Relationship between methamphetamine-induced behavioral activation and hyperthermia

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available at www.sciencedirect.com

www.elsevier.com/locate/brainres

Research Report

Relationship between methamphetamine-induced behavioral activation and hyperthermia Greg Phelps c , H. Anton Speaker a , Karen E. Sabol a,b,⁎ a

Department of Psychology, University of Mississippi, USA Department of Pharmacology, University of Mississippi, USA c Department of Engineering, University of Mississippi, USA b

A R T I C LE I N FO

AB S T R A C T

Article history:

Methamphetamine (METH) changes core temperature and induces behavioral activation.

Accepted 6 August 2010

Behavioral activation is also known to change core temperature. The purpose of this report

Available online 13 August 2010

was to 1.) evaluate the extent to which the behavioral activation induced by METH showed a temporal relationship to METH-induced hyperthermia; and 2.) describe the temporal pattern

Keywords:

of METH-induced hyperthermia over an extended dose range. Rats were treated with saline

Methamphetamine

or METH (0.5–10.0 mg/kg) in computer-controlled chambers with ambient temperature

Core temperature

maintained at 24 °C. Continuous telemetric core temperature measurements were made

Behavioral activation

during a 7 h test period. Behavioral observations were made once every 15 min using an 11point scale ranging from 0 (quiet awake) to 10 (focused licking or biting). The onset of METHinduced behavioral activation occurred at 15–30 min after treatment for all doses and preceded core temperature increases; the onset of METH-induced hyperthermia ranged from 45 min post-treatment to 120 min post-treatment. This behavior-temperature delay was 15– 30 min at the lowest (0.5 and 1.0 mg/kg) and the highest (7.0, 8.0, and 10.0 mg/kg) doses tested; the delay was increased between 1.0 and 4.0 mg/kg METH (105 min delay at 4.0 mg/kg) and then decreased again from 4.0 to 10.0 mg/kg. The strongest relationship between core temperature and behavioral activation occurred at 180 min post-treatment. These data suggest that factors other than behavior are primarily responsible for the observed core temperature effects during the initial post-treatment period (60 min peak); possible effects from movement are masked. For the latter post-treatment period (180 min peak) the stronger relationship between temperature and behavior suggests a role for movement in METHinduced hyperthermia. © 2010 Elsevier B.V. All rights reserved.

1.

Introduction

Methamphetamine (METH) is a drug of abuse. After highdose exposure, METH causes long-lasting neurochemical (neurotoxic) and behavioral deficits in laboratory animals

(Ricaurte et al., 1980; Sabol et al., 2000; Schroder et al., 2003). In humans, the effects of chronic METH are manifested as decreased dopamine (DA) transporter availability as well as cognitive and motor deficits (Chang et al., 2002; Volkow et al., 2001).

⁎ Corresponding author. Department of Psychology, 207 Peabody Building, University of Mississippi, Mississippi 38677, USA. E-mail address: [email protected] (K.E. Sabol). Abbreviation: METH, methamphetamine 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.08.017

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METH also induces hyperthermia. Amphetamine (AMPH)like stimulants cause the release of the three monoamine neurotransmitters, all of which have significant roles in temperature regulation (norepinephrine (NE) in the peripheral nervous system (PNS); NE, DA, and serotonin (5HT) through central nervous system (CNS) regulation) (Cannon and Nedergaard, 2004; Salmi and Ahlenius, 1998; Salmi et al., 1993). This increase in core temperature is dependent on ambient temperature, can enhance DA neurotoxicity (Bowyer et al., 1994), and/or can result in death (Ishigami et al., 2003). In previous research we found that the timing of METH's effects on core temperature depends on dose. At 1.0 mg/kg, METHinduced hyperthermia at 60 min post-treatment while at 5.0 mg/kg, hyperthermia peaked at 180 min (at 24 °C ambient temperature). At 10.0 mg/kg the response shifted left again, peaking at 60 min, but maintained elevation up to 360 min post-treatment (Myles et al., 2008). In addition to the temperature and neurotoxic effects of METH, it is well established that stimulants such as METH and AMPH induce locomotor and stereotypic movements in rodents; these movements are mediated by DA release in the nucleus accumbens and striatum respectively (Kelly et al., 1975). The expression of these behavioral effects depends on time after administration, as well as dose of drug (Bachand et al., 2009; Schiorring, 1979; Segal and Kuczenski, 1987; Segal et al., 2005; Wolgin and Kinney, 1992). For example, low doses of AMPH (0.5 mg/kg) induce locomotion that peaks at 30 min post-injection. At higher doses (4.0–5.0 mg/kg) a shortened locomotor phase is replaced by focused stereotypic head and mouth movements. As drug levels decline, locomotor behavior reappears (Kuczenski and Segal, 1999). Exercise alone (in the non-drugged state) results in increased core temperature (Kenny et al., 2003; Rodrigues et al., 2008; Staib et al., 2009; Wilkins et al., 2004); therefore, the increased movement associated with METH exposure, may itself contribute to METH-induced increases in core temperature. Since both behavioral activation and changes in core temperature demonstrate different temporal patterns with different doses of METH, we were interested in the temporal relationship between these variables. Several reports demonstrated a relationship between the hyperthermia and behavioral activation induced by METH, with the peak of behavioral activation either paralleling or preceding the temperature increase by 20–30 min (Crean et al., 2007; Yoshida et al., 1993). Increased behavioral activation and core temperature, however, were not always clearly linked after stimulant treatment. For example Crean et al. (2006) tested rhesus monkeys in the low dose range of 0.1–1.0 mg/ kg and found an increase in temperature with all doses, but activity only increased at the 0.32 dose. On the other hand, using a multiple-injection METH regimen (5.0 mg/kg, 4 times, 2 h intervals), Fantegrossi et al. (2008), reported a non-significant and delayed temperature effect in mice with a 5.0 mg/kg METH dose, while locomotor behavior was increased immediately and remained high throughout the test session. Finally Borbely et al. (1974) showed that AMPHinduced hyperthermia occurred in curarized rats; and AMPH-induced hypothermia (at cold ambient temperatures) occurred in the presence of behavioral activation (Yehuda and Kastin, 1980; Yehuda et al., 1980).

