Brain Hyperthermia Is Induced by Methamphetamine and Exacerbated by Social Interaction

Methamphetamine effects under quiet resting conditions

Figure 1 shows mean changes in temperature in each recording location after drug administration under quiet resting conditions. Under these conditions, saline injection by itself induced movement activation as well as a significant and generally correlated temperature increase (∼0.5°C) in all recording sites. Although movement activation was visually evident for a few minutes after the injection, the temperature increase was more prolonged (∼30 min), peaking at ∼15 min. The temperature increase was more rapid in both brain sites (especially in the NAcc) than in the muscle, resulting in the appearance of a transient but significant increase in the brain–muscle differential.

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Fig. 1.

Mean changes in brain and muscle temperature after subcutaneous administration of methamphetamine at low, moderate, and high doses as well as after two control injections of saline. Absolute temperatures (A), temperature changes normalized with respect to the moment of injection (B), and relative brain–muscle difference (i.e., differences in temperature dynamics in different recording sites with the preinjection baseline set as zero) (C) are shown. Both absolute temperature changes and brain–muscle difference were analyzed for each set of data with one-way ANOVA with repeated measures; filled symbols show values significantly different (Fisher test) from preinjection baseline. Values of ANOVA for temperature elevation are as follows: saline injection 1 (Saline-1):F_(22,137) = 6.30, 4.73, 6.10 for the NAcc, muscle, and hippocampus (Hippo), respectively, andp < 0.01 for each case; 1 mg/kg METH:F_(28,173) = 34.90, 26.71, 23.73 andp < 0.001 for each case; 3 mg/kg METH:F_(28,173) = 2.34, 2.854, 2.02 andp < 0.05 for each case; 9 mg/kg METH:F_(30,185) = 17.73, 18.84, 17.29 andp < 0.001 for each case. Values of ANOVA for NAcc–muscle and hippocampus–muscle difference are as follows: saline injection 1 (Saline-1): F_(22,137) = 3.12, 2.34 and p < 0.05 for each case; 1 mg/kg METH: F_(28,173) = 7.55, 2.83 andp < 0.01 for each case; 3 mg/kg METH:F_(28,173) = 3.60, 3.56 andp < 0.05 for both cases; 9 mg/kg METH:F_(30,185) = 17.73, 17.22 andp < 0.001 for each case. The effects of time for saline 2 (Saline-2) were nonsignificant in both cases (p > 0.1).

METH injection induced dose-dependent hyperthermia. Compared with transient temperature elevation after saline injection, METH at the lowest dose (1 mg/kg) induced a larger (∼1°C) and much longer (135–145 min depending on area) elevation, which was more rapid and stronger in both brain structures than in the muscle (Fig.1B). Because of this dynamic, the brain–muscle temperature differential (Fig. 1C) rapidly increased after drug injection and remained elevated for 50 (hippocampus) or 110 (NAcc) min. A similar pattern was observed after METH at the moderate dose (3 mg/kg), with a mean temperature elevation of ∼1.3°C and a duration of 205–215 min. The strongest response occurred at the highest dose (9 mg/kg), with a mean elevation of ∼3.5°C and a duration longer than the entire period of postinjection recording (>315 min). Similar to other situations, brain temperature increase in this case was more rapid and stronger than in the muscle, and the change in brain–muscle differential was exceptionally strong and prolonged (Fig.1C). The temperature difference between the NAcc and muscle rapidly increased for the first 10 min after drug administration, peaked at 40–50 min (∼0.5°C), and maintained an increased level for the entire period of observation. Similar but smaller changes were seen for the hippocampus–muscle difference. A saline injection during the fifth daily session produced no significant change in temperature.

Consistent with our previous observations (Kiyatkin et al., 2002), basal temperatures in the NAcc in the present study (Fig.1A) were significantly higher than in the hippocampus, whereas muscle had intermediate values. These between-site differences were consistent in all animals both within and between sessions.

Methamphetamine effects during social interaction

Introduction of a female conspecific led to consistent behavioral activation and significant hyperthermia (Fig.2). The amplitude of temperature elevation was relatively stable over repeated sessions (∼1.3, 1.7, 1.5, 1.5, and 1.2°C respective to each day). In general, temperature elevation in all areas reached a plateau 15–25 min after the start of social interaction (Fig. 2B), the temperature acceleration was maximal during the first 10 min, and absolute temperature declined during the subsequent 40–50 min. Saline injection during social interaction had no effect on temperatures, which slowly decreased, reaching baseline values at ∼100–110 min (i.e., 10–20 min before the female was removed from the cage). The removal of the female resulted in a transient temperature increase that did not reach the level of statistical significance. In contrast to the control injections, METH injections significantly modified the thermal response associated with social interaction, and METH-induced temperature increases under these conditions were significantly stronger and longer than that under quiet resting conditions. The mean peak values of NAcc temperature after METH were, for example, 38.06 (range, 37.55–38.74), 38.30 (range, 38.05–39.33), and 40.27°(range, 39.63–41.52) at 1, 3, and 9 mg/kg, respectively, whereas the durations of significant elevation were 165, 205, and >345 min. Similar increases in the magnitude and durations of METH-induced temperature were evident in all other recording sites. The second saline session revealed a pattern similar to the first saline session.

