The activation of kainate receptors modulates GABAergic synaptic transmission, but the mechanisms are currently a matter of intense debate. In the basolateral amygdala (BLA), the glutamate receptor 5 (GluR5) subunit of kainate receptors is heavily expressed, and GluR5 antagonists block a novel form of synaptic plasticity; yet little is known about the role of GluR5-containing kainate receptors in the physiology of the amygdala. Here we show that GluR5 agonists bidirectionally modulate the strength of synaptic transmission from GABAergic interneurons to pyramidal cells in a concentration-dependent manner. Low concentrations of (RS)-S-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) (ATPA) (0.3 microm) or glutamate (5 microm) reduced the number of failures of GABAergic synaptic transmission and enhanced the frequency of miniature IPSCs (mIPSCs). High concentrations of ATPA (10 microm) or glutamate (200 microm) increased the number of synaptic failures and reduced the frequency of mIPSCs. The facilitation or suppression of GABAergic transmission by the GluR5 agonists did not require activation of voltage-gated calcium channels or presynaptic GABA(B) receptors. It was also found that extracellular, endogenous glutamate tonically reduces the rate of failures of GABAergic transmission. These results suggest that the terminals of GABAergic neurons in the BLA carry two subtypes of GluR5-containing kainate receptors, which have different agonist affinities and activate opposing mechanisms of action. The GluR5-mediated, bidirectional modulation of GABA release by glutamate in the BLA may play an important role in the regulation of synaptic plasticity and neuronal excitability in this structure, under normal and pathological conditions.