Department of Neurobiology, Pharmacology and Physiology, University
of Chicago, Chicago, Illinois
Agonist-induced decrease in core body temperature has commonly been
used as a measure of serotonin1A (5-HT1A) receptor
sensitivity in mood disorder. The thermoregulatory basis for
5-HT1A receptor agonist-induced temperature responses in
humans and rats remains unclear. Therefore, the influence of ambient
temperature on 5-HT1A receptor-mediated decreases in core
body temperature were measured in rat lines bred for high (HDS) or low
(LDS) sensitivity to the selective 5-HT1A receptor agonist
8-hydroxy-dipropylaminotetralin (8-OH-DPAT). HDS and LDS rats were
injected with either saline, 0.25 or 0.50 mg/kg 8-OH-DPAT at ambient
temperatures of 10.5, 24, 30, or 37.5°C, and core temperature was
measured by radiotelemetry. For both lines, the thermic response to
acute 8-OH-DPAT was greatest at 10.5°C and decreased in magnitude as
ambient temperature increased to 30°C, consistent with hypothermia.
HDS rats displayed a greater hypothermic response than LDS rats at
10.5, 24, and 30°C. At 37.5°C, LDS rats showed a lethal elevation
of temperature in response to 0.50 mg/kg 8-OH-DPAT. All thermic
responses to 8-OH-DPAT, including the lethality, were effectively
blocked by pretreatment with the 5-HT1A receptor antagonist
WAY100635, suggesting line differences in thermoregulatory circuits
that are influenced by 5-HT1A receptor activation.
Following repeated injection of 8-OH-DPAT, the magnitude of the
hypothermic response decreased in both lines at 10.5°C, but increased
in HDS rats treated with 0.50 mg/kg 8-OH-DPAT at 30 and 37.5°C. This
pattern was reversed in HDS rats following 8-OH-DPAT challenge at
24°C, suggesting that a compensatory thermoregulatory response
accounts for changes in the hypothermic response to chronic 8-OH-DPAT.
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Introduction |
Serotonergic
dysfunction has been implicated in several human disease states
including depression and anxiety (Bell et al., 2001
). Drugs that modify
serotonergic transmission have proven to be efficacious in the
treatment of patients with mood disorder (Goodnick and Goldstein, 1998;
Gorman and Kent, 1999; Shelton and Brown, 2001). Although there are
environmental contributions to these diseases, a subset of the
population appears to be biologically or genetically predisposed,
possibly through altered sensitivity of serotonin receptor-dependent
circuitry (Peroutka, 1998; Roy et al., 1999). Physiological measures
that evince differences in the response to serotonergic drugs provide a
bridge between animal models of behavior and human disease states,
allowing for a better understanding of serotonergic function and mood
disorder (Yadid et al., 2000).
Core body temperature is influenced by serotonin 1A
(5-HT1A) receptor activation in rats and humans
and has been considered a reliable physiological measure of
5-HT1A receptor sensitivity (Lesch et al., 1990b;
Millan et al., 1993). Systemic administration of
5-HT1A receptor agonists including flesinoxan,
ipsapirone, and 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) result in a
dose-dependent decrease in body temperature that is effectively blocked
by selective 5-HT1A receptor antagonists (Cryan
et al., 1999). A blunted thermic response to
5-HT1A receptor agonists has been observed in
patients with depression and anxiety, suggesting a decrease in
5-HT1A receptor sensitivity (Lesch et al., 1992;
Meltzer and Maes, 1995; Dinan et al., 1997; Yatham et al., 1999). The
thermic response to 5-HT1A receptor activation is
easily measured and provides an important tool for understanding the
mechanisms underlying mood disorder.
It remains unclear whether the 5-HT1A receptor
agonist-induced decrease in core body temperature reflects a
hypothermic event or a decrease in temperature set point (Oerther,
2000; Zuideveld et al., 2001). Under normal conditions, cool
environments activate cold sensitive cutaneous thermoreceptors,
resulting in the activation of set point pathways that produce heat
conservation and thermogenesis, thereby returning core temperature to
set point values. Similarly, hot environments result in the activation
of pathways that promote heat loss (Nagashima et al., 2000). A lowered
set point would cause heat loss in an animal with a natural resting
core temperature of 37.5°C, until core temperature reached the
lowered set point values of, for example, 35°C (Gordon, 1993).
