, 2001; Lévénés et al., 1998; Shen et al., 1996; Szabo et al., 1998). Unlike classical neurotransmitters like those derived from amino acids or peptides, ECs are not stored in vesicles. Their synthesis and release occurs on-demand during periods of intense synaptic activity and membrane depolarization via Ca2+-dependent processes. Depolarization-induced suppression of inhibition and excitation are two physiological protocols that depend on EC synthesis in the post-synaptic neuron to activate pre-synaptic CB1 receptors on GABAergic (Kreitzer and Regehr, 2001a; Wilson et al., 2001; Wilson and Nicoll, 2001; Yoshida et al., 2002) and glutamatergic (Kreitzer and Regehr, 2001b) terminals, respectively. These physiological protocols demonstrate how prolonged cell depolarization can lead to EC release; however, there are other mechanisms that can give rise to EC release and CB1 activation. These include activation of other GPCRs, such as the metabotropic glutamate receptor 5 (mGluR5; Maejima et
