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The Journal of Neuroscience, May 1, 2003, 23(9):3924
Brain Hyperthermia Is Induced by Methamphetamine and Exacerbated by Social Interaction
P. Leon Brown, Roy A. Wise, and Eugene A. Kiyatkin Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224
ABSTRACT
TOP
ABSTRACT
Introduction
Hyperthermia is a symptom of methamphetamine (METH) intoxication and a factor implicated in neurotoxicity during chronic METH use. To characterize the thermic response to METH, it was injected once daily into rats at increasing doses (0, 1, 3, and 9 mg/kg, s.c.) while brain [nucleus accumbens (NAcc), hippocampus] and body (deep temporal muscle) temperatures were continuously monitored. METH produced dose-dependent hyperthermia, with brain structures (especially the NAcc) showing a more rapid and pronounced temperature increase than the muscle. At the highest dose, brain and body temperatures increased 3.5-4.0°C above basal levels and remained elevated for 3-5 hr. Stressful and other high-activity situations such as interaction with a conspecific female are also known to induce a significant hyperthermic response in the rat. A combination of social interaction and METH administration was tested for additive effects. Male rats were exposed daily to a conspecific female for a total of 120 min, and METH was injected at the same doses 30 min after the initial contact with the female. An initial hyperthermic response (~1.5°C) to social interaction was followed by a large and prolonged hyperthermic response (3.5-5.0°C, 5-7 hr at 9 mg/kg) to METH, which was again stronger in brain structures (especially in the NAcc) than in the muscle. Although the combined effect of the hyperthermic events was not additive, METH administration during social interaction produced stronger and longer-lasting increases in brain and body temperature than that induced by drug alone, heating the brain in some animals near its biological limit (>41°C).
Key words: brain temperature; hyperthermia; metabolic neural activation; nucleus accumbens; hippocampus; social interaction
Introduction
Methamphetamine (METH) and related compounds [amphetamine, paramethoxyamphetamine, and methylenedioxymethamphetamine ("ecstasy")] are addictive substances that can cause serious health problems ranging from acute overdose toxicity and mortality to brain damage with chronic use (Davidson et al., 2001
; Kalant, 2001
Although the pattern of body hyperthermia after METH administration is well known (Sandoval et al., 2000
Because brain and body hyperthermia are also induced by various stressful and arousing situations, such as interaction with conspecifics (Kiyatkin et al., 2002
Materials and Methods
Animals and surgery. Twelve male Long-Evans rats, weighing between 400 and 500 gm (Charles River Laboratories, Greensboro, NC), were used. Each rat was housed individually (12 hr light cycle beginning at 7:00 A.M.) with ad libitum access to food and water. Protocols were performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (publication 865-23) and were approved by the Animal Care and Use Committee of the National Institute on Drug Abuse Intramural Research Program.
Each rat was anesthetized with a mixture of ketamine HCl (80 mg/kg, i.m.) and xylazine (10 mg/kg, i.m.) and mounted in a stereotaxic apparatus. Holes were drilled through the skull over two areas of interest: the NAcc (antero-posterior, 1.2 mm; lateral, 0.9 mm) and the hippocampus (antero-posterior,
3.5 mm; lateral, 2.0 mm). The dura matter was carefully retracted, and each temperature probe was slowly lowered to the intended target area (7.2 and 4.0 mm for the NAcc and hippocampus, respectively). A third temperature probe was implanted in deep temporal muscle. The probes were secured with dental cement to three stainless-steel screws threaded into the skull. Experimentation began after a 3 d recovery period and continued for the next six daily sessions.
Temperature probes and recording instruments. The thermocouple probes were prepared from copper and constantin wires (TW-35P; diameter, ~125 µm) obtained from Physitemp Instruments (Clifton, NJ). After mechanically removing the insulation 200-400 µm from the tip of each wire, the tips were welded together and reinsulated with polyester microshrink tubing and epoxy. The wires were connected to copper and constantin pins and fixed in a plastic connector with epoxy. During experiments, the probes were connected to the recording instrument (Thermes-16; Physitemp Instruments) via individual sockets, a common cord, and a nine channel electric swivel commutator.
During the session, temperatures were continuously recorded and stored in computer memory at 10 sec intervals. The temperature in the room was maintained automatically at 23°C, and the stability of the temperature in the chamber throughout the sessions (fluctuations between 23 and 24°C) was confirmed by an additional thermosensor.
Experimental protocol. All recordings took place during the light phase of the animal's cycle (8:00 A.M. to 8:00 P.M.) in an electrically shielded Plexiglas chamber (35 × 35 × 40 cm). Each day, the rats were brought from their housing facility, placed in the chamber, connected to the recording instrument, and allowed to habituate to the experimental environment. During habituation, the rats engaged in locomotion, grooming, and rearing that was accompanied by increases in both brain and body temperature (Kiyatkin and Wise, 2001
Histology. After completion of the experiments, each rat was deeply anesthetized and decapitated; brains were removed and stored in 10% formalin solution for subsequent histological processing. The location of the recording sites was determined from cryostat-cut, 30 µm slices mounted on glass slides.
Data analysis. The significance of temperature differences was evaluated using ANOVA with repeated measures followed by Fisher tests comparing 10 min intervals. The data were presented as changes in absolute temperature, changes relative to the pre-event baseline, and temperature differences between recording sites. Because the generative source of hyperthermia within brain and body can vary, the latter parameter (i.e., brain site-muscle difference relative to the point immediately preceding the injection) was instructive in determining the source of the hyperthermic response (Kiyatkin and Wise, 2001
Results
Data were obtained in 12 male rats (59 sessions) that had thermocouple probes located in the intended target areas and artifact-free recordings in each of three sites.
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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Figure 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, and p < 0.01 for each case; 1 mg/kg METH: F(28,173) = 34.90, 26.71, 23.73 and p < 0.001 for each case; 3 mg/kg METH: F(28,173) = 2.34, 2.854, 2.02 and p < 0.05 for each case; 9 mg/kg METH: F(30,185) = 17.73, 18.84, 17.29 and p < 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 and p < 0.01 for each case; 3 mg/kg METH: F(28,173) = 3.60, 3.56 and p < 0.05 for both cases; 9 mg/kg METH: F(30,185) = 17.73, 17.22 and p < 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
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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Figure 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; all p 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
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Figure 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's t 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 4 shows 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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Figure 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.
Discussion
The present study revealed two new findings about METH-induced hyperthermia. First, METH induces dose-dependent brain hyperthermia that precedes and is greater than overall body hyperthermia, suggesting METH-induced neuronal activation as a contributing source of that hyperthermia. Second, the hyperthermia induced by METH is potentiated in animals already hyperthermic from social interaction. These findings raise the possibility that the use of METH and related compounds in social or otherwise arousing situations increases the risk for adverse effects inherent to these drugs.
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
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
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
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
FOOTNOTES Received Dec. 3, 2002; revised Jan. 29, 2003; accepted Feb. 11, 2003.
Correspondence should be addressed to Eugene A. Kiyatkin at the above address. E-mail: ekiyatki{at}intra.nida.nih.gov.
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