Fig 1.
Schematic of the model neuronal circuitry involved in responses to methamphetamine.
Stress input and the orexin receptors (shown by gray rectangles labeled “OX”) are added to extend the circuitry used in [30]. Effect of Stress and/or Meth can be affected by the orexin receptor antagonist SB-334867. Each circle represents a neural population. Abbreviations: Exc—excitatory node, Inhib—inhibitory node, HD—high-dose activated node, Med—medullary node, SPN—sympathetic preganglionic node, TEMP—temperature. See text for a detailed description.
Table 1.
Values of parameters of the model, which were considered not affected by SB (adapted from [30]).
Fig 2.
Effect of SB-334867 on stress-induced body temperature increase associated with i.p. injections (n = 24–26 per group).
Black circles, solid line—pooled vehicle data; open circles, solid line—SB 10 mg/kg; open circles, dashed line—SB 30 mg/kg. Injection was performed at t = –30 min.
Fig 3.
Changes in the body temperature evoked by methamphetamine after two doses of SB-334867.
Meth is injected at t = 0 min (dashed lines). SB is injected 30 min prior to Meth. A-D: SB 10 mg/kg; E-H: SB 30 mg/kg. Each plot contains responses to the dose of Meth shown on the left: 0 (Saline), 1, 5 or 10 mg/kg after injection of either vehicle (black circles) or SB (open circles).
Fig 4.
Parameter estimates generated by Monte-Carlo simulations.
A-B: Statistical ensembles of parameters (amplitude of stress, and Meth-sensitivities of three Meth-dependent populations) projected onto (wS, wHD)-plane (A) and (wExc, wInh)-plane (B) for each of the three doses of SB (vehicle, 10 and 30 mg/kg). C-F: Individual parameters for each dose of SB. * denotes statistically significant difference from vehicle (SB 0, p<0.05); #—between SB 10 and SB 30 (p<0.05).
Fig 5.
Activation curves of nodes of the model compared with pharmacokinetics of Meth.
A-D: Activity of the network nodes as functions of Meth concentration in the blood after three doses of SB-334867: 0 (Veh), 10 and 30 mg/kg using best fit parameters. E: Time courses of the Meth concentration after different doses of Meth (1, 5 and 10 mg/kg) as generated by the model.
Fig 6.
Comparison of experimental data and model responses.
Experimental data shown by open circles (average temperature); error bars represent standard deviations over a group of rats. Model responses using best fit parameters are shown as a thick lines. SB vehicles for both doses were pooled into a single group. Columns of graphs correspond to different doses of the antagonist (A-D: Vehicle, E-H: 10 mg/kg and I-K: 30 mg/kg as marked at the top), rows of graphs correspond to different doses of Meth (Saline, 1, 5 and 10 mg/kg, as marked at the left).
Fig 7.
Interpretation of HD sensitization as a change of inhibitory tone to the HD.
A: The mechanism of HD sensitization by the orexin receptor antagonist. SB suppresses activation of the inhibitory population InhHD by orexinergic input which disinhibits HD and thus lowers its activation threshold. B: Effect of SB on the basal inhibitory tone to HD population γHD when it is used as an SB-affected parameter instead of wHD. *—the estimate is statistically significantly different from the one for Vehicle (SB-0, p<0.05); #—the estimates are statistically significantly different between SB 10 and SB 30 (p<0.05). See Results for more details.
Fig 8.
Reduced model and effect of inhibitory failure on the response.
A. The extended model schematic in which the inhibitory tone to HD originates from Inhib population (see explanations in the Results). B: Effect of inhibitory failure in the modified model on the response to 3 mg/kg of Meth (see details in the Results).