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Reactive oxygen species scavenger N-acetyl cysteine reduces methamphetamine-induced hyperthermia without affecting motor activity in mice.

Sanchez-Alavez M, Bortell N, Galmozzi A, Conti B, Marcondes MC - Temperature (Austin) (2014 Oct-Dec)

Bottom Line: In a previous study we found that the anti-oxidant N-acetyl cysteine (NAC) can prevent the high increase in temperature in a mouse model of Meth-hyperthermia.The effects of NAC were seen in spite of its inability to recover the decrease of mitochondrial superoxide induced in BAT by Meth.In addition, NAC did not prevent the Meth-induced decrease of BAT glutathione.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Molecular Neurosciences; The Scripps Research Institute; La Jolla, CA USA.

ABSTRACT

Hyperthermia is a potentially lethal side effect of Methamphetamine (Meth) abuse, which involves the participation of peripheral thermogenic sites such as the Brown Adipose Tissue (BAT). In a previous study we found that the anti-oxidant N-acetyl cysteine (NAC) can prevent the high increase in temperature in a mouse model of Meth-hyperthermia. Here, we have further explored the ability of NAC to modulate Meth-induced hyperthermia in correlation with changes in BAT. We found that NAC treatment in controls causes hypothermia, and, when administered prior or upon the onset of Meth-induced hyperthermia, can ameliorate the temperature increase and preserve mitochondrial numbers and integrity, without affecting locomotor activity. This was different from Dantrolene, which decreased motor activity without affecting temperature. The effects of NAC were seen in spite of its inability to recover the decrease of mitochondrial superoxide induced in BAT by Meth. In addition, NAC did not prevent the Meth-induced decrease of BAT glutathione. Treatment with S-adenosyl-L-methionine, which improves glutathione activity, had an effect in ameliorating Meth-induced hyperthermia, but also modulated motor activity. This suggests a role for the remaining glutathione for controlling temperature. However, the mechanism by which NAC operates is independent of glutathione levels in BAT and specific to temperature. Our results show that, in spite of the absence of a clear mechanism of action, NAC is a pharmacological tool to examine the dissociation between Meth-induced hyperthermia and motor activity, and a drug of potential utility in treating the hyperthermia associated with Meth-abuse.

No MeSH data available.


Related in: MedlinePlus

Effect of NAC on Meth hyperthermia, Motor activity and on RER. Mice were treated with NAC (1000 mg/kg) 30 min before, or 1, 2 or 4 hrs after Meth (5 mg/kg), and were monitored during 24 hours for Temperature and Respiratory Exchange Ratio. The figure shows the 6 hours in which the actions of Meth were observed. (A) Core body temperature, (B) Calculation of AUC for temperature, (C) Motor Activity, (D) AUC for Motor Activity. (E) RER, (F) AUC for RER, (G) Heat, extrapolated from CV and body mass and (H) AUC for Heat. Arrows indicate color-coded critical injection time-points. Red arrows indicate Meth injection (5 mg/kg), and colored arrows indicate NAC (1000 mg/kg) injection at indicated time-points. Baseline values for each variable were calculated by the average between −2 and 0, for determination of the AUC for a total of 6 hours, from time 0, using both positive and negative peaks. Values represent the Average ± SEM of one representative experiment with 5 mice/group, out of a total of 3 experiments performed. * p < 0.05.
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Figure 2: Effect of NAC on Meth hyperthermia, Motor activity and on RER. Mice were treated with NAC (1000 mg/kg) 30 min before, or 1, 2 or 4 hrs after Meth (5 mg/kg), and were monitored during 24 hours for Temperature and Respiratory Exchange Ratio. The figure shows the 6 hours in which the actions of Meth were observed. (A) Core body temperature, (B) Calculation of AUC for temperature, (C) Motor Activity, (D) AUC for Motor Activity. (E) RER, (F) AUC for RER, (G) Heat, extrapolated from CV and body mass and (H) AUC for Heat. Arrows indicate color-coded critical injection time-points. Red arrows indicate Meth injection (5 mg/kg), and colored arrows indicate NAC (1000 mg/kg) injection at indicated time-points. Baseline values for each variable were calculated by the average between −2 and 0, for determination of the AUC for a total of 6 hours, from time 0, using both positive and negative peaks. Values represent the Average ± SEM of one representative experiment with 5 mice/group, out of a total of 3 experiments performed. * p < 0.05.