Therefore, if 8-OH-DPAT lowers temperature set point, then a smaller
decrease in core body temperature should be observed at cold ambient
temperatures and a greater decrease in core body temperature should be
observed at hot ambient temperatures. Following an 8-OH-DPAT-induced
decrease in set point, thermal input from skin receptors in a hot
environment would increase the drive toward set point, resulting in the
promotion of heat loss and a subsequently larger decrease in core body
temperature. Thermal input from skin receptors in a cold environment
would decrease the drive toward set point, resulting in a smaller
decrease in core body temperature (Gordon, 1993; Nagashima et al.,
2000). If, however, 8-OH-DPAT causes a hypothermic event, defined as a
decrease in core body temperature that is independent of a change in
set point, then the decrease in core body temperature would be larger
at cold ambient temperatures and smaller at hot ambient temperatures.
Our goal was to examine the effects of ambient temperature on the
8-OH-DPAT-induced core body temperature response to determine how its
magnitude changes in hot and cold environments, thereby determining
whether 8-OH-DPAT causes a decrease in temperature set point or a
hypothermic event.
To investigate possible mechanisms underlying
5-HT1A receptor dysfunction in depressed
patients, we chose to conduct our experiments in two rat lines
established through genetic selection for high or low sensitivity to
the temperature effects of 8-OH-DPAT. Bred from National Institutes of
Health heterogeneous stock rats, the low sensitivity (LDS) line
displays a blunted decrease in core body temperature in response to
subcutaneous (s.c) injection of 8-OH-DPAT, whereas the high sensitivity
(HDS) line exhibits an enhanced decrease in core body temperature
(Overstreet et al., 1994, 1996). These stable lines provide a valuable
tool for studying drug responses in relation to genetic variability of
sensitivity in pathways influenced by 5-HT1A
receptor activation, as determined by the thermic response to
5-HT1A receptor agonists.
In the following study we analyzed the HDS and LDS rat lines using core
body temperature measures of 5-HT1A receptor
pathway activation to better characterize these lines as possible
animal models of mood disorder. The decrease in core body temperature provides a clear quantifiable measure that is easier to interpret than
the outcome of tests designed to measure rat equivalents of human mood
states. 8-OH-DPAT was administered to HDS and LDS lines at four
different ambient temperatures to define whether the temperature
response represents hypothermia or a change in temperature set point.
This physiological response was measured in response to acute and
chronic treatment with 8-OH-DPAT to determine whether line differences
exist, and how HDS and LDS rats adapt to repeated treatment.
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Materials and Methods |
Animals.
Selectively bred male HDS and LDS rats were
obtained from the University of North Carolina's Center for Alcohol
Studies. The breeding protocol and description of the initial rat stock
have been described in detail (Overstreet et al., 1994, 1996; Knapp et
al., 2000). Briefly, these lines were established by selectively breeding National Institutes of Health heterogeneous stock rats using a
within-family procedure. From the initial population, 10 males and
females with the largest hypothermic response to 8-OH-DPAT (0.5 mg/kg
s.c.) were randomly mated to establish the HDS group. Similarly, 10 males and females with the smallest response to 8-OH-DPAT were randomly
mated to establish the LDS line. The most and least hypothermic male
and female from each of the 10 litters were then selected. By the
fourth generation, HDS and LDS rats differed significantly in
hypothermic response from their parental means. Line differences in
hypothermic response to 8-OH-DPAT were stable by generation nine, with
HDS rats showing an average decrease of 4.0°C and LDS rats showing a
decrease of 0.6°C in response to 0.25 mg/kg 8-OH-DPAT. HDS and LDS
rats from generations 15-17 were used for these experiments. Rats were
shipped in standard plastic Taconic shipping cartons (Petersburgh, NY),
four rats per box, with food, apples, and liquid gel (for fluid). HDS
and LDS rats were matched for age and weight. All rats weighed 300 to
450 g and were housed two per cage upon arrival, under standard laboratory conditions (constant temperature of 23 ± 1°C and
relative humidity of 40-60%; 12-h light/dark cycle with lights on at
7:00 AM).