From the findings summarized above, it can be seen that 1.) METH induces hyperthermia (Bowyer et al., 1994; Myles et al., 2008); 2.) movement alone (in the non-drug state) induces heat production (Kenny et al., 2003; Rodrigues et al., 2008 , Staib et al., 2009; Wilkins et al., 2004); 3.) stimulants induce behavioral activation (Bachand et al., 2009; Schiorring, 1979; Segal and Kuczenski, 1987; Segal et al., 2005; Wolgin and Kinney, 1992); 4.) the timing and duration of the stimulantinduced locomotion vs. focused stereotypy are dosedependent (Kuczenski and Segal, 1999); and 5.) the timing of METH-induced temperature change is also dose-dependent (Myles et al., 2008). Based on these outcomes, our first purpose was to study the temporal relationship between movement and core temperature after METH treatment. If behavioral activation (or a specific subcomponent) and hyperthermia are predictably linked to each other over time, this outcome would suggest a contribution from movement to METH-induced hyperthermia. The second purpose was to focus on METH-induced hyperthermia, and clarify the relationship between the dose of METH and the temporal response of METH-induced hyperthermia at 24 °C ambient temperature. As noted above, the 60 min response was dominated by hyperthermia at 1.0 and 10.0 mg/kg, but not at 5.0 mg/kg METH (Myles et al., 2008). We wanted to clarify the timing of the temperature response to METH in the intervening doses, and determine whether the suppression of hyperthermia with 5.0 mg/kg METH at 60 min post-treatment was unique, or part of an orderly doseresponse relationship. In the present report, we analyzed locomotion, rearing, and focused stereotypic responding (using an eleven point scale) in relation to temperature changes after 0.5–10.0 mg/kg METH treatment. We chose this dose range for several reasons. First, we wanted to build on our previous findings with 1.0, 5.0 and 10.0 mg/kg regarding the timing of hyperthermia (see above). Second, humans who abuse METH escalate their consumption over time, and may consume as much as 0.7–1.0 g/day by self-administering throughout the day (Cho and Melega, 2002); researchers emulating the abuse patterns in humans have developed different paradigms using escalating doses from 0.1 to 4.0 mg/kg (O'Neil et al., 2006), and/or administering multiple injections of a single dose at 2 h intervals, e.g., 10.0 mg/kg 4 times (Johnson-Davis et al., 2003). We therefore studied the effects of both low and high doses of METH on core temperature and spontaneous behavior. Third, we were interested in studying the relationship between the full range of behavioral and temperature responses induced by METH, which again suggests the need for a large range of doses. Finally, to avoid ambiguity following multiple injection regimens (e.g., 4 injections at 2 h intervals) we chose a single injection paradigm. This allowed us to accurately track the temporal pattern of the temperature and behavioral responses to METH. After a systematic study of the relationship between core temperature and behavioral response, we can apply this information to the study of chronic exposure and high-dose neurotoxic regimens. We hypothesized that both temperature and behavior would increase with all doses of METH at 24 °C ambient temperature. Since the pattern of behavioral activation changes from whole body movements to focused stereotypy

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as the dose of METH increases, it was expected that all components of the behavioral response would be related to METH-induced hyperthermia. However, since the timing of the temperature response was delayed at the 5.0 mg/kg dose in prior work (Myles et al., 2008), the expectation of the behavioral activation/temperature relationship was weakened.