Mentions: In a previous study we have shown that the administration of NAC before Meth injection was able to prevent hyperthermia, suggesting a role for ROS in the control of temperature in drug abuse. Our prior observations also linked Meth-induced hyperthermia and BAT, ROS levels in BAT, and the ability of NAC to modulate temperature. Here we tested the effect of NAC at various time points, both before and after Meth injection. Interestingly, NAC alone caused temperature to decrease significantly (Fig. 2A and 2B, green line and green bar). In addition, confirming what we have previously reported,15 the injection of NAC 30 minutes prior to the injection of Meth delayed the onset and prevented the increase in temperature caused by Meth (Fig. 2A and 2B). Repeated measures ANOVA revealed significant differences between all the NAC-treated, Meth-injected animals when compared to Meth alone (P < 0.05). A single dose of NAC 1 or 2 hrs after Meth (when temperature starts rising), or at 4hrs after Meth (when the temperature is at its peak), was able to effectively cause a transient drop of temperature, which was followed by a partial recovery (P = 0.0001, P = 0.0005, P = 0.00098, respectively, Fig. 2A). Regression analysis showed a negative slope for NAC alone (−0.4629), but interaction between NAC and Meth was not identified. In addition, the regression analysis did not identify a difference between NAC-treated Meth groups and Meth alone. However, the analysis of the Area under the curve (AUC) for temperature revealed that the NAC treatment at any time-point was able to efficiently decrease the temperature in comparison to the Meth-injected group (Fig. 2B). Regarding motor activity, repeated measures ANOVA showed a significant impact for Meth (P < 0.05). Importantly, NAC did not decrease motor activity in Meth-injected mice (Fig. 2C), by any of the applied analytical methods, suggesting that the control of temperature and motor activity are dissociated in the mouse model of Meth administration. This was confirmed by the analysis of the AUC for motor activity (Fig. 2D). Meth decreased RER as detected by repeated measures ANOVA (p < 0.0001), which was significant from 1 hour to 3 hours after Meth-injection (Fig. 2E). The NAC treatment, at any of the administered regimens, did not impact the decrease in RER caused by Meth, according to posthoc tests or to regression analysis (Fig. 2E). On the other hand, the analysis of the AUC for RER showed that the NAC treatment aggravated the decrease in RER that was induced by Meth (Fig. 2F). These data suggest that the alterations in metabolic substrate utilization caused by Meth were not shifted by NAC. The Meth administration caused a significant heat output in comparison to controls, according to repeated measures ANOVA (p < 0.0001), and detectable at 1 hour and at 3 hrs after injection (Fig. 2G). which was not significantly changed by NAC at any time point (Fig. 1G and 1H).


Reactive oxygen species scavenger N-acetyl cysteine reduces methamphetamine-induced hyperthermia without affecting motor activity in mice.

Sanchez-Alavez M, Bortell N, Galmozzi A, Conti B, Marcondes MC - Temperature (Austin) (2014 Oct-Dec)

