PMC

PopPK model structure of modafinil acid, combined with the model of modafinil, comprises of four compartments: gastrointestinal tract (GI), central and peripheral compartment for modafinil, and central compartment for modafinil acid. X1, V1, X2, and V2 are amount (X) and volume of distribution (V) of modafinil in central (systemic circulation and liver) and peripheral (tissues) compartments, respectively. And X3 and V3 are amount and volume of distribution of modafinil acid in its central compartment. Rate constants for the compartments are Ka (absorption), K12, K21, K1m (modafinil is metabolized into modafinil acid) and Km (elimination from central compartment for modafinil acid). F₁ is the bioavailability of modafinil, while F₂ is the conversion fraction of modafinil to modafinil acid.

Effects of substitution of saline, vehicle for modafinil, modafinil (lower and higher ranges of the doses), or the standard DA uptake inhibitor methylphenidate (dissolved in the modafinil vehicle), in rats trained to self-administer cocaine. Ordinates, responses per second; abscissae, dose of each drug in milligrams per kilogram per injection or saline or modafinil vehicle sequential component of the session. Each point represents the mean, with vertical bars representing S.E.M. (n = 6). a cocaine and saline. b vehicle, methylphenidate, modafinil (0.1–3.2 mg/kg/inj) and modafinil (0.32–10 mg/kg/inj). EXT extinction.

A. Cartoon illustrating the approach used to measure intra-PFC connectivity via optical stimulation.
B. The evoked response of a PFC neuron to intra-PFC stimulation (blue bar) is much stronger with Modafinil injection
C. Modafinil significantly increased strength of evoked peak responses, demonstrating that modafinil can increase intra-PFC connectivity. (N= 2 mice, n=155 neurons, sign-rank test)
D. Example rasters and PSTHs from a PFC neuron showing that the effect of modafinil on stimulated intra-PFC connections (Blue bar) disappeared when MD was silenced (Yellow bar).
E. Modafinil effects on intra-PFC connectivity disappeared with MD suppression (N = 2 mice, n=155 neurons, sign-rank test)
F. Quantification of the positive coupling strengths in the PFC of control (grey) and KO (red) mice during the delay period with or without modafinil. Modafinil restored connectivity to control levels in the KO (p < 1.3x10⁻²³, MANOVA; N = 4 control, 4 KO mice, n = 863 control, 947 KO neurons recorded; rank-sum test).
G. Example rasters and PSTHs of a KO PFC neuron during delay of the cued noisy auditory discrimination task following injection of vehicle (top) or modafinil (bottom). Following modafinil administration a new task related response peak was observed (scale bar: z-score = 1).
H. Distribution of peak times for control (top, black) or KO (bottom, red) mice following modafinil injection as a percentage of total neurons. Peak numbers and temporal distribution were comparable between control and KO following modafinil administration (totals for each genotype shown as inset pie-charts, yellow – peak cells; p < 0.01, KO modafinil vs vehicle non-significant for KO vs control with modafinil binomial test, N = 4 control, 4 KO mice, n = 863 control, 947 KO neurons).
I. Poisson Naïve bayes decoding of predictive cue against unpredictive cue in control (grey) or KO (red) mice showing that modafinil (right) significantly increased cue encoding in the KO compared with vehicle (left). Shaded region indicates 95% confidence intervals.
J. Quantification of the comparisons of decoding with and without modafinil shown in I (p < 8.5x10⁻⁸⁹ MANOVA, N = 4 control, 4 KO mice, n = 863 control, 947 KO neurons recorded, *** p < 0.001, binomial test).
Boxplots: median (line), quartiles (box), 95% confidence interval (whiskers)
See also

Typical examples of EEG and EMG recordings and corresponding hypnograms in mice treated with vehicle or modafinil at 180 mg/kg. A–G, WT mice were treated with vehicle (A), modafinil only (B), SCH23390 + modafinil (C), or raclopride + modafinil (D), and D₂R KO mice were treated with vehicle (E), modafinil only (F), and SCH23390 + modafinil (G). The open arrows indicate pretreatment with D₁R or D₂R antagonists or its vehicle, and closed arrows represent the time of modafinil injection or its vehicle. W, Wakefulness; R, REM sleep; N, NREM sleep.