Endogenous Cannabinoids: The activity of cortical pyramidal cells, the sole output cells of the cortex, is tightly controlled by distinct classes of GABAergic inhibitory interneurons. These interneurons maintain high firing rates in vivo and provide potent inhibition to pyramidal cells, thus regulation of this inhibitory tone is essential for proper cortical function. Recent data from our laboratory and others indicate that the cannabinoid system may play an important role in modulating GABAergic inhibition. The type 1 cannabinoid (CB1) receptor, found in presynaptic terminals of GABAergic neurons, is one of the most highly expressed G-protein coupled receptors in the forebrain, and mediates the well-known effects of exogenous cannabinoids on cognition, mood, and behavior. Endogenous cannabinoid-like compounds are released from pyramidal neurons with a high degree of spatial and temporal specificity and travel backwards across the synapse to regulate GABA release from presynaptic terminals. Little is known, however, about the physiological role of this endogenous system. Our current strategy combines electrophysiological, biochemical, pharmacological, and optical imaging techniques to: 1) determine the neuronal activity patterns that induce the release of endogenous cannabinoids, 2) identify the specific inhibitory inputs to pyramidal cells that are modulated by cannabinoids, and 3) investigate the consequences of cannabinoid signaling on synaptic integration in cortical circuits.