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Fig. 2.

Mean changes in brain and muscle temperature after subcutaneous administration of methamphetamine at low, moderate, and high doses as well as after two control injections of saline during social interaction. The first and third vertical hatched lines in each graph show the moments when the female was placed and removed from the cage, and the second vertical line shows the moment of subcutaneous injection. The format is the same as described for Figure 1. ANOVA values for temperature elevation are as follows: for Saline-1,F_(25,155) = 18.47, 17.04, 20.11, respectively, for the NAcc, muscle, and hippocampus (Hippo); for 1 mg/kg METH, F_(32,197) = 35.47, 36.51, 38.25; for 3 mg/kg METH, F_(33,203) = 17.22, 14.39, 15.98; for 9 mg/kg METH,F_(39,239) = 14.99, 15.18, 16.07; for Saline-2, F_(23,119) = 4.28, 3.58, 4.51 (all p < 0.05; Fisher test). The increase in brain–body temperature difference for the first 30 min of social interaction was significant for the first saline injection (F_(25,155) = 2.25, 1.96, respectively, for NAcc–muscle and hippocampus–muscle; p < 0.05), 1 mg/kg METH (F_(32,197) = 3.73, 3.46; p < 0.05), and the second saline injection (F_(23,119) = 3.58, 4.51; p < 0.05). The increase after injection was absent in both saline cases but was significant after METH at all three doses (1 mg/kg: F_(32,197) = 3.73, 3.46,p < 0.05; 3 mg/kg:F_(32,197) = 5.24, 3.62; allp values <0.05; 9 mg/kg:F_(35,215) = 2.45, 1.91,p < 0.05).

The mean brain–body temperature difference (Fig. 2C) rapidly increased after placement of the female, but the degree of this change decreased across repeated sessions. After an injection of METH, the temperature difference increased for all three doses, again varying by structure. At 1 and 3 mg/kg, the difference was significant for ∼65 min, and at 9 mg/kg, it remained elevated, and especially strong for the NAcc, for the entire postinjection period. Brain–body difference did not increase after either saline injection.

Because previous work has shown fluctuations of up to 2°C to be within normal physiological function (Kiyatkin and Wise, 2001; Kiyatkin et al., 2002), time spent above this limit can be considered a measure of the duration of abnormal hyperthermia. Mean temperature at quiet resting conditions (i.e., time before injection or introduction of the female) was determined to be 36.72, 35.93, and 36.39°C (n = 59 for each case) for the NAcc, hippocampus, and muscle, respectively. Time spent 2°C above these levels is shown in Figure 3. For each recording site, temperature after 9 mg/kg METH remained elevated longer in the rats that experienced social interaction, although this effect was significant only for the NAcc and hippocampus.

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Fig. 3.

Mean ± SEM time spent 2° above baseline temperatures, compared by group at 9 mg/kg. t values were t₁₀ = 2.851 (*p < 0.05), 3.548 (*p < 0.01), and 2.134 (p = 0.0596) for the NAcc, hippocampus (Hippo), and muscle, respectively (unpaired Student'st test).

Although both the magnitudes and durations of METH-induced temperature elevations were higher when the drug was used during social interaction, in two of six animals, METH-induced hyperthermia at 9 mg/kg was especially robust and clearly pathological, with NAcc temperatures exceeding 41°C. These two animals also showed atypically strong and long-term stereotypy and other signs of excessive autonomic activation (i.e., urination), and one of the rats died after the session. Although, between-animal variability was also high when METH was given under control conditions, NAcc temperature peaks of >40°C were seen only in two animals. Figure 4shows an example of such pathological responding. Although the two rats had almost identical body weight and were recorded simultaneously in the same environment, in the first case NAcc temperature peaked at 39.58°C, whereas in the second case NAcc temperature was elevated above 40°C for 192 min. There were also striking between-animal differences in the brain–muscle dynamic. When METH was injected under quiet resting conditions, NAcc– and hippocampus–muscle differences were increased for ∼3 hr, but when the drug was administered during social interaction, these differences remained abnormally elevated for >6 hr.

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Fig. 4.

Two original records of temperature dynamics after METH administration to rats under quiet resting conditions (left) and during social interaction (right). Top graphs show absolute temperatures in each recording location, and bottom graphs depict changes in NAcc– and hippocampus (Hippo)–muscle difference.

