Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors

Ampakines are small benzamide compounds that allosterically produce the pos itive modulation of AMPA receptors and improve performance on a variety of behavioral tasks. To test if the native synaptic membrane is necessary for the effects of such positive modulators, the mechanism of action of the Amp akine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (CX509) w as investigated in isolated rat brain AMPA receptors reconstituted in lipid bilayers, The drug increased the open time of AMPA-induced single channel current fluctuations with an EC50 of 4 muM. The action of CX509 was highly selective since it had no effect on the amplitude or close time of channel events. The open time effect had a maximum enhancement of 70-fold and the m odulated currents were blocked by CNQX, It is concluded that the synaptic m embrane environment is not necessary for Ampakine effects. In fact, CX509 w as about 100 times more potent on the reconstituted AMPA receptors than on receptors in their native membrane. These findings indicate that centrally active Ampakines modulate specific kinetic properties of AMPA currents. The y also raise the possibility that AMPA receptors are regulated by factors p resent in situ, thus explaining the more efficient modulatory effects of CX 509 when acting on receptors removed from their synaptic location. Synapse 40:154-158, 2001. (C) 2001 Wiley-Liss, Inc.