Effects of the nootropic drug nefiracetam on the GABA(A) receptor-channel complex in dorsal root ganglion neurons

The effects of nefiracetam on GABA-induced chloride currents were studied with rat dorsal root ganglion neurons in primary culture using the whole-cell patch-clamp technique. The dose-response curve for GABA-induced currents was shifted by 16 μM to lower concentrations by 10 μM nefiracetam while the maximal response was reduced by 22.84 ± 0.68%. Thus at a low concentration (10 μM) of GABA, the chloride currents were potentiated by nefiracetam in a concentration-dependent manner. With 10 μM nefiracetam, the potentiation occurred slowly and the recovery after washout was also slow. The desensitization of the GABA(A) receptor at a high concentration (100 μM) of GABA was accelerated by nefiracetam. The recovery process of chloride currents from desensitization was not affected by nefiracetam. KT 5720 (0.56 μM), aspecific protein kinase A (PKA) inhibitor, blocked the transient potentiation of GABA-activated currents by nefiracetam, but did not affect the acceleration of desensitization. Nefiracetam suppression of GABA-induced currents was also abolished by KT 5720 or the pertussis toxin. Thus, nefiracetam may inhibit G(i)/G(o) proteins leading to a cascade of events that increase the intracellular cAMP level, activate the PKA system, and suppress GABA-induced currents. Nefiracetam-induced transient potentiation and acceleration of desensitization of GABA-induced currents may involve other pathways. The nefiracetam modulation of the GABA(A) receptor function will result in a nootropic effect on the central nervous system through modification of synaptic transmission.