Core Body Temperature Regulation and Locomotor Activity

poster abstractMethamphetamine (Meth) enhances locomotor activity, and is known to cause life-threatening hyperthermia. There has been much debate about whether the locomotion plays a major role in hyperthermia caused by Meth or other stimulants. The existing model of the neural circuitry putatively involved in this phenomenon [1] accurately reproduces the temperature response to the different doses of Meth. We compared locomotor activity observed in the same experiments with activation patterns of neuronal populations as predicted by the model. We found that time-courses of locomotor activity closely resembles the activity of one particular node in the model putatively representing the medullary level. However, the data on locomotion did not match the model in the initial phase of the response within 1 hour after the injection. Therefore, we hypothesized that there were some changes in thermogenesis and heat exchange mechanisms that largely control temperature response during the first hour and make the influence of locomotion relatively small. The objective of the study was to measure the temperature dynamics in rats running on a treadmill at different speeds and to construct a mathematical model explaining the mechanism of their core body temperature response to such an intervention that takes into account potential changes in heat exchange, sensory input and feedback control mechanisms. In the experiments for every speed of 0, 6, 12, and 18 m/min we had 4 rats running for 15 min. For each speed we averaged the temperature over 4 rats to get the average temperature response curve. First, we found that the temperature response curves for different treadmill speeds were not different statistically. Second, every response curve starts with a short but profound (~0.25 deg C in the first 5 min) drop in the body temperature followed by virtually linear rise of the temperature which significantly (by ~1 deg C) overshoots the baseline temperature. To explain these findings we set up a model in a form of a system of two differential equations that described the change in the body temperature and the change in the body heat production under the hypothesis that there are contributions of varying heat exchange, sensory input and feedback mechanisms in thermogenesis. All parameters in the system were subject to fitting experimental time series of temperature response of rats to 4 consistent speeds of 0, 6, 12, and 18 m/min on treadmills. We found, that a sudden drop of the body temperature below the baseline in the first five minutes after rats were removed from their cages and placed on a treadmill was a result of the increased heat dissipation caused by changes in the body position and movement of rats. The following fast recovery of the body temperatures to the normal level was provided by the feedback mechanisms activated by the temperature drop and changed sensory input. Meth continues to stimulate thermogenesis even after the baseline temperature is achieved from feedback mechanisms. Estimated contribution of the locomotion was negligible as compared to the latter and hence played a relatively small role in the temperature change. We predict that varying locomotion might manifest itself in temperature dynamics after much longer (~1 hour) exposure to running. The suggested system, which considers major factors defining body temperature response, can help to uncover the mechanisms of hyperthermia elicited by Meth, but also can be used to understand the thermoregulatory mechanisms which underlie the responses to simultaneous changes in environmental and physical conditions

Effect of Low Dose of Amphetamine on Thermoregulation System and Performance of Rats Running on Treadmills

poster abstractAmphetamine has been used widely as a performance-enhancing drug among athletes. There are numerous reports showing that low dose of amphetamine increases one’s performance by suppressing sensations of fatigues. However, a little has been known about the mechanism by which such an effect of amphetamine is caused. The goal of this study was to investigate how a low dose of amphetamine changed the duration and the capacity of running in rats by studying thermoregulation system of rats running on treadmills with experimental results and a mathematical model. 12 rats were separated into two groups of 6 and rats in the experimental group were injected with 2mg/kg of amphetamine and ones in the control group were injected with saline. Then each rat in both groups ran on a treadmill at the room temperature (25°) while the speed and the incline of the treadmill were increased stepwise in every 3 minutes. The running time of individual rats were determined by their ability of keeping up with the intensity of running and the core body temperatures and the oxygen consumptions ()of rats were recorded during the experiments. Then a mathematical model was constructed to describe rates of temperature changes in the core and muscles by quantifying the heat dissipations and heat productions using . Modeling revealed that amphetamine increases the heat dissipation in the core body, which slowed down the core temperature increase. Therefore rats injected with amphetamine were kept their core temperatures below approximately 40 °C for longer time, at which both groups were unable to run anymore. Additionally, the fact that the core temperature at the end of run was not significantly different between two groups, while muscle temperature was significantly different, suggests that the indicator of running capacity was the core temperature, rather than the muscle temperature. Finally, the level of overheating in muscles for the amphetamine group was severe enough to cause damages in muscles

