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

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

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

Orexinergic Neurotransmission in Temperature Responses to Amphetamines

poster abstractDerivatives of amphetamines are widely abused all over the world. After long-term use cognitive, neurophysiological, and neuroanatomical deficits have been reported. Neurophysiological deficits are enhanced by hyperthermia, which itself is major mortality factor in drug abusers. Temperature responses to injections of methamphetamine are multiphasic and include both hypothermic and hyperthermic phases, which are highly dependent on ambient temperature and previous exposure to the drug. Also, amphetamine derivatives differentially affect various neuromediator systems, such as dopaminergic, noradrenergic and serotonergic. Temperature responses to methamphetamine (Meth) at room temperature have non-trivial dose-dependence, which is far from being understood. Intermediate doses of Meth cause less hyperthermia than both low and high doses of the drug. Also, maxima of all responses have different latency responses to low and high doses are virtually immediate, while a response to an intermediate dose appears to be delayed. In our previous modeling study we demonstrated that such dose-dependence could be explained by interaction of inhibitory and excitatory drives induced by Meth [1]. Recently, we have published data on the involvement of orexinergic neurotransmission in Meth-induced temperature responses [2] where the low dose (10 mg/kg, i.p.) of SB-334867 (SB), an antagonist of the first type of orexin receptors (ORX1), was injected 30 min prior to various doses of Meth. While this dose of antagonist clearly suppressed the response to low (1 mg/kg) and intermediate (5 mg/kg) doses of Meth, the effect was statistically significant only at the late phase (t > 60 min) of the response to intermediate dose. At the early phase (t < 60 min) any drug-related changes were marred by stress-induced temperature fluctuations resulting from two intraperitoneal injections. In a separate set of experiments a high dose of the same antagonist (30 mg/kg, i.p.) suppressed the effect of low doses of Meth even more, but in contrast, it significantly amplified the responses to the higher doses (5 and 10 mg/kg) of Meth. Understanding the mechanism that differentially affect excitatory and inhibitory components of temperature responses can have profound importance for explaining cases of life-threatening hyperthermia after Meth administration. Therefore, we performed a mathematical modeling study to provide mechanistic interpretation of SB action. Our previous model [1] was created to describe Meth-sensitive compartments and dynamics of the neural populations defining temperature responses for various doses of Meth. We hypothesized that a specific distribution of orexin receptors over the structures involved in the neural control of temperature is responsible for the complex dependence of the Meth-induced responses on the dose of orexin antagonist. To test this hypothesis we extended the model by incorporating ORX receptors that mediated Meth- and stress-dependent inputs. We showed that the low dose of antagonist almost fully suppresses the responses to both stress and intermediate doses of Meth by disruption of the corresponding inputs to the control structures. This allows hypothesizing that the excitatory component in temperature response to both stress and low dose of Meth is mediated by ORX1 receptors. Amplification of the response to the high dose of Meth at high dose of the antagonist points out to the involvement of a mechanism different from ORX1 receptor blockade. We speculate that at high doses SB becomes non-specific to ORX1 receptors and starts affecting ORX2 receptors. Further, ORX2 activation disinhibits the structure activated by high doses of Meth, which underlies the exaggerated responses to high doses of Meth at the presence of a high dose of SB. We conclude that both excitatory and inhibitory components in temperature responses to Meth administration and stress are mediated by orexinergic pathways. Non-specificity of SB at high doses to ORX1 receptors manifests itself in additional suppression of inhibition resulting in facilitation of the responses to high-doses of Meth

Thermoregulatory Effects of Psychostimulants and Exercise: Data-driven Modeling and Analysis

Thermoregulation system in mammal keeps their body temperature in a vital and yet narrow range of temperature by adjusting two main activities, heat generation, and heat loss. Also, these activities get triggered by other causes such as exercise or certain drugs. As a result, thermoregulation system will respond and try to bring back the body temperature to the normal range. Although these responses are very well experimentally explored, they often can be unpredictable and clinically deadly. Therefore, this thesis aims to analytically characterize the neural circuitry components of the system that control the heat generation and heat loss. This modeling approach can help us to analyze the relationship between different components of the thermoregulation system without directly measuring them and explain its complex responses in mathematical form. The first chapter of the thesis is dedicated to introducing a mathematical modeling approach of the circuitry components of the thermoregulation system in response to Methamphetamine which was first published in [1]. Later, in other chapters, we will expand this mathematical framework to study the other components of this system under different conditions such as different circadian phases, various pharmacological interventions, and exercise. This thesis is composed by materials from the following papers. CHAPTER 1 uses the main idea, model, and figures from References [1]. Meanwhile, CHAPTER 2 is based on [2] coauthored with me and is reformatted according to Purdue University Thesis guidelines. Also, CHAPTER 3 interpolates materials from reference [3] coauthored and is reformatted to comply with Purdue University Thesis guidelines. CHAPTER 4 is inserted from the reference [4] and is reformatted according to Purdue University Thesis guidelines. Finally, CHAPTER 5 is based on Reference [5] and is reformatted according to Purdue University Thesis guidelines. Some materials from each of these references have been used in the introduction Chapter

Circadian variability of body temperature responses to methamphetamine

Vital parameters of living organisms exhibit circadian rhythmicity. Although rats are nocturnal animals, most of the studies involving rats are performed during the day. The objective of this study was to examine the circadian variability of the body temperature responses to methamphetamine. Body temperature was recorded in male Sprague-Dawley rats that received intraperitoneal injections of methamphetamine (Meth, 1 or 5 mg/kg) or saline at 10 AM or at 10 PM. The baseline body temperature at night was 0.8°C higher than during the day. Both during the day and at night, 1 mg/kg of Meth induced monophasic hyperthermia. However, the maximal temperature increase at night was 50% smaller than during the daytime. Injection of 5 mg/kg of Meth during the daytime caused a delayed hyperthermic response. In contrast, the same dose at night produced responses with a tendency toward a decrease of body temperature. Using mathematical modeling, we previously showed that the complex dose dependence of the daytime temperature responses to Meth results from an interplay between inhibitory and excitatory drives. In this study, using our model, we explain the suppression of the hyperthermia in response to Meth at night. First, we found that the baseline activity of the excitatory drive is greater at night. It appears partially saturated and thus is additionally activated by Meth to a lesser extent. Therefore, the excitatory component causes less hyperthermia or becomes overpowered by the inhibitory drive in response to the higher dose. Second, at night the injection of Meth results in reduction of the equilibrium body temperature, leading to gradual cooling counteracting hyperthermia

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

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