EFFECTS OF A MEMORY-ENHANCING DRUG ON LPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTOR CURRENTS AND SYNAPTIC TRANSMISSION IN HIPPOCAMPUS

The benzoylpiperidine drug BDP-12 (1-(quinoxalin-6-ylcarbon-yl)piperid ine) enhances the encoding of transient and stable forms of memory by rats. Results reported here show that the drug increases fast, excitat ory (glutamatergic) synaptic responses in hippocampal slices by about 50% with an EC(50) of 170 mu M. Analyses with polysynaptic responses i ndicated that the drug has a facilitatory action at concentrations as low as 12.5 mu M. BDP-12 at 1 mM did not change the resting membrane p otential, input resistance or spiking threshold and it did not alter m onosynaptic potentials mediated by gamma-aminobutyric acid (GABA) rece ptors; it did, however, enhance disynaptic inhibitory responses. In me mbrane patches excised from hippocampal neurons, BDP-12 at moderate co ncentrations (50 mu M) increased the steady-state currents mediated by lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) recept ors and slowed the rate at which the receptors desensitize, with a muc h larger effect on the former; the drug delayed the closing of the AMP A receptor channel after 1-msec agonist pulses. BDP-12 had no detectab le effect on [H-3]AMPA binding affinity. A related and more potent ana log produced a different pattern of results in that it had about equal effects on steady-state currents and desensitization rates and signif icantly increased binding to AMPA receptors, These results indicate th at the benzoylpiperidine family of modulators has functionally distinc t subclasses. The findings also establish that BDP-12, 1) enhances syn aptic responses in the same concentration range at which it alters AMP A receptor kinetics, 2) has a lower apparent threshold for effects on complex network operations than on monosynaptic transmission, 3) does not directly influence inhibitory responses and 4) is likely to modula te AMPA receptors on interneurons as well as on pyramidal neurons.