GABA(B) RECEPTOR-MEDIATED PRESYNAPTIC INHIBITION IN GUINEA-PIG HIPPOCAMPUS IS CAUSED BY REDUCTION OF PRESYNAPTIC CA2+ INFLUX

1. The hypothesis that activation of GABA(B) receptors inhibits evoked synaptic transmission by reducing the presynaptic Ca2+ influx was tested using a recently developed technique for simultaneously recording the presynaptic Ca2+ transient ([Ca2+](t)) and the field excitatory postsynaptic potential (fEPSP) evoked by a single electrical stimulus at CA3 to CA1 synapses of guinea-pig hippocampus. 2. The GABA(B) receptor agonist baclofen reversibly blocked, in a dose-dependant manner, both the fEPSP and the presynaptic [Ca2+](t) with similar time courses. During application of baclofen, the fEPSP was proportional to about the fourth power of the presynaptic [Ca2+](t), and the presynaptic fibre volley and the resting Ca2+ level did not change. These results are similar to those ive previously observed following application of several voltage-dependent Ca2+ channel blockers, suggesting that baclofen inhibits the fEPSP by blocking the presynaptic Ca2+ influx. 3. The inhibition by baclofen of both the fEPSP and the presynaptic [Ca2+](t) was blocked by the GABA(B) receptor antagonist CGP 35348, consistent with the causal relationship between the GABA(B) receptor-mediated presynaptic inhibition of the [Ca2+](t) and the fEPSP. 4. The inhibition by baclofen of the [Ca2+](t) was partially occluded by application of the voltage-dependent Ca2+ channel blocker omega-conotoxin-GVIA (omega-CgTX-GVIA), but not omega-agatoxin-IVA (omega-AgaTX-IVA), suggesting that baclofen reduces the presynaptic [Ca2+](t) by blocking Ca2+ channels including the omega-CgTX-GVIA-sensitive type. 5. We conclude that baclofen inhibits evoked transmitter release by reducing presynaptic Ca2+ influx. These results, together with other findings showing that baclofen inhibits spontaneous transmitter release in cultured hippocampal slices by a mechanism downstream to Ca2+ influx, suggest that different mechanisms may underlie spontaneous and evoked transmitter release.