Temperature Measurement.
Radio transmitters (resolution of
0.01°C; Minimitters, Sun River, OR) were implanted into the
peritoneal cavity of anesthetized rats (ketamine 1 ml/kg and xylazine
0.33 ml/kg) (Balcells-Olivero et al., 1998). Following surgery, all
rats were housed singly. After a 7-day recovery period, the core
temperatures of HDS (n = 48) and LDS (n = 48) rats were measured noninvasively by radiotelemetry. Temperature
box chambers that allowed ambient temperature to be controlled to
within ± 0.1°C were used to examine the effects of
environmental temperature on drug response (Malberg and Seiden, 1998).
On the day of experimentation, rats were placed into temperature chambers maintained at 10.5 (cool), 24 (neutral), 30 (warm), or 37.5°C (hot). After a 25-min acclimation period, individual rats were
briefly removed, injected, and returned to their temperature boxes. Rat
core body temperatures were continuously recorded, before and after
injection, and averaged each minute for a 1.5- to 5-h period. All rats
received 0.9% saline on the 1st day. On the subsequent 14 days, rats
received 0.5 mg/kg or 0.25 mg/kg s.c. 8-OH-DPAT (Research Biochemicals
International, Natick, MA). On days 7 and 14 of 8-OH-DPAT treatment,
all groups were injected with 8-OH-DPAT at a neutral ambient
temperature. The 0.25 (low) and 0.5 (high) mg/kg doses of 8-OH-DPAT
were chosen for these studies because they cause significant decreases
in core temperature compared with saline for both HDS and LDS rat lines
at room temperature (Overstreet et al., 1994, 1996). On day 15, rats
were pretreated with 0.1 mg/kg s.c. of the selective
5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; gift from Wyeth-Ayerst, Princeton, NJ) 25 to 27 min
before treatment with 8-OH-DPAT at cool, neutral, warm, or hot ambient
temperatures. Due to unexpected lethality in response to 8-OH-DPAT,
chronic studies for low- and high-dose 8-OH-DPAT were not run for LDS
rats at a hot ambient temperature. Therefore, a group of naïve
LDS rats, was pretreated with WAY100635 (0.1 mg/kg s.c.) 25 to 27 min
before receiving an acute injection of 8-OH-DPAT (0.5 mg/kg s.c.) at a
hot ambient temperature.
Data Analysis.
For all experiments, the 1st minute core
temperature, preinjection, and postinjection change in core body
temperature were determined. For each rat, the preinjection change in
core body temperature was defined as the difference between the 1st
minute temperature and the temperature taken 1 min prior to injection. For each rat, the postinjection change in core body temperatures was
defined as the difference between the maximal and minimal core body
temperature within 60 min postinjection. The core temperature values
for each data set were averaged for each combination of line,
treatment, and ambient temperature and analyzed using three-way repeated measures analysis of variance. In case of significance (P < 0.05), post hoc comparisons were analyzed using
Fisher's protected least significant difference and Bonferroni
adjustment when appropriate. Analysis was run using StatView
statistical software by SAS (Cary, NC).
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Results |
Influence of Ambient Temperature on the Core Body Temperature
following Saline Injection.
HDS and LDS rats were treated with
acute saline at cool (10.5°C), neutral(23°C), warm(30°C), or hot
(37.5°C) ambient temperatures, and core body temperature responses
were recorded by radiotelemetry (Fig. 1).