Rats were treated with saline, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, or 5.0 mg/kg METH in an ambient temperature of 24 °C.

2.0 mg/kg

Saline Temperature

12

4 37.0

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Experiment 1

Rating Score

2.1.

Rating Score

Results

Temperature

There were significant main effects of dose [F(7,64) = 2.8, p < 0.05] and time after treatment [F(11,704) = 31.7, p < 0.0001]; the interaction was also significant [F(77,704) = 6.0, p < 0.0001]. See Fig. 1 and Table 1. Post hoc analysis indicated the following. At 0.5 mg/kg, core temperature was significantly increased above saline 45–60 min post-treatment. At 1.0 mg/ kg, core temperature was significantly increased at 45– 120 min post-treatment; at 1.5 mg/kg, the significant increase occurred at 105–120 min; at 2.0 mg/kg, the significant temperature increase occurred at 90–120 min post-treatment; at 3.0 mg/kg, the temperature increase was significant at 105– 180 min post-treatment; at 4.0 the significant increase occurred at 120–240 min; and at 5.0 mg/kg temperature was significantly increased at 105–240 min.

Rating Score

2.

2.1.1.

Minutes

Fig. 1 – Core body temperature and behavioral rating score (mean ± SEM) of rats treated with saline or METH: 0.5–5.0 mg/kg. METH was administered at time 0. Behavioral rating scale ranged from 0 (quiet awake) to 10 (focused licking or biting). Each animal received only one dose of METH. N = 9/treatment group.

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Table 1 – Relationship between METH-induced changes in core temperature and behavioral activation: time course of significant effects. Treatment Saline 0.5 mg/kg 1.0 1.5 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

15 min

30 min

45 min

60 min

75 min

90 min

105 min

120 min

180 min

240 min

300 min

B

B B B B B B B B B B B B

TB TB B B B B B B B B B TB

TB TB B B B B B B TB TB B TB

TB B B B B T#B B TB TB TB TB

TB B TB B B T#B TB TB TB TB TB

TB TB TB TB B TB TB TB TB TB TB

T TB TB TB TB TB TB TB TB TB TB

TB TB TB TB TB TB TB TB

T T T T TB TB TB

T B TB

B B B B B*

T = temperature of METH treated animals was different from saline treated animals, same time interval. B = behavioral activation of METH treated animals was different from saline treated animals, same time interval. T# = temperature; not significant in experiment 1 (0.5–5.0 mg/kg METH dose range), but significant in experiment 2 (5.0–10.0 mg/kg METH dose range). B* = behavior; significant in experiment 1 (0.5–5.0 mg/kg METH dose range) but not significant at this time period in experiment 2 (5.0–10.0 mg/kg METH dose range).

2.1.2.

Behavior (0–10 rating scores)

At time 0 there were no significant differences. Behavioral activation was significantly altered at 15 min [H(7) = 28.9, p < 0.0005], 30 min [H(7) = 42.1, p < 0.0001], 45 min [H(7) = 42.5, p < 0.0001], 60 min [H(7) = 51.7, p < 0.0001], 75 min [H(7) = 51.5, p < 0.0001], 90 min [H(7) = 53.4, p < 0.0001], 105 min [H(7) = 58.1, p < 0.0001], 120 min [H(7) = 58.2, p < 0.0001], 180 min [H(7) = 56.6, p < 0.0001], and at 240 min post-treatment [H(7) = 19.6, p < 0.01]. At time 300 min there were no significant differences. See Fig. 1 and Table 1. Post hoc analysis indicated the following. For the 0.5 mg/kg dose, METH-induced behavior was significantly increased above saline at 15–60 min; for 1.0 mg/kg METH, at 30–105 min; for 1.5 mg/kg, at 15–120 min; for 2.0 mg/kg, at 15– 120 min; for 3.0, 4.0, and 5.0 mg/kg, METH-induced behavior was significantly increased above saline at 15–180 min. In order to determine if behavioral topography would clarify the relationship between activation and temperature changes, we grouped the behavioral rating scale into three categories associated with drug-induced activation. The “low” category included the behavioral scores of 3–5 and included locomotion (with or without sniffing) and rearing (with or without sniffing). The “medium” category, 6–8, included rearing with sniffing, but without locomotion; sniffing and the focus of the head movements became narrower and more intense as the scale increased; 8 is an infrequent behavior that appeared with higher doses and is defined by the animal slowly crawling on its belly with sniffing. The “high” category, 9–10, included focused sniffing (more focused than the medium range) in the absence of locomotion or crawling; also in this category were licking or biting. See Fig. 2. A descriptive analysis indicates that for 0.5 mg/kg METH the low category predominated; at 1.0 mg/kg the low and medium categories were equally represented. For doses 1.5–3.0 mg/kg the medium category predominated; for the 4.0 mg/kg dose the medium category was still dominant, but the high category began to make a notable contribution to the behavioral response. At 5.0 mg/kg METH, the high category dominated during the first half of the session, and the medium category dominated in the latter half of the session.

