Kainate receptors are abundantly expressed in the nucleus accumbens but their functional characterization and their role in synaptic transmission has not yet been investigated. Using patch-clamp recordings in mouse nucleus accumbens slices, we show the presence of functional kainate receptors activated by low concentrations of kainate (100-300 nM) in medium size neurons. These somatodendritic receptors are comprised of the GluR6 subunit, since they are absent in GluR6-deficient mice. Kainate receptors do not directly participate in glutamatergic synaptic transmission evoked by electrical stimulation of cortical afferent fibers in nucleus accumbens neurons. However, application of low concentrations of kainate inhibits cortico-accumbens synaptic transmission, by increasing synaptic failure rate and increasing variation coefficient, thus indicating a presynaptic site of action. Presynaptic kainate receptors are observed both in GluR6 and in GluR5-deficient mice, but are absent in mice devoid of both subunits. Hence, at variance with somatodendritic kainate receptors, presynaptic kainate receptors on cortical afferents are composed of both GluR5 and GluR6 kainate receptor subunits. These results indicate that different subtypes of kainate receptors, representing distinct pharmacological targets, should play important roles in the synaptic integration properties of nucleus accumbens neurons.