Influences of Ambient Temperature and Exercise on Stimulant-Induced Hyperthermia
G.D. Dickinson, J.U.L. Price, S.A. Davis, M.A. Taffe
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA
37.5
30
60
90
120
Minutes Post-Injection
37.0
-10
30
60
90
120
Minutes Post-Injection
-2
0
100
200
300
400
37.0
500
T otal Wheel Revolutions
30
60
90
Effect of Wheel Access and TA
43.0
21 C No Wheel
21 C Wheel
42.0
30 C No Wheel
30 C Wheel
#
Minutes Post-Injection
*
5-30
35-60
65-90
Minutes Post-Injection
300
250
225
200
175
150
125
100
75
50
275
.
Minutes Post-Injection
Veh
1.0 mg/kg MDMA
5.6 mg/kg MDMA
200
150
100
375
350
20
10
(*used developed criteria for euthanasia)
Minutes Post-Injection
A standard locomotor stimulating dose of MDMA
in rats is lethal under high ambient temperature.
Wheel running is increased by MA or MDMA
at about the same doses which increase
homecage locomotion.
Wheel does not provide a simple manipulation
of activity; homecage activity increased
when wheel is available.
50
Minutes Post-Injection
Wheel access was associated with more home cage activity.
360
330
300
270
240
210
180
150
120
90
0
60
Quarter Revolutions
0
250
30
0
10
300
10
20
275
20
30
250
30
40
225
40
30
Rectal temp is less sensitive than IP temp
to the effects of MDMA or MA.
Wheel Running
Veh
1.0 mg/kg MDMA
5.6 mg/kg MDMA
50
200
*
Veh
1.0 mg/kg MDMA
5.6 mg/kg MDMA
50
60
175
*#
*
25
0
-25
-75
-50
Core Temperature
300
275
N=8
36
150
* * *
Vehicle
1.0 mg/kg
5.6 mg/kg
60
125
Radiotelemetry confirms differences in
Methamphetamine-induced hyperthermia
across the NIH Guide recommended range
of ambient temperatures.
36.5
Differences:
Rats older, ~700 g
Some might have survived
40
When high levels of activity are produced by
MDMA, mortality is observed at low and
high ambient temperatures.
Veh
1.0 mg/kg MDMA
5.6 mg/kg MDMA
TA)
100
Minutes Post-Injection
Vehicle
1.0 mg/kg
5.6 mg/kg
TA)
75
Wheels UnLocked
50
65-90
25
35-60
0
5-30
-25
250
225
200
175
150
125
100
75
50
25
36.5
200
180
160
140
120
100
80
60
40
20
0
37.5
(magnitude of decrease w/ wheel is similar to that observed for both wheel/nowheel
#
Minutes Post-Injection
37
38
Minutes Post-Injection
-50
37.5
37.5
38.5
37
homecage
test chamber
The temperature response to MA or MDMA
depends on ambient temperature in rats.
Increased activity was associated with greater MDMA effect...on hypothermia
* *
-75
*
Homecage Activity
*
300
*
*
*
275
(1-5.6 mg/kg s.c.)
*#
#
37
39
A temperature reduction was observed at an ambient temperature that
produced no change in rectal temperature in our earlier study.
250
(1-10 mg/kg, s.c.)
38
Activity
Challenge Drugs (supplied by NIDA):
3,4-Methylenedioxymethamphetamine HCl
38.5
*
*#
39
38
0
Data Sciences International (Transoma)
38.5
-25
Radiotelemetric monitoring of intraperitoneal
temperature and spontaneous locomotor activity.
39
-50
Med Associates Model ENV-046
39.5
-75
Running wheel (35.6 cm dia) attached to housing cage
Core Temperature
Ambient Room Temperature
Veh (25
5.6 mg/kg MA (19
5.6 mg/kg MA (25
N =7
#
225
TA
40
Male Wistar rats (350 g at entry)
Methamphetamine HCl
vs
36
200
Effect of 19
Body Temperature Ave
Methods
36.5
TA)
Minutes Post-Injection
40
39.5
Veh
1.0 mg/kg MDMA
5.6 mg/kg MDMA
-75
Rectal temperature is only changed in response to 1-5.6 mg/kg MA or
MDMA, s.c.
Can access to an activity wheel model the ravedancing context in the investigation of Ecstasyinduced hyperthermia?
37
250
mg/kg s.c.
225
mg/kg s.c.
37.5
200
MDMA
175
5.6
150
3.2
125
1.0
100
5.6
MethAmp
Veh
Minutes Post-Injection
3.2
75
1.0
120
175
90
50
60
38
150
30
38.0
38.5
25
5.6 mg/kg MA 21C
125
5.6mg/kg MA 30C
0
-10
Hundt and Premack, 1963; Belke and Wagner, 1005
Veh 21C
100
37
39.0
Veh 30C
75
38
TA)
39
-25
40.0
Wheels UnLocked
50
39
*
-50
41.0
*
25
40
*
50
Gordon 1991
-70%, 20 mg/kg @
-100%, 30 mg/kg @
Discussion
MDMA-induced hypothermia
*
0
42.0
*
-50
41
N=8
-25
43.0
60
Malberg 1998- 20, 40 mg/kg @
-no reported death with cooling
-20% after 40 mg/kg
(Restoration of body temp to normal range, even for many
hours is not sufficient to ensure survival of rat.)