2.2.

Experiment 2

Rats were treated with saline, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 mg/kg METH in an ambient temperature of 24 °C.

2.2.1.

Temperature

There were significant main effects of dose [F(6,41) = 4.2, p < 0.005] and time after treatment [F(11,451) = 39.3, p < 0.0001]; the interaction was also significant [F(66,451) = 4.0, p < 0.0001]. See Fig. 3 and Table 1. Post hoc analysis indicated the following. For 5.0 mg/kg, METH treatment resulted in significant hyperthermia compared to saline, at 75–240 min; for 6.0 mg/kg METH significant temperature increases occurred at 90–240 min; for 7.0 mg/kg, significant temperature increases occurred at 60–240 min; for 8.0 mg/kg, at 60–300 min; for 9.0 mg/kg, at 75–240 min; for 10 mg/kg METH, significant increases in temperature occurred at 45–300 min post-treatment.

2.2.2.

Behavior

At time 0, there were no group differences. Behavioral activation was not altered at 15 min but showed a borderline level of significance [H(6) = 11.9, p = 0.064]. Behavioral activation was significantly altered (relative to saline) at 30 min [H(6) = 23.4, p < 0.001], 45 min [H(6) = 27.7, p < 0.001], 60 min [H(6) = 26.6, p < 0.001], 75 min [H(6) = 27.4, p < 0.001], 90 min [H(6) = 25.5, p < 0.001], 105 min [H(6) = 32, p < 0.0001], 120 min [H(6) = 25.9, p < 0.001], 180 min [H(6) = 28.5, p < 0.001], 240 min [H(6) = 24.4, p < 0.001], and at 300 min [H(6) = 22.1, p < 0.005]. See Fig. 3 and Table 1. Post hoc analysis indicated the following. For 5.0, 6.0, and 7.0 mg/kg METH, behavioral activation was significantly increased from 30 through 180 min post-treatment. For 8.0 mg/kg METH, behavioral activation was significantly increased from 30 through 240 min. For 9.0 and 10.0 mg/kg METH, behavioral activation was significantly increased from 30 min through the end of the session at 300 min post-treatment. Similar to experiment 1, we grouped the behavioral scale into scores of 3–5 (low), 6–8 (medium), and 9–10 (high) to determine if behavioral topography would clarify the

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2.0 mg/kg Temperature Beh 3,4,5 Beh 6,7,8 Beh 9,10

Minute

Fig. 2 – Core body temperature (mean) and subcomponents of the behavioral rating score of rats treated with saline or METH: 0.5–5.0 mg/kg. Behavior rating is presented in terms of the number of animals exhibiting the 3–4–5 category (low), 6–7–8 category (medium), or 9–10 category (high) at each 15 min interval. N = 9/treatment group.

relationship between activation and temperature changes. See Fig. 4. A descriptive analysis indicates that for 5.0 mg/kg METH, the medium category predominated; for 6.0–10.0 mg/kg a pattern developed in which the medium category predominated during the early and late segments of the posttreatment period, with the high category dominating in the middle of the post-treatment period (near the 2 h mark). The one exception to this progression is 9.0 mg/kg METH, in which the medium category predominated throughout.

2.3. Relationship between temperature and behavioral activation To statistically analyze the relationship between behavior and temperature, we combined the data from experiments 1 and 2 and performed correlational analyses (Kendall's tau) at

specific intervals during the 0–300 min post-treatment period. As can be seen from Table 2, the strongest relationship exists at 180 min post-treatment (correlation coefficient = 0.598). Other significant relationships were found at 30, 120, 240 and 300 min post-treatment (correlation coefficient = − 0.158, 0.334, 0.562, and 0.421 respectively).

3.

Discussion

Rats were treated with saline or METH (dose range of 0.5–10.0 mg/kg) and telemetric core temperature measurements were made for 5 h post-treatment in an ambient temperature of 24 °C. Spontaneous behavior was also measured using an 11 point scale from 0 (quiet awake) to 10 (focused licking or biting).

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8.0 mg/kg

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Fig. 3 – Core body temperature and behavioral rating score (mean ± SEM) of rats treated with saline or METH: 5.0–10.0 mg/kg. METH was administered at time 0. Behavioral rating scale ranged from 0 (quiet awake) to 10 (focused sniffing or biting). Each animal received only one dose of METH. N = 6 for the 5.0 mg/kg dose; N = 7 for all other doses.