METH induces pathological metabolic neural activation and hyperthermia

Our finding that METH induces dose-dependent hyperthermia that develops consistently faster and is greater in brain structures than in the head muscle suggests neural activation as a source of brain hyperthermia and as the primary force behind subsequent body hyperthermia. Although sympathetic activation may be a major contributor to body hyperthermia, this activation is centrally determined. Increased body temperature, therefore, is a consequence of the central action of the drug rather than a secondary consequence of movement activation or some other action in the periphery. METH-induced hyperthermia was structure-specific (stronger and longer lasting in the NAcc than in hippocampus). It was more robust and sustained than hyperthermia seen under a variety of behavioral conditions in the absence of drug (Kiyatkin and Wise, 2001) (social interaction in the present study). Excessive and prolonged heat production induced by METH at the highest dose was especially evident in the brain–muscle temperature differential. The differential between the NAcc and muscle after 9 mg/kg METH rapidly increased to ∼0.5°C and was maintained above normal physiological levels (0.3–0.4°C) for >5 hr. Because heat is continuously removed from brain tissue by circulating blood, and because the lungs cool the blood just before it enters the brain, the strength of the brain–muscle difference induced by the drug gives evidence of the strength of the drug-induced neural activation.

Change in brain temperature is a factor that affects various neural functions ranging from the activity of ionic channels and receptor sensitivity (Thompson et al., 1985; Rosen, 2001) to such global neuronal alterations as release and uptake of neurotransmitters (Andersen and Moser, 1995; Xie et al., 2000). Thus, the METH-induced metabolic activation suggested by our temperature measurements could be a “common denominator” for various abnormalities in neural functions (i.e., thermal stress, oxidative stress, abnormal transmitter release, decrease in ATP, etc.) that are suggested as factors determining acute and chronic adverse effects of this drug, including neurotoxicity (Alberts and Sonsalla, 1995; Ali et al., 1996; Clausing and Bowyer, 1999). In some animals, NAcc elevation exceeded 41°C (5°C above resting baseline), a temperature associated with irreversible damage of mitochondrial and plasma membranes and cellular organelles (Lepock et al., 1983; Iwagami, 1996; Willis et al., 2000). Thus the degree of METH-induced hyperthermia under conditions of social arousal may have toxic consequences above and beyond the temperature-sensitive toxicity of monoamine terminals (Bowyer et al., 1993, 1994).

High-activity state exacerbates METH-induced hyperthermia

The hyperthermic effect of METH was significantly potentiated by social interaction, with clearly pathological overheating in all animals and one animal fatality at the highest drug dose. Although the effects were not additive, the magnitude of METH-induced hyperthermia during social interaction increased ∼0.5°C, and higher temperatures were maintained for significantly longer times. It is known that both toxicity and mortality induced by METH and its analogs are powerfully increased in mice by social crowding and aggregation (Shintomi, 1975; Blackshear et al., 1979; Vargas-Rivera et al., 1990). Although crowding itself may cause hyperthermia by restricting the airflow essential for radiant cooling, this factor was unlikely to have contributed to the hyperthermia seen during social interaction. First, we used only two animals, which interacted in a large cage and did not huddle together. Second, the air temperature in the cage did not increase during the period of social interaction. Third, the maximum brain temperature increase was seen in the first 10 min of social interaction, too early for significant accumulation of body heat. Perhaps the most significant evidence against overheating from aggregation was that the temperature increases during these social interactions were always more rapid and stronger in the brain than in the muscle. This suggests that neural activation within the male animal, and not heat transfer from body contact with the female, was the source of the brain hyperthermia we observed.

The present experiments underscore the importance of set (the current brain state) and setting (the environment and its impinging stimuli) in determining the effectiveness of drugs for a given action in a given situation. This is particularly important with respect to the toxic effects of stimulant drugs such as METH. These effects are temperature dependent (Bowyer et al., 1993, 1994; Miller and O'Callaghan, 1994; Alberts and Sonsalla, 1995; Farfel and Seiden, 1995; Ali et al., 1996; Davidson et al., 2001), and a wide range of conditions can influence brain as well as core temperature. In the present case, administration of the drug at 9 mg/kg during a social interaction was often sufficient to bring brain temperature close to its biological limit, resulting in the death of one of our animals. Although humans use METH and related substances at much lower doses, some individuals repeatedly administer METH intravenously, and this route of administration is more likely to lead to death (Kalant and Kalant, 1975). In addition, intake of the drug usually occurs during high-activity social situations, which are accompanied by a stronger neural activation and a presumably more profound hyperthermia than that seen during modest social interaction in our experiments. These drug intakes are frequently associated with dancing and sexual interactions (Rawson et al., 2002), which strongly contribute to overall hyperthermia through cardiac and striatal muscle exertion, and with loud music, which is known to potentiate gliolysis in mice (Morton et al., 2001). Whether these activities would exacerbate METH-induced hyperthermia in a manner similar to the interaction with a nonreceptive female in the present study remains to be explored.