Depolarization-induced suppression of excitation and inhibition (DSE/DSI) are forms of short-term neuronal plasticity involving post-synaptic release of an endocannabinoid (eCB) and the activation of presynaptic cannabinoid CB1 receptors. We have recently reported that CB1-dependent DSE can be elicited in autaptic cultures of excitatory hippocampal neurons of the mouse (Straiker & Mackie, 2005). We now report that the same preparation exhibits a parallel G_q-coupled receptor-dependent production of endocannabinoids causing retrograde inhibition, also via CB1 receptors, that we will refer to as metabotropic suppression of excitation (MSE). We tested a spectrum of G_q-coupled receptor agonists and found that both muscarinic and metabotropic glutamate receptors (group I) mediate retrograde inhibition via CB1 receptors in autaptic hippocampal neurons. Thus these neurons possess not only the pre- and postsynaptic machinery necessary for DSE but also that for MSE. This permitted a closer examination of MSE and its interaction with other aspects of the endocannabinoid retrograde signalling machinery: MSE mimics and occludes DSE and is itself occluded by the endocannabinoid 2-AG, consistent with 2-AG as a likely mediator of MSE. In contrast to DSE, MSE undergoes heterologous desensitization over the course of minutes. In keeping with what has been reported for MSI and DSI in the hippocampus, subthreshold MSE and DSE act synergistically. We additionally found that 9-tetrahydrocannabinol (9-THC) which has been shown to attenuate DSE (Straiker & Mackie, 2005) also antagonizes MSE. Finally, we have distinguished a neuronal subpopulation that exhibits DSE and a differential complement of MSE-mediating G_q-coupled receptors, making possible contrasting studies of MSE. Autaptic endocannabinoid signaling is rich, robust, and complex in a deceptively simple package, including a previously unreported post-synaptic mechanism of adaptation in addition to known presynaptic CB1 desensitization. These adaptive sites offer novel targets for modulation of endogenous cannabinoid signaling.