3.1.

Temperature

1.0 mg/kg METH resulted in a peak increase in temperature at 60 min post-treatment (onset 45 min), 5.0 mg/kg METH peaked at 165–180 min (onset 75–105 min), and 10.0 mg/kg METH significantly increased temperature from 45 to 300 min posttreatment. These findings are consistent with our prior work (Myles et al., 2008). In a comparison between the effects of 5.0 mg/kg it can be seen that the onset of hyperthermia was at 105 min in experiment 1 and 75 min in experiment 2; offset was 240 min for both. The reason for this discrepancy in onset

is not clear, but may reflect variation in uncontrolled factors across experiments (e.g., humidity, subject factors, etc.). The intervening doses between 1.0 and 5.0 resulted in a gradual delay in onset times such that the onset of hyperthermia for the 2.0 mg/kg dose occurred at 90 min, and for the 4.0 mg/kg dose, at 120 min. The doses between 5.0 and 10.0 mg/kg maintained their late hyperthermia; however, the onset of hyperthermia began to shift left, with the 6.0 mg/kg dose showing its first hyperthermic response at 90 min, the 7.0 and 8.0 mg/kg doses significantly increased at 60 min, and 10.0 mg/kg at 45 min. See Table 1, and Figs. 1 and 3. Although

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Saline

4 2

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38.0

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8.0 mg/kg METH

temperature Beh 3, 4,5 Beh 6,7,8 Beh 9,10

-2

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7.0 mg/kg METH

Degrees C

6 38.0

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37.0

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8

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Minutes Fig. 4 – Core body temperature (mean) and subcomponents of the behavioral rating score of rats treated with saline or METH: 5.0–10.0 mg/kg. Behavior rating is presented in terms of the number of animals exhibiting the 3–4–5 category (low), 6–7–8 category (medium), or 9–10 category (high) at each 15 min interval. N = 6 for the 5.0 mg/kg dose; N = 7 for all other doses.

Table 2 – Relationship between METH-induced changes in core temperature and behavioral activation.

Correlation coefficient P value

0 min

30 min

60 min

120 min

180 min

240 min

300 min

0.028 ns

−0.158 0.018

0.078 ns

0.334 0.000

0.598 0.000

0.562 0.000

0.421 0.000

All 11 behavioral categories (0–10) were included in this analysis, and data from experiment 1 and experiment 2 combined. The strongest relationship between METH-induced core temperature changes and behavioral activation occurred at 180 and 240 min after treatment.

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several doses diverged from the pattern (1.5 and 9.0 mg/kg), these findings demonstrated a systematic progression at 24 °C: as the dose of METH increased from 0.5 to 4.0 mg/kg, the onset of hyperthermia was delayed; as the dose increased further, the delay was eliminated in a dose-dependent manner. In prior research we suggested a two-phase temperature response to METH: a flexible phase 1 was hyperthermic or hypothermic depending on factors such as ambient temperature. It peaked around 60 min post-treatment. Phase 2 was hyperthermic, and less responsive to ambient temperature; it peaked around 180 min post-treatment. For a given dose (5.0 mg/kg) peak 1 was not present under certain conditions (24 °C ambient temperature), but was present at other conditions (28° ambient temperature) (Myles et al., 2008). The apparent delay with changing doses may reflect simultaneous hypothermic and hyperthermic mechanisms competing with each other during phase 1 (Myles et al., 2008; Rusyniak et al., 2007); as dose of METH was increased, perhaps the influence of these two mechanisms changed, resulting in the pattern of hyperthermia onset seen in this report.

3.2.

Behavior

In contrast to the pattern demonstrated by core temperature, METH-induced increases in behavioral activation were consistently seen at 15–30 min post-treatment. Increasing doses led to a longer duration response: 0.5 mg/kg was different from saline at 15–60 min post-treatment while 10.0 mg/kg METH was different from saline from 30 min to the end of the session (300 min post-treatment). Note that the analysis of the lower dose experiment resulted in significant behavioral increases at 15 min, while the higher dose experiment did not show increases until 30 min. At 15 min post-treatment in the higher dose group, the p value was borderline (P = 0.06). The reason for this discrepancy is unclear, but may be related to a.) the difference in sample size (low-dose experiment: N = 9; highdose experiment: N = 6/7); or b.) a transient increase in behavioral activation in the saline group from experiment 2 at 15 min post-treatment (see Fig. 3); the activation declined thereafter, suggesting it was an artifact of the injection itself. This artifact may have decreased the difference between doses of METH and saline at the 15 min time point.

