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Activation of cannabinoid type-1 receptors (CB₁) is universally recognized as a powerful endogenous orexigenic signal, but the detailed underlying neuronal mechanisms are not fully understood. Using combined genetic and pharmacological approaches in mice, we found that ventral striatal CB₁ receptors exerted a hypophagic action through inhibition of GABAergic transmission. Conversely, brain CB₁ receptors modulating excitatory transmission mediated the well-known orexigenic effects of cannabinoids.