Figure 8. Ampakine application to schizophrenic model.

Ampakines act by increasing maximum conductance of the AMPA channel (denoted by g_max), increasing the delay time constant (denoted by τ₂), or both. Moreover, various ampakines can differentially affect maximum amplitude and decay properties of the AMPA current [72]–[74]. To operationalize ampakine effects in model, we increased AMPA g_max by 0 to 60% (six gradations of 10%) and increased τ₂ by 0 to 100% (five gradations of 20%), for a total of 30 iterations; we drove the model at 20, 30, and 40 Hz in each case. Color scale applies to all panels, and is identical to that of Figure 4, to facilitate comparison. Here, % change refers to change from the unaffected case; therefore, 0 represents re-equilibration. From the figure, it is clear that there is no particular effect on 40 Hz activity—within a reasonable range of parameter assumptions, a virtual ampakine that effectively normalized 40 Hz resonance would create supraphysiologic levels of 30 and 20 Hz activity. This is consistent with clinical findings: On theoretical grounds, it was felt that this class of drugs may have an ameliorative effects on schizophrenia and, a number of ampakines have been developed for clinical use (CX516 [Ampalex], CX717, CX691/Org24448 [Faramptor], and LY451395) [75]. However, clinical trials [76] have not borne out their effectiveness in patient populations.