Allosteric potentiation of quisqualate receptors by a nootropic drug aniracetam.

Abstract

SUMMARY1. Allosteric potentiation of the ionotropic quisqualate (iQA) receptor by a nootropic drug aniracetam (1 -p-anisoyl-2-pyrrolidinone) was investigated using Xenopus oocytes injected with rat brain mRNA and rat hippocampal slices.2. Aniracetam potentiates the iQA responses induced in Xenopus oocytes by rat brain mRNA in a reversible manner. This effect was observed above the concentrations of 0.1 mm. Kainate, N-methyl-D-aspartate and y-aminobutyric acid responses induced in the same oocytes were not affected.3. The specific potentiation of iQA responses was accompanied by an increase in the conductance change of iQA and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses, but the affinity of receptors for agonist and the ion-selectivity of the channels (reversal potentials) were not changed. 4. Aniracetam reversibly potentiated the iQA responses recorded intracellularly from the pyramidal cells in the CAI region of rat hippocampal slices. The excitatory postsynaptic potentials (EPSPs) in Schaffer collateral-commissural-CAl synapses were also potentiated by aniracetam.5. Population EPSPs recorded in the mossy fibre-CA3 synapses as well as Schaffer-commissural synapses were also potentiated by aniracetam. The amplitudes of the potentiation were not changed by the formation of long-term potentiation.

Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

“…Recent advances in understanding NMDA receptor physiology have highlighted the critical role of AMPA receptor-mediated events in the NMDA receptor currents and functional output such as long-term potentiation (47,48). AMPA receptors are known to undergo rapid attenuation of function (43,47), and drugs interfering with this process (also referred to as AMPAkines) have been shown to regulate synaptic strength at glutamatergic synapses (42)(43)(44)(45)(46)49).…”

“…To test this notion, positive modulators of AMPA receptordependent glutamatergic transmission, aniracetam (42,44,(50)(51)(52) and the AMPAkines 1-(quinoxalin-6-ylcarbonyl) piperidine, CX516 (34-36, 45, 46), and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine, CX546 (49,53) were tested for their effects on hyperactivity in DAT-KO mice (Fig. 2 A, B, D, and E).…”

Glutamate-activated currents in outside-out patches from spiny versus aspiny hilar neurons of rat hippocampal slices

“…These results imply that desensitization will not contribute significantly to the decay of the synaptic current. Yet other studies using agents that remove desensitization do, in fact, affect synaptic current decay times (Ito et al, 1990;Isaacson and Nicoll, 1991;Tang et al, 1991;Vyklicky et al, 1991;Patneau et al, 1992;Yamada, 1992;Yamada and Rothman, 1993). However, it has been pointed out that drugs that remove desensitization might do so either by decreasing the desensitization rate constant or by decreasing the channel closing rate constant (Vyklicky et al, 1991).…”

Aniracetam Reversed Learning and Memory Deficits Following Prenatal Ethanol Exposure by Modulating Functions of Synaptic AMPA Receptors

“…At the molecular level, aniracetam is an allosteric modulator of the AMPA type of glutamate receptors (Ito et al, 1990;Black, 2005), slowing the deactivation and desensitization of these receptors by stabilizing the glutamate bound conformation (Jin et al, 2005). Thus, the measurement of AMPA receptor-mediated synaptic currents in the hippocampal pyramidal cells of rats with cognitive deficits following both prenatal ethanol exposure and post-natal aniracetam treatment helped to establish the synaptic mechanism of memory improvement by aniracetam.…”