3.3. Possible causes of METH-induced increases in hyperthermia METH causes an increased release of DA, NE, and 5HT. All three monoamines have a role in temperature regulation in the CNS and PNS (Cannon and Nedergaard, 2004; Salmi and Ahlenius, 1998; Salmi et al., 1993), and therefore play roles in METH-induced hyperthermia (for example see Bowyer et al. (1994), Mantegazza et al. (1970) and Rusyniak et al. (2008)). As noted above, METH also induces an increase in behavioral activation. It is known that exercise in drug-free organisms induces hyperthermia; ATP is required to maintain muscle contractions (Constable et al., 1987) and heat is generated in the process of ATP production through both aerobic and anaerobic metabolisms (Krustrup et al., 2003). Rodrigues et al. (2008) and Staib et al. (2009) measured core temperature in rats running forced treadmills. In both cases the animals were habituated to

the treadmill for five days prior to the experimental procedures. Rodrigues et al. (2008) reported a 1.5 °C increase after 50 min of treadmill activity at 23 °C ambient (20 m/min with an incline of 5%), and Staib et al. (2009) reported a 3.2° increase after 60 min of treadmill activity at 22 °C ambient temperature. It should be noted that the increased core temperature resulting from treadmill activity in the rodent may also be attributed to an enhanced stress-induced sympathetic activation due to the forced nature of the task (Kiyatkin and Wise, 2001); however, the habituation periods may have mitigated against this. In humans, core temperature increased by 1.3° after 60 min of cycling, in 23 °C ambient temperature (Wilkins et al., 2004), and by 0.5° after 15 min of bilateral knee extensions at 22 °C (Kenny et al., 2003). The increased heat generation from behavioral activation, therefore, may also contribute to METH-induced increases in core temperature.

3.4. The role of movement in METH-induced increases in core temperature In order to investigate this question, we studied the temporal relationship between METH-induced changes in core temperature and behavioral activation. Several previous investigators looked at stimulant-induced hyperthermia and behavioral activation at the same time, focusing on locomotor activity. Yoshida et al. (1993) testing 1.0 mg/kg METH (i.p.), found that locomotor activity peaked 30 min and temperature peaked 50 min post-treatment. In the rhesus monkey after oral administration, onset of METH-induced hyperthermia occurred at 30–40 min post-treatment and was maintained for 5 h post-treatment; behavioral activation (reported in 1 h blocks) was increased during the first 4 h post-treatment (Crean et al., 2007), suggesting a parallel increase in the two variables. Intracranial injections of 50 ug METH resulted in similar onset times for behavioral activation (10 min posttreatment) and temperature increases (5 min), with the peak behavioral response preceding the peak temperature response by approximately 30 min (20 min vs. 50 min). These reports indicate that a temporal relationship between METH-induced hyperthermia and behavioral activation exists, with the peak of behavioral activation either paralleling the temperature increase or preceding temperature by 20–30 min. Not all reports, however, demonstrated a consistent relationship between temperature and behavioral activation after METH. For example, Fantegrossi et al. (2008) reported a non-significant and delayed temperature effect in mice with a 5.0 mg/kg METH dose (4 times at 2 h intervals), while locomotor behavior was increased immediately and remained high throughout the test session. At higher doses (10.0 mg/kg, 4 times) temperature was increased with each of the 4 treatments; locomotor activation was minimal, and only seen during the first METH treatment (Fantegrossi et al., 2008). The authors indicated that stereotypy replaced the locomotor activity but this response was not quantified. By studying a range of METH doses, and the progression of behavioral change from locomotion to focused stereotypy, we demonstrated that the change in temporal relationship between core temperature and behavioral activation after METH administration is dependent on dose. Table 1 best illustrates the overall relationship between METH-induced