Effect of NAC on Meth hyperthermia, Motor activity and on RER. Mice were treated with NAC (1000 mg/kg) 30 min before, or 1, 2 or 4 hrs after Meth (5 mg/kg), and were monitored during 24 hours for Temperature and Respiratory Exchange Ratio. The figure shows the 6 hours in which the actions of Meth were observed. (A) Core body temperature, (B) Calculation of AUC for temperature, (C) Motor Activity, (D) AUC for Motor Activity. (E) RER, (F) AUC for RER, (G) Heat, extrapolated from CV and body mass and (H) AUC for Heat. Arrows indicate color-coded critical injection time-points. Red arrows indicate Meth injection (5 mg/kg), and colored arrows indicate NAC (1000 mg/kg) injection at indicated time-points. Baseline values for each variable were calculated by the average between −2 and 0, for determination of the AUC for a total of 6 hours, from time 0, using both positive and negative peaks. Values represent the Average ± SEM of one representative experiment with 5 mice/group, out of a total of 3 experiments performed. * p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Effect of NAC on Meth hyperthermia, Motor activity and on RER. Mice were treated with NAC (1000 mg/kg) 30 min before, or 1, 2 or 4 hrs after Meth (5 mg/kg), and were monitored during 24 hours for Temperature and Respiratory Exchange Ratio. The figure shows the 6 hours in which the actions of Meth were observed. (A) Core body temperature, (B) Calculation of AUC for temperature, (C) Motor Activity, (D) AUC for Motor Activity. (E) RER, (F) AUC for RER, (G) Heat, extrapolated from CV and body mass and (H) AUC for Heat. Arrows indicate color-coded critical injection time-points. Red arrows indicate Meth injection (5 mg/kg), and colored arrows indicate NAC (1000 mg/kg) injection at indicated time-points. Baseline values for each variable were calculated by the average between −2 and 0, for determination of the AUC for a total of 6 hours, from time 0, using both positive and negative peaks. Values represent the Average ± SEM of one representative experiment with 5 mice/group, out of a total of 3 experiments performed. * p < 0.05.
Mentions: In a previous study we have shown that the administration of NAC before Meth injection was able to prevent hyperthermia, suggesting a role for ROS in the control of temperature in drug abuse. Our prior observations also linked Meth-induced hyperthermia and BAT, ROS levels in BAT, and the ability of NAC to modulate temperature. Here we tested the effect of NAC at various time points, both before and after Meth injection. Interestingly, NAC alone caused temperature to decrease significantly (Fig. 2A and 2B, green line and green bar). In addition, confirming what we have previously reported,15 the injection of NAC 30 minutes prior to the injection of Meth delayed the onset and prevented the increase in temperature caused by Meth (Fig. 2A and 2B). Repeated measures ANOVA revealed significant differences between all the NAC-treated, Meth-injected animals when compared to Meth alone (P < 0.05). A single dose of NAC 1 or 2 hrs after Meth (when temperature starts rising), or at 4hrs after Meth (when the temperature is at its peak), was able to effectively cause a transient drop of temperature, which was followed by a partial recovery (P = 0.0001, P = 0.0005, P = 0.00098, respectively, Fig. 2A). Regression analysis showed a negative slope for NAC alone (−0.4629), but interaction between NAC and Meth was not identified. In addition, the regression analysis did not identify a difference between NAC-treated Meth groups and Meth alone. However, the analysis of the Area under the curve (AUC) for temperature revealed that the NAC treatment at any time-point was able to efficiently decrease the temperature in comparison to the Meth-injected group (Fig. 2B). Regarding motor activity, repeated measures ANOVA showed a significant impact for Meth (P < 0.05). Importantly, NAC did not decrease motor activity in Meth-injected mice (Fig. 2C), by any of the applied analytical methods, suggesting that the control of temperature and motor activity are dissociated in the mouse model of Meth administration. This was confirmed by the analysis of the AUC for motor activity (Fig. 2D). Meth decreased RER as detected by repeated measures ANOVA (p < 0.0001), which was significant from 1 hour to 3 hours after Meth-injection (Fig. 2E). The NAC treatment, at any of the administered regimens, did not impact the decrease in RER caused by Meth, according to posthoc tests or to regression analysis (Fig. 2E). On the other hand, the analysis of the AUC for RER showed that the NAC treatment aggravated the decrease in RER that was induced by Meth (Fig. 2F). These data suggest that the alterations in metabolic substrate utilization caused by Meth were not shifted by NAC. The Meth administration caused a significant heat output in comparison to controls, according to repeated measures ANOVA (p < 0.0001), and detectable at 1 hour and at 3 hrs after injection (Fig. 2G). which was not significantly changed by NAC at any time point (Fig. 1G and 1H).

Bottom Line: In a previous study we found that the anti-oxidant N-acetyl cysteine (NAC) can prevent the high increase in temperature in a mouse model of Meth-hyperthermia.The effects of NAC were seen in spite of its inability to recover the decrease of mitochondrial superoxide induced in BAT by Meth.In addition, NAC did not prevent the Meth-induced decrease of BAT glutathione.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Molecular Neurosciences; The Scripps Research Institute; La Jolla, CA USA.

ABSTRACT

Hyperthermia is a potentially lethal side effect of Methamphetamine (Meth) abuse, which involves the participation of peripheral thermogenic sites such as the Brown Adipose Tissue (BAT). In a previous study we found that the anti-oxidant N-acetyl cysteine (NAC) can prevent the high increase in temperature in a mouse model of Meth-hyperthermia. Here, we have further explored the ability of NAC to modulate Meth-induced hyperthermia in correlation with changes in BAT. We found that NAC treatment in controls causes hypothermia, and, when administered prior or upon the onset of Meth-induced hyperthermia, can ameliorate the temperature increase and preserve mitochondrial numbers and integrity, without affecting locomotor activity. This was different from Dantrolene, which decreased motor activity without affecting temperature. The effects of NAC were seen in spite of its inability to recover the decrease of mitochondrial superoxide induced in BAT by Meth. In addition, NAC did not prevent the Meth-induced decrease of BAT glutathione. Treatment with S-adenosyl-L-methionine, which improves glutathione activity, had an effect in ameliorating Meth-induced hyperthermia, but also modulated motor activity. This suggests a role for the remaining glutathione for controlling temperature. However, the mechanism by which NAC operates is independent of glutathione levels in BAT and specific to temperature. Our results show that, in spite of the absence of a clear mechanism of action, NAC is a pharmacological tool to examine the dissociation between Meth-induced hyperthermia and motor activity, and a drug of potential utility in treating the hyperthermia associated with Meth-abuse.

No MeSH data available.


Related in: MedlinePlus