Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

Behrouzvaziri, Abolhassan; Fu, Daniel Y.; Tan, Patrick; Yoo, Yeonjoo; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.

doi:10.1371/journal.pone.0126719

Cited by 7 publications

(8 citation statements)

References 44 publications

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“…Therefore, the aforementioned intricate dose dependence is a result of delicate balance between activation of excitatory and inhibitory pathways controlling heat generation (Molkov and Zaretsky ), while both components are mediated by orexinergic neurotransmission (Behrouzvaziri et al. ). In that study, based on existing literature data, we explicitly assumed that at room temperature amphetamines do not increase heat dissipation; an assumption that may require reassessment in light of the findings presented in this study.…”

Section: Discussionmentioning

confidence: 99%

Amphetamine enhances endurance by increasing heat dissipation

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Amphetamine enhances endurance by increasing heat dissipation

et al. 2016

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“…The inhibitory drive (Inh) puta- tively originates from supramedullary (preoptic nucleus or ventrolateral periaqueductal gray matter) and/or intramedullary (rostroventral lateral medulla) structures. Previously, we demonstrated that temperature responses to Meth are mediated by orexinergic neurotransmission (1). Moreover, using our mathematical model (11), we inferred that both the excitatory and inhibitory components are likely to be activated by orexinergic signals induced by Meth administration.…”

Section: Putative Neuronal Structures and Neurotransmissionmentioning

confidence: 60%

“…First, amphetamines induce arousal, which could be due to alterations in the neuronal activity controlling circadian rhythms. Administration of Meth results in the activation of orexin-containing neurons (1)(2)(3), which are critical for normal circadian rhythmicity and are activated during the active phase of the day cycle. Chronic use of Meth leads to disruption of normal circadian rhythmicity.…”

Section: Introductionmentioning

confidence: 99%

Circadian variability of body temperature responses to methamphetamine

Behrouzvaziri

Zaretskaia

Rusyniak

et al. 2018

American Journal of Physiology-Regulatory, Integrative and Comp

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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.

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“…As shown above, at equilibrium, if there is no heat exchange between the organ and its environment (other than through the circulation), the organ temperature cannot be more than 1.3 C higher than the arterial blood temperature. Furthermore, the core temperature in rats fluctuates between »37 and 38 C, with a potential to decrease to »36 C during sleep [25,26] and to increase to »39 C during intense exercise [27][28][29][30][31][32] or pharmacological stimulation [33][34][35]. As such, the physiological range of the core temperature is almost three times wider than the maximum effect of local metabolism.…”

Section: Brain Temperaturementioning

confidence: 99%

“…Obviously, in extreme situations, deep core body temperature may be even lower than 36 C or higher than 39 C, but the brainblood temperature gradient is still bounded by 1.3 C. This does not diminish the importance of local metabolism; in many situations, having a brain temperature 1.3 C lower or higher is equivalent to living or dying (see, e.g., ref. [35]).…”

Section: Brain Temperaturementioning

confidence: 99%

Tissue oxidative metabolism can increase the difference between local temperature and arterial blood temperature by up to 1.3^oC: Implications for brain, brown adipose tissue, and muscle physiology

et al. 2018

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Tissue temperature increases, when oxidative metabolism is boosted. The source of nutrients and oxygen for this metabolism is the blood. The blood also cools down the tissue, and this is the only cooling mechanism, when direct dissipation of heat from the tissue to the environment is insignificant, , in the brain. While this concept is relatively simple, it has not been described quantitatively. The purpose of the present work was to answer two questions: 1) to what extent can oxidative metabolism make the organ tissue warmer than the body core, and, 2) how quickly are changes in the local metabolism reflected in the temperature of the tissue? Our theoretical analysis demonstrates that, at equilibrium, given that heat exchange with the organ is provided by the blood, the temperature difference between the organ tissue and the arterial blood is proportional to the arteriovenous difference in oxygen content, does not depend on the blood flow, and cannot exceed 1.3C. Unlike the equilibrium temperature difference, the rate of change of the local temperature, with respect to time, does depend on the blood flow. In organs with high perfusion rates, such as the brain and muscles, temperature changes occur on a time scale of a few minutes. In organs with low perfusion rates, such changes may have characteristic time constants of tens or hundreds of minutes. Our analysis explains, why arterial blood temperature is the main determinant of the temperature of tissues with limited heat exchange, such as the brain.

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Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

Cited by 7 publications

References 44 publications

Amphetamine enhances endurance by increasing heat dissipation

Amphetamine enhances endurance by increasing heat dissipation

Circadian variability of body temperature responses to methamphetamine

Tissue oxidative metabolism can increase the difference between local temperature and arterial blood temperature by up to 1.3^oC: Implications for brain, brown adipose tissue, and muscle physiology

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Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

Cited by 7 publications

References 44 publications

Amphetamine enhances endurance by increasing heat dissipation

Amphetamine enhances endurance by increasing heat dissipation

Circadian variability of body temperature responses to methamphetamine

Tissue oxidative metabolism can increase the difference between local temperature and arterial blood temperature by up to 1.3oC: Implications for brain, brown adipose tissue, and muscle physiology

Contact Info

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Tissue oxidative metabolism can increase the difference between local temperature and arterial blood temperature by up to 1.3^oC: Implications for brain, brown adipose tissue, and muscle physiology