Effect of SB-334867 on stress-induced body temperature increase associated with i.p. injections (n = 24–26 per group).

<p>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 <i>t</i> = –30 min.</p

Parameter estimates generated by Monte-Carlo simulations.

<p>A-B: Statistical ensembles of parameters (amplitude of stress, and Meth-sensitivities of three Meth-dependent populations) projected onto (<i>w</i>_<i>S</i>, <i>w</i>_<i>HD</i>)-plane (A) and (<i>w</i>_<i>Exc</i>, <i>w</i>_<i>Inh</i>)-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).</p

Schematic of the model neuronal circuitry involved in responses to methamphetamine.

<p>Stress input and the orexin receptors (shown by gray rectangles labeled “OX”) are added to extend the circuitry used in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126719#pone.0126719.ref030" target="_blank">30</a>]. Effect of Stress and/or Meth can be affected by the orexin receptor antagonist SB-334867. Each circle represents a neural population. Abbreviations: <i>Exc</i>—excitatory node, <i>Inhib</i>—inhibitory node, <i>HD</i>—high-dose activated node, <i>Med</i>—medullary node, <i>SPN</i>—sympathetic preganglionic node, <i>TEMP</i>—temperature. See text for a detailed description.</p

Interpretation of HD sensitization as a change of inhibitory tone to the HD.

<p>A: The mechanism of HD sensitization by the orexin receptor antagonist. SB suppresses activation of the inhibitory population Inh_HD by orexinergic input which disinhibits HD and thus lowers its activation threshold. B: Effect of SB on the basal inhibitory tone to HD population <i>γ</i>_<i>HD</i> when it is used as an SB-affected parameter instead of <i>w</i>_<i>HD</i>. *—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 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126719#sec015" target="_blank">Results</a> for more details.</p

Comparison of experimental data and model responses.

<p>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).</p

Changes in the body temperature evoked by methamphetamine after two doses of SB-334867.

<p>Meth is injected at <i>t</i> = 0 min (dashed lines). SB is injected 30 min prior to Meth. <b>A-D</b>: SB 10 mg/kg; <b>E-H</b>: 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).</p

Values of parameters of the model, which were considered not affected by SB (adapted from [30]).

<p>Values of parameters of the model, which were considered not affected by SB (adapted from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126719#pone.0126719.ref030" target="_blank">30</a>]).</p

Activation curves of nodes of the model compared with pharmacokinetics of Meth.

<p>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.</p