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Browsing by Author "Morozova, Ekaterina"
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Item Amphetamine enhances endurance by increasing heat dissipation(APS, 2016-09-01) Morozova, Ekaterina; Yoo, Yeonjoo; Behrouzvaziri, Abolhassan; Zaretskaia, Maria; Rusyniak, Daniel; Zaretsky, Dmitry; Molkov, Yaroslav; Department of Mathematical Sciences, School of ScienceAthletes 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.Item Circadian variability of body temperature responses to Methamphetamine (Meth)(Office of the Vice Chancellor for Research, 2015-04-17) Behrouzvaziri, Abolhassan; Yoo, Yeonjoo; Morozova, Ekaterina; Zaretskaia, Maria; Zaretsky, Dmitry; Molkov, YaroslavVital 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.Item Circuit-level Mechanisms of EtOH-dependent dopamine release.(2017-06-30) DiVolo, Matteo; Morozova, Ekaterina; Lapish, Christopher; Kuznetsov, Alexey; Gutkin, Boris; Mathematical Sciences, School of ScienceAlcoholism is the third leading cause of preventable mortality in the world. In the last decades a large body of experimental data has paved the way to a clearer knowledge of the specific molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms play together to result in a dysregulated dopamine (DA) release under alcohol influence remains unclear. In this manuscript, we delineate potential circuit-level mechanisms responsible for EtOH-dependent increase and dysregulation of DA release from the ventral tegmental area (VTA) into nucleus accumbens (Nac). For this purpose, we build a circuit model of the VTA composed of DA and GABAergic neurons, that integrate external Glutamatergic (Glu) inputs to result in DA release. In particular, we reproduced a non-monotonic dose dependence of DA neurons firing activity on EtOH: an increase in firing at small to intermediate doses and a drop below baseline (alcohol-free) levels at high EtOH concentrations. Our simulations predict that a certain level of synchrony is necessary for the firing rate increase produced by EtOH. Moreover, EtOH effect on the DA neuron firing rate and, consequently, DA release can reverse depending on the average activity level of the Glu afferents to VTA. Further, we propose a mechanism for emergence of transient (phasic) DA peaks and the increase in their frequency in EtOH. Phasic DA transients result from DA neuron population bursts, and these bursts are enhanced in EtOH. These results suggest the role of synchrony and average activity level of Glu afferents to VTA in shaping the phasic and tonic DA release under the acute influence of EtOH and in normal conditions.Item Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine(Society for Neuroscience, 2020-07-07) Morozova, Ekaterina; Faure, Philippe; Gutkin, Boris; Lapish, Christoper; Kuznetsov, Alexey; Mathematical Sciences, School of ScienceThe addictive component of tobacco, nicotine, acts via nicotinic acetylcholine receptors (nAChRs). The β2 subunit-containing nAChRs (β2-nAChRs) play a crucial role in the rewarding properties of nicotine and are particularly densely expressed in the mesolimbic dopamine (DA) system. Specifically, nAChRs directly and indirectly affect DA neurons in the ventral tegmental area (VTA). The understanding of ACh and nicotinic regulation of DA neuron activity is incomplete. By computational modeling, we provide mechanisms for several apparently contradictory experimental results. First, systemic knockout of β2-containing nAChRs drastically reduces DA neurons bursting, although the major glutamatergic (Glu) afferents that have been shown to evoke this bursting stay intact. Second, the most intuitive way to rescue this bursting—by re-expressing the nAChRs on VTA DA neurons—fails. Third, nAChR re-expression on VTA GABA neurons rescues bursting in DA neurons and increases their firing rate under the influence of ACh input, whereas nicotinic application results in the opposite changes in firing. Our model shows that, first, without ACh receptors, Glu excitation of VTA DA and GABA neurons remains balanced and GABA inhibition cancels the direct excitation. Second, re-expression of ACh receptors on DA neurons provides an input that impedes membrane repolarization and is ineffective in restoring firing of DA neurons. Third, the distinct responses to ACh and nicotine occur because of distinct temporal patterns of these inputs: pulsatile versus continuous. Altogether, this study highlights how β2-nAChRs influence coactivation of the VTA DA and GABA neurons required for motivation and saliency signals carried by DA neuron activity.Item Effect of Low Dose of Amphetamine on Thermoregulation System and Performance of Rats Running on Treadmills(Office of the Vice Chancellor for Research, 2015-04-17) Behrouzvaziri, Abolhassan; Molkov, Yaroslav; Morozova, Ekaterina; Yoo, Yeonjoo; Zaretskaia, Maria; Zaretsky, DmitryAmphetamine 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.Item A role of local VTA GABAergic neurons in mediating dopamine neuron response to nicotine(BMC Neuroscience, 2015-12-18) Morozova, Ekaterina; Myroshnychenko, Maxym; Rooy, Marie; Gutkin, Boris; Lapish, Christopher C.; Kuznetsov, Alexey; Department of Physics, School of Science