(Q: Locomotor time budget?)
Methamphetamine (s.c.)
TA
Homecage Activity
Access to running wheel functions as reinforcer in rats.
Effect of MA and MDMA
Core Temperature
TA
-75
Comparison of 21 vs
5.6 mg/kg
1.0 mg/kg
Vehicle
70
0
Ambient temperature is the major influence
High Ambient Temperature increases
stimulant-induced hyperthermia
42
Gold et al, 1988; McCreary et al, 1999; Stephenson et al, 1999
Minutes Post-Injection
Minutes Post-Injection
38.0
Taffe et al., 2006; Crean et al, 2006; VonHuben et al, 2007; Crean et al, 2007
The locomotor activity of rats is increased by MDMA.
120
Dramatic increases in wheel running not observed
39.0
Unrestrained rhesus monkeys exhibit hyperthermia when MDMA
or Methamphetamine is administered orally or intramuscularly
in recreational doses. Locomotor activity is suppressed by
MDMA in monkeys.
Dafters 1994; Malberg and Seiden, 1998; Myles et al, 2008
90
N=7
40.0
Gillman, 1997; Greene et al., 2003; Mallick and Bodenham, 1997
Temperature of rats is increased or decreased by MDMA
depending on ambient temperature. MA interation with
ambient temp less well established.
60
Wheel Access does not affect MA-induced
hyperthermia.
41.0
Emergency departments report elevated body temperature
in MDMA-associated mentions and fatalities.
Minutes Post-Injection
30
120
Minutes Post-Injection
data presented at CPDD Annual Meeting 2007
Introduction
120
80
-10
10 mg/kg MDMA, i.p.
TA). Wheel
access did not influence mean temperature. Rectal temp (and lethality?)
was correlated with wheel revolutions after 10 mg/kg MDMA.
90
36.0
325
5.6 mg/kg Wheel
60
0
300
5.6 NoWh
30
37.0
275
Veh Wheel
50
250
Veh NoWh
38.0
225
38.0
-1
0
39.0
100
200
0
40.0
150
175
1
50
Despite cooling at 42 C,
24 hr mortality* was 100%
41.0
150
*
39.0
100
200
125
38.0
2
5.6 mg/kg MA s.c.
100
*
*
38.5
*
40.0
3
150
42.0
1 mg/kg MA s.c.
75
39.0
*
*
*
10 mg/kg
4
5.6 mg/kg MA s.c.
200
250
50
*
*
39.5
*
*
5 mg/kg
41.0
5
43.0
Vehicle
25
*
40.0
SALINE
1 mg/kg MA s.c.
300
0
40.5
90
80
70
60
50
40
30
20
10
0
Vehicle
-25
10 mg/kg (Wheel)
A
-80
-60
-40
-20
0
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5 mg/kg (Wheel)
300
250
T )
TA)
Homecage Activity
Veh (Wheel)
TA)
A
-50
T )
10 mg/kg MDMA s.c.
-75
Effect of 5.6 mg/kg
Quarter Revolutions
10 mg/kg (No Wh)
Max Body Temp Change ( C)
5 mg/kg (No Wh)
Wheel Revolutions
41.0
Veh (No Wh)
MDMA-induced Lethality
MA-induced hyperthermia is uninfluenced by wheel access
42.0
Rectal Temperature ( C)
Human mortality from exposure to the recreationally abused drugs
methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA,
thermoregulatory distress
including malignant hyperthermia. Popular use environments such as the
nightclub setting may feature elevated ambient temperature and sustained
skeletal muscle activity which are potential risk factors for hyperthermia.
Studies were conducted to evaluate the extent to which voluntary exercise
and ambient temperature can modify the hyperthermia induced by MA and
MDMA using a rat model. Animals were challenged with acute doses of
MDMA (1-10 mg/kg) or MA (1-5.6 mg/kg) in a range of ambient temperature
noninvasively and
continuously using radiotelemetry was contrasted with rectal temperature.
Intraperitoneal body temperature was elevated by drug challenge to a
greater degree under higher ambient temperature conditions. MA and
MDMA increased wheel running without additionally elevating body
temperature. Rectal temperature was comparatively less sensitive to druginduced increases; methodological considerations are discussed. These
data suggest that elevated ambient temperature poses a greater additional
risk factor than does repetitive locomotor activity for the recreational MA or
MDMA user.
Supported by NIH Grants DA018418 and DA024705.
Background: MDMA-induced hyperthermia
is correlated with wheel running amount.
Quarter Revolutions
Abstract
When high levels of activity are produced by
MDMA, mortality is observed at low and
high ambient temperatures.