The effects of glycine and structurally related amino acids, serine, alanine and valine, on generation of long-term potentiation (LTP) of evoked potentials were investigated in the CA1, CA3 and dentate regions of rat hippocampal slices. In the Schaffer collateral-CA1 pyramidal cell synapses and in the perforant path-dentate granule cell synapses, glycine (5 x 10(-4) M) significantly enhanced the short-term potentiation (STP) induced by subthreshold tetanic stimulation, without affecting baseline responses. The effects of glycine resulted in generation of LTP in both synapses. On the other hand, glycine did not influence STP induced by subthreshold tetanus in the mossy fiber-CA3 pyramidal cell synapses. These results suggest that exogenous glycine can facilitate the generation of LTP in the CA1 region and in the dentate gyrus but not in the CA3 region. In the CA1 region and the dentate gyrus, D- and L-serine and D-alanine (10(-3) M) also showed the LTP-facilitating effects in a similar manner to glycine, but D- and L-valine had no effect on LTP generation. Furthermore, glycine and D-serine, but not L-valine, enhanced NMDA receptor-mediated synaptic responses in the absence of extracellular Mg2+. Together, these results make it probable that exogenously applied glycine and related amino acids facilitate the generation of LTP in the CA1 and dentate region by activating the glycine modulatory sites associated with NMDA receptors.