Although GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in the brain, intense activation of GABA receptors can cause excitation under certain conditions. In the superficial layers of the guinea-pig superior colliculus (SC) slice the excitatory action of GABA (< or = 3 mM) is dominant and sufficient to induce a robust and novel form of long-term potentiation, termed LTPG, of evoked field excitatory postsynaptic potentials (fEPSPs). This action of GABA could neither be mimicked by GABA-A nor -B agonists which were found to suppress synaptic transmission. Additionally, LTPG was not inhibited by the GABA-A receptor antagonist bicuculline while the GABA-C receptor antagonist imidazol-4-acetic acid prevented LTPG. Glutamatergic synaptic transmission was found to be required, as LTPG was partially use-dependent and did not emerge when glutamate receptors of the non-NMDA type were blocked during GABA application. Moreover, LTPG declined to baseline values in the presence of the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (APV). In addition, the L-type calcium channel blocker nifedipine inhibited the induction of LTPG. It is suggested that activation of excitatory GABA non-A, non-B receptors can lead to LTP in the SC, which may be of major importance for plastic events since the content of GABA and GABA receptors are particularly high in this brain area.