Circadian variability of body temperature responses to Methamphetamine (Meth)

poster abstractVital parameters of living organisms exhibit circadian rhythmicity. Despite rats are nocturnal animals, most of drugs of abuse studies in rodents are performed during the day. Virtually no data on circadian variability of responses to amphetamines is currently available. However, the amplitude of circadian variations of body temperature is comparable to the magnitude of temperature responses to Meth. Accordingly, one can expect that the responses may be qualitatively different during the day and at night. Experiments were performed on male Sprague-Dawley rats implanted with telemetric probes reporting body temperature. Rats received i.p. injections of Meth (1 or 5 mg/kg) or saline at 10-11am or at 10-11pm. Each rat received only one injection of Meth to avoid the effects of repeated administration. The responses were recorded for at least 5 h. The baseline body temperature at night was 0.8ºC higher than during the day. The body temperature increased after injections of saline during both day and night but returned to its baseline within 1 h. This response was developing faster, and more pronounced at night. The temperature responses to Meth were different during the day and at night. In both cases the lower dose of Meth (1 mg/kg) induced monophasic hyperthermia. However, the maximal deviation of the temperature from baseline was appr. twice smaller at night than during the day. Injection of the higher dose of Meth (5 mg/kg) at day time caused a delayed hyperthermic response, preceded by a slight increase of the body temperature immediately after injection. In contrast, at night the same dose produced immediate hypothermia, which was not observed during the day. Recently, we created a model which showed that the complex dose-dependence of day-time temperature responses to Meth results from the delicate balance between inhibitory and excitatory drives which have different sensitivity to the drug. To interpret the night time data, we extended this mathematical model by assuming that the excitatory and/or inhibitory components and general metabolism are affected by the circadian input. Our model revealed that during the night the baseline activity of the excitatory node is greater than during the day. Besides, after injection of either dose of Meth the equilibrium body temperature appears significantly lower than the temperature observed before injection. The suppression of the response to the lower dose of Meth is, therefore, explained by a combination of two factors. First, the excitatory drive, which is predominantly responsible for monophasic hyperthermia after low doses of Meth, gets partially saturated. Second, the reduced general metabolism, which underlies the lower equilibrium temperature, leads to gradual cooling thus limiting the hyperthermia. Same mechanisms mediate the observed hypothermia during the night after the higher dose of Meth, as the inhibitory drive starts dominating the excitatory one. The reduction of the equilibrium temperature after Meth injection during the active time period represents a major perturbation of the thermoregulatory system status, and may reflect a Meth-triggered disturbance of circadian rhythmicity

Amphetamine enhances endurance by increasing heat dissipation

Athletes use amphetamines to improve their performance through largely unknown mechanisms. Considering that body temperature is one of the major determinants of exhaustion during exercise, we investigated the influence of amphetamine on the thermoregulation. To explore this, we measured core body temperature and oxygen consumption of control and amphetamine‐trea ted rats running on a treadmill with an incrementally increasing load (both speed and incline). Experimental results showed that rats treated with amphetamine (2 mg/kg) were able to run significantly longer than control rats. Due to a progressively increasing workload, which was matched by oxygen consumption, the control group exhibited a steady increase in the body temperature. The administration of amphetamine slowed down the temperature rise (thus decreasing core body temperature) in the beginning of the run without affecting oxygen consumption. In contrast, a lower dose of amphetamine (1 mg/kg) had no effect on measured parameters. Using a mathematical model describing temperature dynamics in two compartments (the core and the muscles), we were able to infer what physiological parameters were affected by amphetamine. Modeling revealed that amphetamine administration increases heat dissipation in the core. Furthermore, the model predicted that the muscle temperature at the end of the run in the amphetamine‐treated group was significantly higher than in the control group. Therefore, we conclude that amphetamine may mask or delay fatigue by slowing down exercise‐induced core body temperature growth by increasing heat dissipation. However, this affects the integrity of thermoregulatory system and may result in potentially dangerous overheating of the muscles