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changes in core temperature and behavior. Our low-dose results showed a small delay between behavioral activation and hyperthermia (15–30 min for 0.5 and 1.0 mg/kg). As our dose increased however, this pattern was not maintained. Between 1.0 and 4.0 mg/kg METH the interval between the onset of behavioral activation and hyperthermia increased (from a 15 min delay at 1.0 mg/kg to a 105 min delay at 4.0 mg/ kg). As our dose increased further, from 5.0 to 10.0 mg/kg METH, this gap was closed again. In an effort to clarify the temperature–behavior relationship, we investigated whether any of the subcomponents of METHinduced behavioral activation maintained a consistent temporal relationship to core temperature across doses. We grouped the behavioral ratings into 3–5 (low), 6–8 (medium), and 9–10 (high), with the lower ratings corresponding to large, whole body movements and the higher ratings corresponding to increasingly more focused head and oral movements (see the Procedure section for details). As expected (Kuczenski and Segal, 1999), locomotion predominated in the lowest dose, while rearing, and the more focused sniffing, licking and biting predominated at the higher doses. Visual inspection of Figs. 2 and 4 illustrates the relationship between the number of animals showing specific behavioral components, and core temperature at each dose. For example, at 0.5–1.0 mg/kg METH, 3–4–5 behavior (low category) peaked 30–45 min prior to the hyperthermic peak. However, at doses of 7.0, 8.0, and 10.0 mg/kg METH, 3–4–5 behavior diminished, while hyperthermia was maintained and persisted for longer intervals. A second example can be seen with 6–7– 8 behavior (medium category). At 4.0 mg/kg METH the 6–7– 8 category remained elevated from 30 to 210 min, but hyperthermia onset was delayed until 120 min; at the 7.0 mg/kg dose the 6–7–8 behavior was elevated by 15 min, than dropped at 105 min and was reinstated again from 180 to 255 min, but temperature was consistently elevated from 60 to 240 min. This first analysis suggests that there is no relationship between METH-induced changes in core temperature and behavioral subcomponents, when comparing across doses. Since there was no relationship over time between temperature and movement, we next asked whether there were specific time periods at which a strong relationship existed between temperature and behavior rating score (11 point scale). Correlational analyses (all doses were included) showed that a weak, and even negative, relationship existed for early time periods (30 min, correlation coefficient = −0.158). For later time periods, however, as temperature increased, behavioral score increased; the strongest positive relationship occurred at 180 min (correlation coefficient = 0.598). As noted above, we discussed two phases of temperature response to METH (Myles et al., 2008). Phase 1 peaks at about 60 min post-treatment. It is flexible in that the direction of temperature change is altered by factors such as ambient temperature. Phase 2 peaks at about 180 min post-treatment, and is less responsive to ambient temperature than phase 1. Because these two phases responded differently to environmental temperature, we suggested that they are mediated by different underlying mechanisms. The findings of the present report may offer some clarification regarding the role of movement in the two-phased temperature response. The correlational analysis showed a weak negative relationship between temperature and movement during phase 1, and a

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strong positive relationship between temperature and movement during phase 2. This outcome suggests that factors other than movement influenced the temperature response during phase 1; factors, such as 1.) the direct effect of the increased monoamine release on temperature regulation and sympathetic activation, and 2.) ambient temperature. The factors in play during phase 1 may not have been present in phase 2, allowing the contribution of movement to core temperature to be unmasked. Additional research will be necessary to determine whether the contribution of movement to the phase 2 METHinduced temperature response has further support, and whether other factors, such as pharmacokinetics, contribute to the phase 2 response as well. Human METH users sometimes suffer hyperthermia, which can be lethal (Ishigami et al., 2003), and can enhance neurotoxicity (Bowyer et al., 1994). Since METH exposure induces activity, and often occurs in situations associated with elevated activity, (e.g. raves (Irvine et al., 2006; McCaughan et al., 2005; Parks and Kennedy, 2004)), understanding the contribution of increased physical activity to METH-induced hyperthermia is important. In addition to the possible role of movement in METH-induced changes in core temperature, the present data also demonstrated the importance of dose in determining the timing of the hyperthermic peak. By understanding these factors, more approaches become available for understanding and preventing the lethal or neurotoxic consequences of METH exposure.

4.

Summary

There was no consistent temporal relationship between core temperature and behavioral activation that maintained itself across doses, through the first 5 h post-METH. Behavioral activation always followed METH administration within 15– 30 min, while the onset time of hyperthermia varied, and was dose-dependent. The fact that movement and temperature patterns differed indicates that the expectation (movement and hyperthermia are related) is not overtly borne out, and that the timing of the temperature response is influenced by multiple factors. It is possible that movement always contributes to METH-induced hyperthermia; however, other stronger factors (e.g. neurotransmitter release that directly induces hypothermia or hyperthermia) may have more prominent roles and mask the contribution, particularly during the phase 1 temperature response. When different time periods were evaluated individually, the data supported the view that at early time periods nonbehavioral factors were more important in METH-induced temperature changes; however, the relationship between core temperature and behavior strengthened at later time points, suggesting a role for movement in phase 2 hyperthermia.

5.

Experimental procedures

5.1.

Animals

One hundred and twenty male Sprague Dawley rats (Harlan, Indianapolis, USA) weighing 300–325 g on arrival were used. Rats were singly housed in hanging metal stainless steel

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cages; food and water were ad lib except as described below. Light cycle was from 7:00 am to 7:00 pm. All procedures were approved by the University of Mississippi Institutional Animal Care and Use Committee.

5.2.

