Medium spiny neurons in the dorsal striatum receive glutamatergic excitatory synaptic inputs from the cerebral cortex. These synapses undergo long-term depression that requires release of endocannabinoids from medium spiny neurons and activation of cannabinoid CB I receptors. However, it remains unclear how cortico-striatal synapses exhibit endocannabinoid-mediated short-term suppression, which has been found in various brain regions including the hippocampus and cerebellum. Endocannabinoids are released from postsynaptic neurons by strong depolarization and resultant Ca2+ elevation or activation of postsynaptic G(q/11)-coupled receptors such as group I metabotropic glutamate receptors (mGluRs) and M-1/M-3 muscarinic acetylcholine receptors. Moreover, endocannabioids are effectively released when weak depolarization is combined with G(q/11)-coupled receptor activation. We found that muscarinic activation induced transient suppression of excitatory synaptic transmission to medium spiny neurons, which was independent of retrograde endocannabinoid signaling but was mediated directly by presynaptic muscarinic receptors. Neither postsynaptic depolarization alone nor depolarization and muscarinic activation caused suppression of cortico-striatal synapses. In contrast, activation of group I mGluRs readily suppressed cortico-striatal excitatory synaptic transmission. Furthermore, postsynaptic depolarization induced clear suppression when combined with group I mGluR activation. These results indicate that group I mGluRs but not muscarinic receptors contribute to endocannabinoid-mediated short-term suppression of cortico-striatal excitatory synaptic transmission. (c) 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.