Amphetamine enhances endurance by increasing heat dissipation

Athletes use amphetamines to improve their performance through largely unknown mechanisms. Considering that body temperature is one of the major determinants of exhaustion during exercise, we investigated the influence of amphetamine on the thermoregulation. To explore this, we measured core body temperature and oxygen consumption of control and amphetamine‐trea ted rats running on a treadmill with an incrementally increasing load (both speed and incline). Experimental results showed that rats treated with amphetamine (2 mg/kg) were able to run significantly longer than control rats. Due to a progressively increasing workload, which was matched by oxygen consumption, the control group exhibited a steady increase in the body temperature. The administration of amphetamine slowed down the temperature rise (thus decreasing core body temperature) in the beginning of the run without affecting oxygen consumption. In contrast, a lower dose of amphetamine (1 mg/kg) had no effect on measured parameters. Using a mathematical model describing temperature dynamics in two compartments (the core and the muscles), we were able to infer what physiological parameters were affected by amphetamine. Modeling revealed that amphetamine administration increases heat dissipation in the core. Furthermore, the model predicted that the muscle temperature at the end of the run in the amphetamine‐treated group was significantly higher than in the control group. Therefore, we conclude that amphetamine may mask or delay fatigue by slowing down exercise‐induced core body temperature growth by increasing heat dissipation. However, this affects the integrity of thermoregulatory system and may result in potentially dangerous overheating of the muscles

Novel Benzoxazoles Containing 4-Amino-Butanamide Moiety Inhibited LPS-Induced Inflammation by Modulating IL-6 or IL-1β mRNA Expression

LPS induces inflammatory cytokines, including IL-1β, IL-6, and TNF-α, and causes an inflammatory response. The development of small molecules that have suppressive effect on those inflammatory cytokines is a desirable strategy for the treatment of inflammatory diseases. We synthesized 12 novel compounds with 4-amino-N-(4-(benzo[d]oxazol-2-ylamino)phenyl)butanamide moiety and evaluated their biological activities. Among them, 4 compounds (compound 5d, 5c, 5f, 5m and synthetic intermediate 4d) showed potent inhibition activities on IL-1β and IL-6 mRNA expression in vitro. Further, in vivo activity was evaluated with two compounds (5f and 4d) and mRNA levels of IL-1β, IL-6, and TNF-α were significantly decreased without hepatotoxicity. From the in vivo and in vitro test results, we confirmed that our synthesized compounds are effective for suppression of representative inflammatory cytokines

Exercise activates compensatory thermoregulatory reaction in rats: a modeling study

The importance of exercise is increasingly emphasized for maintaining health. However, exercise itself can pose threats to health such as the development of exertional heat shock in warm environments. Therefore, it is important to understand how the thermoregulation system adjusts during exercise and how alterations of this can contribute to heat stroke. To explore this we measured the core body temperature of rats (Tc) running for 15 min on a treadmill at various speeds in two ambient temperatures (Ta = 25°C and 32°C). We assimilated the experimental data into a mathematical model that describes temperature changes in two compartments of the body, representing the muscles and the core. In our model the core body generates heat to maintain normal body temperature, and dissipates it into the environment. The muscles produce additional heat during exercise. According to the estimation of model parameters, at Ta = 25°C, the heat generation in the core was progressively reduced with the increase of the treadmill speed to compensate for a progressive increase in heat production by the muscles. This compensation was ineffective at Ta = 32°C, which resulted in an increased rate of heat accumulation with increasing speed, as opposed to the Ta = 25°C case. Interestingly, placing an animal on a treadmill increased heat production in the muscles even when the treadmill speed was zero. Quantitatively, this "ready-to-run" phenomenon accounted for over half of the heat generation in the muscles observed at maximal treadmill speed. We speculate that this anticipatory response utilizes stress-related circuitry

Orexinergic neurotransmission in temperature responses to methamphetamine and stress: mathematical modeling as a data assimilation approach.

Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t > 60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t < 60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult.We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods

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