Mean striatal dopamine responses observed in rats (A and B) and NHPs (C) versus time, and in relation to predicted brain ECF D-amphetamine concentrations (D and E), and reported total plasma or whole brain concentrations (F). A, B and C: Legend refers to dose in mg/kg (mpk) reported in original work (see Supplemental Table 1 for details). In figure A, two independent studies for the 5 mpk/IV case are shown (1 from Melega et al., 1995 and 2 from Bardo et al., 1999). Data in figure B are from Kuczenski and Segal (1989). D: Mean observed peak dopamine response in relation to the time-matched predicted D-amphetamine ECF concentrations in rats (solid line, open circles) and non-human primates (dashed line, closed squares) for the various doses noted in A – C. Also shown are the correlation coefficients from linear regression analysis. E: Figure D with X-axis on the log₁₀ scale. F: Mean observed peak dopamine response in relation to the time-matched observed D-amphetamine concentrations observed in rat plasma (closed circles from 0.1 mg/kg, and those reported by Melega et al., 1995 from 1.0 and 5.0 mg/kg) and whole brain (open squares as reported by Melega et al., 1995 from 1.0, 2.5 and 5.0 mg/kg). Correlation coefficients from linear regression analysis are also shown.

Mean d-amphetamine concentrations observed over time in rats (A) and NHPs (B) following a single intravenous bolus dose of d-amphetamine. (A) Concentrations in rats observed in plasma (unbound concentrations), brain ECF of the prefrontal cortex, and CSF following the indicated doses (mpk, milligrams per kilogram). For the 0.1-mg/kg dose, error bars represent S.E.M. for 1–11 rats (plasma, via a sparse sampling approach), four rats (ECF), and five rats (CSF). (B) Concentrations in NHPs observed following a 0.1-mg/kg dose in plasma (unbound concentrations, one to three animals per time point using a sparse sampling approach), brain ECF (one animal in four brain regions), and CSF (two monkeys). Error bars represent S.E.M. in plasma and ECF, and S.D. in CSF.

Observed dopamine response in relation to time-matched predicted D-amphetamine ECF concentration in rats. Figures A to F represent the following respective doses as reported in the original work (see Supplemental Table 1 for details): 0.1, 0.5 (Kuczenski and Segal 1989), 1.0 (Melega et al., 1995 red circles; Kuczenski and Segal 1989 blue squares), 2.0 (Kuzcenski and Segal 1989), 2.5 (Melega et al., 1995 red circles; Kuczenski and Segal 1989 blue squares) and 5.0 mg/kg (Melega et al., 1995 red circles; Kuczenski and Segal 1989 blue squares; Bardo et al., 1999 green triangles). Individual animal data are shown in Figure A (0.1 mg/kg); mean data are shown in Figures B – F. Arrows represent the direction of increasing time after administration.

Observed dopamine response in relation to d-amphetamine ECF concentration in NHPs. Average dopamine response is in relation to time-matched predicted d-amphetamine concentrations in ECF for all doses. Circles refer to a 0.1-mg/kg dose, diamonds refer to a 0.3-mg/kg dose, triangles refer to a 0.5-mg/kg dose, and squares refer to a 1-mg/kg dose. The 0.1-mg/kg data represent the average from a single animal (n = 3 doses); whereas, for all other dose groups, mean reported data were used. The smaller figure on the right are the results from the 0.1-mg/kg dose on an expanded (y-axis) and linear (x-axis) scale; error bars represent S.E.M. All doses were by the intravenous bolus route. Arrows represent the direction of increasing time after administration.

Structure of the final PK/PD model. A two-compartment model for systemic disposition (“Peripheral d-amphetamine” compartment) applies only to the rat. Pharmacokinetic parameter definitions: Cl_csf, clearance from ECF to CSF; Cl_in, uptake clearance from plasma to brain ECF; Cl_out, efflux clearance from brain ECF to plasma; Cl_p, clearance from the central compartment; Q, intercompartmental distribution clearance; Q_csf-plasma, distributional clearance between plasma and CSF; V_b, unbound volume of distribution in the brain; V_c, volume of central compartment; V_csf, volume of the CSF compartment; V_p, volume of the peripheral compartment. Pharmacodynamic parameter definitions: k_in, zero-order rate constant for dopamine release into the synapse; k_out, first-order rate constant for dopamine reuptake into the presynaptic nerve terminal; k_tol, first-order rate constant for production and dissipation of the moderator response. Buffering of the moderator response owing to dose-dependent increases in the duration and extent of the dopamine effect is indicated by the dashed outlined box, and corresponds to eq. 8a in the text. Circled numbers in the figure correspond to those used in Fig. 1.

Observed and model-predicted dopamine responses, and conditional weighted residuals for predicted dopamine responses in rats (A–D) and NHPs (E–H). Population predicted concentrations (A and E), and individual (0.1 mg/kg)/interoccasion predicted concentrations (B and F) are shown. Conditional weighted residuals are shown in relation to population-predicted values (C and G), and in relation to time (D and H).

Observed (symbols) and model predicted (lines) dopamine time courses in rats following D-amphetamine administration. Figures A – C doses to rats were 0.1 mg/kg (black circles), 1 mg/kg (red diamonds, reference 17), 2.5 mg/kg (green squares, Melega et al., 1995), 5 mg/kg (open blue triangles, solid line for study 1, Melega et al., 1995, and open blue triangles, dashed line for study 2, Bardo et al., 1999). Figures D – F doses to rats were 0.5 mg/kg (open black circles), 1 mg/kg (red diamonds), 2 mg/kg (green closed circles), 2.5 mg/kg (blue squares), 5 mg/kg (black triangles), all from Melega et al., 1995. Doses are as reported in the original work (see Supplemental Table 1 for details). Figures A and D represent no moderator component, Figures B and E represent a response-independent moderator component, and Figures C and F represent a response-adjusted moderator component in the model.