The effects of the ß1 antagonist, metoprolol, on methamphetamine-induced changes in core temperature in the rat.

Methamphetamine (METH) results in hyperthermia or hypothermia depending on environmental conditions. Here we studied the role of the ß1 adrenergic receptor in mediating METH's temperature effects. Core temperature measurements were made telemetrically over a 7.5h session, two days/week, in test chambers regulated at either 18°C, 24°C, or 30°C ambient temperature. Rats were treated with the ß1 antagonist metoprolol (5.0, 10.0, and 15.0mg/kg) alone (Experiment 1), or in combination with 5.0mg/kg METH (Experiment 2). In experiment 3, we combined a lower dose range of metoprolol (0.75, 1.5, and 3.0mg/kg) with 5.0mg/kg METH at 18°C and 30°C. Confirming prior findings, METH alone resulted in hyperthermia in warm (30°) and hypothermia in cool environments (18°C). Metoprolol alone induced small but significant increases in core temperature. In combination, however, metoprolol reduced METH-induced changes in core temperature. Specifically, at 30°C, 3.0, 5.0, 10.0, and 15.0mg/kg metoprolol decreased METH-induced hyperthermia; at 18°C, all six doses of metoprolol enhanced METH-induced hypothermia. Our metoprolol findings suggest that one component of METH's temperature effects involves increasing core temperature at all ambient conditions via ß1 receptors. Since ß receptors are involved in brown adipose tissue (BAT)-mediated thermogenesis, skeletal muscle-mediated thermogenesis, heart rate, and the metabolism of glucose and lipids, we discuss each of these as possible mechanisms for metoprolol's effects on METH-induced changes in core temperature.

Methamphetamine and core temperature in the rat: ambient temperature, dose, and the effect of a D2 receptor blocker.

RATIONALE: Methamphetamine (METH) induces hyperthermia in warm and hypothermia in cool environments. Our first goal was to further study the role of ambient temperature in METH's effect on core temperature in rats. Previously, these effects were primarily demonstrated in high doses; we extended this investigation to the low-dose range (1 mg/kg METH). Our second goal was to identify the role of the D2 receptor in METH's effects in cool ambient temperatures. METHOD: Rats received METH (saline, 1, 5, and 10 mg/kg), raclopride (saline, 0.3, 0.6, and 1.2 mg/kg), or a combination (all doses of raclopride combined with 10 mg/kg METH). Treatments occurred in ambient temperatures of 18, 24, or 30 °C. RESULTS AND CONCLUSIONS: Consistent with prior research, 5 and 10 mg/kg METH caused hyperthermia or hypothermia in a dose- and ambient temperature-dependent manner (60 min after METH). In contrast, 1 mg/kg produced similar levels of hyperthermia at all ambient temperatures. These findings suggest that a threshold METH dose exists; below this dose, METH still changes core temperature, but CNS control over temperature regulation is left intact. In our experiments regarding D2 blockade, raclopride decreased METH-induced core temperature at 30 and 24 °C (60 min after METH), consistent with previous findings. We extended these findings by demonstrating that in a cool ambient temperature (18 °C), raclopride pretreatment also lowered the core temperature response to METH. Although the D2 receptor is known to mediate hypothermia, the combination of METH and D2 blockade suggests a complex mediation of the core temperature response, perhaps involving neurotransmitter interactions.

Relationship between methamphetamine-induced behavioral activation and hyperthermia.

Methamphetamine (METH) changes core temperature and induces behavioral activation. Behavioral activation is also known to change core temperature. The purpose of this report 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 of METH-induced hyperthermia over an extended dose range. Rats were treated with saline or METH (0.5-10.0mg/kg) in computer-controlled chambers with ambient temperature maintained at 24°C. Continuous telemetric core temperature measurements were made during a 7h test period. Behavioral observations were made once every 15 min using an 11-point scale ranging from 0 (quiet awake) to 10 (focused licking or biting). The onset of METH-induced 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 1.0mg/kg) and the highest (7.0, 8.0, and 10.0mg/kg) doses tested; the delay was increased between 1.0 and 4.0mg/kg METH (105 min delay at 4.0mg/kg) and then decreased again from 4.0 to 10.0mg/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 METH-induced hyperthermia.

The effects of methamphetamine on core body temperature in the rat--part 1: chronic treatment and ambient temperature.

RATIONALE: Stimulants such as methamphetamine (METH) alter core temperature in a manner that is dependent on ambient temperature and that shows tolerance after chronic use. Our objectives were to (1) determine whether tolerance to METH-induced hyperthermia was a consequence of neurotoxicity to dopamine or serotonin and (2) determine the relationship between ambient temperature and chronic treatment on the METH-induced temperature response. MATERIALS AND METHODS: Rats were treated with 1.0, 5.0, or 10.0 mg/kg METH at 24 degrees C (experiment 1) or treated with 5.0 mg/kg METH at 20 degrees C, 24 degrees C, or 28 degrees C (experiment 2). Treatment occurred for 12 days, and temperature measurements were made once per minute telemetrically during 7-h sessions in computer-regulated environments. RESULTS: Peak increases in core temperature occurred at 60 min post-treatment for the 1.0 and 10.0 mg/kg doses, and at 180 min for the 5.0 mg/kg dose. Tolerance-like effects were seen with chronic 5.0 (mixed results) and 10.0 mg/kg METH in the absence of dopamine or serotonin depletions measured 2 weeks after the completion of treatment. After 5.0 mg/kg METH, variations in ambient temperature resulted in an early flexible change in core temperature (phase 1) (hyperthermia at 28 degrees and hypothermia at 20 degrees ) and a later inflexible hyperthermia (phase 2). CONCLUSIONS: The results suggest that (1) the peak effect of different doses of METH occurs at different times (24 degrees ), (2) the diminished temperature response with chronic METH treatment was not associated with long-term dopamine and serotonin depletions, and (3) a two-phase temperature response to METH may reflect two independent mechanisms.