Apparatus

Animals were tested in individual computer-controlled environmental chambers. The ambient temperature was maintained at 24 °C during testing. Within the environmental chamber, the animals were housed in Plexiglas cages (21 cm × 17.5 cm × 16 cm). Core body temperature was measured telemetrically via an abdominal transmitter (Minimitter, model #VM-FH disc), and recorded once/minute. The system used to control ambient temperature and record core temperature was custom-built (Sabol et al., 2001).

5.3.

Drugs

(+) methamphetamine hydrochloride (Sigma, St. Lewis, MO) and saline vehicle were administered i.p. in an injection volume of 1 ml/kg; doses are expressed as salts.

5.4.

Surgery

One week after arrival, temperature transmitters were implanted into the abdomen of all rats (Mini-mitter, model #VM-FH disc). Anesthesia was ketamine (80 mg/kg) and xylazine (10 mg/kg); atropine sulfate was administered at a dose of 0.54 mg/kg. Ketoprofen (5.0 mg/kg) was administered as a post-surgical analgesic.

5.5.

Procedure

Two weeks after surgery rats were placed into the environmental chambers and tested for the effects of METH on core temperature and spontaneous behavior. Each rat was tested for one day, receiving a single dose of METH. Although each rat received only one treatment, our procedure was designed to insure that differences which might exist between test chambers would not influence the data: we rotated doses through the different test chambers, and rotated the same dose through different days. Two experiments were performed, with experiment 2 beginning after experiment 1 was completed. Doses of METH for experiment 1 were: saline, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, and 5.0 mg/kg; doses for experiment 2 were: saline, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0 mg/kg. Sessions began between 7:00 and 10:00 am, and lasted 7 h. Food and water were not available during the test session. METH was administered after collecting 2 h of baseline data.

5.5.1.

Temperature measurements

Core temperature measurements began as soon as the animals were placed in the environmental chambers, and were made telemetrically, once/minute, via abdominal probes. This procedure allowed temperature measurements without handling the rats.

immobile, looked asleep; (1) stationary activity: standing or sitting in one place; sometimes accompanied by sniffing; (2) grooming; (3) rearing: rat stood on its hind limbs and maintained that posture for most of the 10-s interval; sometimes accompanied by sniffing; (4) locomotion: whole body movements; included exploratory behavior; sometimes accompanied by rearing or sniffing, movement of all four limbs defines locomotion; (5) active sniffing: intense sniffing accompanied by locomotion, rearing, and/or turning; must have included hind limb movement; (6) intense, non-focused sniffing: intense sniffing accompanied by rearing or upperbody turning, but no hind limb movement. Non-focused sniffing was defined by sniffing while making large, unpatterned head movements; (7) focused sniffing while rearing and head weaving: head movements could be side-toside, front to back, or any repetitive movement that accompanied intense sniffing; (8) focused repetitive sniffing with crawl: animal crawled around the cage on his belly while sniffing; (9) focused repetitive sniffing, or stereotyped head movements: side-to-side, circular, or up and down head movements; no whole body locomotion, head movements were small and were directed to one location; they were continuous and occurred rapidly; (10) focused licking or biting: licking and/or biting directed towards the cage or the rat's own body/forelimbs/hindlimbs. This rating scale represents a modification of the 6 point rating scale of Wolgin and Kinney (1992).

5.6.

Data analysis

Temperature data were collected once/min; 15 consecutive min were averaged for each rat for use in data analysis. A 2way ANOVA was conducted, with a between subject factor, dose of METH, and a within subject factor, time after treatment (0, 15, 30, 45, 60, 75, 90, 105, 120, 180, 240, and 300 min post-treatment). Post hoc analyses were conducted with 1-way ANOVAs at each time point. Significant 1-way ANOVAs were followed by Newman–Keuls tests. Behavior was observed once every 15 min. To determine the effects of METH dose, Kruskal–Wallis tests were performed at the following time points (0, 15, 30, 45, 60, 75, 90, 105, 120, 180, 240, and 300 min post-treatment). Significant outcomes were followed by Mann–Whitney U with a Bonferonni correction (experiment 1: 7 comparisons, all doses of METH compared to saline; p = 0.05/7 = 0.007; experiment 2: 6 comparisons, all doses of METH compared to saline; p = 0.05/ 6 = 0.0083). In order to determine whether a relationship between core temperature and behavior existed at specific times postMETH, we conducted non-parametric correlational analyses, using Kendall's tau. To evaluate the relationship between temperature and behavior over the full range of observed responses we combined data from the low-dose and highdose experiments.

Acknowledgments 5.5.2.

Behavioral measurements

Each animal was observed for 10 s, once every 15 min. The following rating scale was used: (0) quiet awake: lying down,

The Sally McDonnell Barksdale Honors College and the College of Liberal Arts, University of Mississippi are acknowledged.

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