SUMMARY1. WAe have examined the effect of picrotoxin on GABA-induced currents in dissociated rat hippocampal neurons. In addition, we used the putative picrotoxin receptor antagonist, ox-isopropyl-Lx-methyl-y-butyrolactone (cIMGBL), and the picrotoxin agonist, /?-ethyl-/I-methyl-y-butyrolactone (,/EMGBL) to explore the mechanisms of picrotoxin's interaction with the GABA-Cl-receptor-ionophore complex.2. The picrotoxin block of GABA current was use dependent, suggesting that the site of picrotoxin block is exposed by the conformational change initiated by GABA binding to the receptor.3. The alkyl-substituted butyrolactone antagonist, aIMGBL, selectively blocked the use-dependent mechanism of picrotoxin effect. After the apparent complete inhibition of the use-dependent effect, there was a residual picrotoxin effect that was independent of the time or concentration of GABA application. This indicates that the picrotoxin block of the GABA current is mediated by two different mechanisms. xIMGBL influences just one of these mechanisms.4. The picrotoxin receptor agonist, 8JEMGBL, exclusively blocked the GABA current in a use-dependent manner. Consistent with a use-dependent mechanism, the rate of onset of block increased with GABA concentration. Surprisingly, the fraction of GABA current block decreased with increasing GABA concentration.5. These results suggest that the relationship of picrotoxin and y-butyrolactones with the GABA-Cl-receptor-ionophore is quite complex. They are consistent with at least two possible models of agonist-antagonist interactions. Both cases require different antagonist affinities for the various kinetic states of the GABA-Clreceptor-ionophore. However, there is no need to require that either picrotoxin or

We examined the effects of adenosine and baclofen on inhibitory (IPSC) and excitatory (EPSC) synaptic currents in dissociated rat hippocampal neurons. Adenosine dramatically reduced monosynaptic EPSCs but failed to diminish IPSCs. This selective effect on EPSCs is likely due to inhibition of excitatory transmitter release because adenosine did not directly alter any properties of postsynaptic neurons. Baclofen depressed both EPSCs and IPSCs to approximately the same extent. These experiments indicate that the presynaptic effects of adenosine and baclofen are clearly separable and that transmitter sensitivities of inhibitory and excitatory neurons can differ. These differences could be exploited in the design of antiepileptic drugs that act at adenosine receptors to limit excitatory neurotransmission without blocking tonic inhibition.

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