No line differences were observed in the 25- to 27-min preinjection
time period. There was no significant difference between the change in
core body temperature measured during the preinjection period for HDS
(Fig. 1B) or LDS (Fig. 1A) rats at a cool, neutral, or warm ambient
temperature. At a hot ambient temperature, a significant increase in
preinjection core body temperature was observed in both lines. The mean
change in core body temperature was 1.3 ± 0.2°C for HDS and
1.3 ± 0.1°C for LDS rats.
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Fig. 1.
Influence of ambient temperature on core body
temperature response to saline and 8-OH-DPAT for LDS and HDS rats. The
graphs show thermal responses to saline or acute low (0.25 mg/kg) dose
8-OH-DPAT for LDS (A) and HDS (B) rats treated at cool, neutral, warm,
or hot ambient temperatures. The arrow represents the time of
injection. Data points represent the mean ± S.E.M. for
n = 6. Response data are given in 10-min
intervals.
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Following saline injection, HDS and LDS rats maintained their core body
temperature at all ambient temperatures to within 1°C of their core
body temperature at the time of injection. No line differences in core
body temperature were observed following saline injection at any
ambient temperature.
Effects of Acute 8-OH-DPAT.
Following acute saline
experiments, HDS and LDS rats were treated with low- or high-dose
8-OH-DPAT at cool, neutral, warm, or hot ambient temperatures (Fig. 1).
The change in core body temperature was defined as the difference
between the highest and lowest temperature recorded following
injection of 8-OH-DPAT (Fig. 2).
There was an overall significant effect of line (P < 0.001), ambient temperature (P < 0.001), and dose
(P < 0.05). On day 1 of treatment, HDS rats (Fig. 2, C
and D) showed a significantly larger core body temperature response
than LDS rats (Fig. 2, A and B) in all conditions (P < 0.001), except at a hot ambient temperature in response to low-dose
8-OH-DPAT.
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Fig. 2.
Influence of ambient temperature on maximal change in
core body temperature on days 1, 6, and 13 of chronic treatment with
low (0.25 mg/kg)- or high (0.5 mg/kg)-dose 8-OH-DPAT; low-dose LDS (A);
high-dose LDS (B); low-dose HDS (C); high-dose HDS (D). Data bars
represent the mean ± S.E.M. for n = 5-6.
*, P < 0.05, **, P < 0.01, ***, P < 0.001, different from
Neutral.  , P < 0.05, , P < 0.01, , P < 0.001, different from
treatment day 1.
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The change in core temperature for HDS rats on day 1 was greatest at a
cool ambient temperature and decreased in magnitude at warmer ambient
temperatures (Fig. 2C,D). The change in core temperature for HDS rats
treated at a neutral ambient temperature was significantly smaller than
that of HDS rats treated at a cool ambient temperature
(P < 0.001) and significantly larger than that of HDS
rats treated at warm (P < 0.001) or hot
(P < 0.001) ambient temperatures on day 1 in response
to both low- and high-dose 8-OH-DPAT. Thus, the magnitude of the
thermic response in HDS rats is highly dependent on ambient temperature
and does not follow the expected pattern for a change in hypothalamic
set point, but rather appears to be a hypothermic event.
LDS rats did not show a significant difference in the magnitude of the
8-OH-DPAT-induced decrease in core temperature for rats treated at
cool, neutral, and warm ambient temperatures (Fig. 2A,B). Following
both low- and high-dose 8-OH-PAT, a significant effect was observed for
LDS rats treated at a hot ambient temperature compared with cool,
neutral, and warm ambient temperatures (P < 0.001).
Following high-dose 8-OH-DPAT at a hot ambient temperature, LDS rats
showed an unexpected, immediate, and lethal increase in core body
temperature (Fig. 2B). Three of four rats perished within 15 min of
injection with core body temperatures of 41, 42, and 44°C.
Consequently, a second group of four LDS rats were injected with
high-dose 8-OH-DPAT and run in hot temperature boxes set to
automatically cool when core body temperatures rose to 41°C. This
rescue attempt was ineffectual and within 20 min of injection, one rat
from this study perished with a core body temperature of 42°C despite
an ambient temperature below neutral. The rats showed excessive
salivation and urination, suggesting that they were actively trying to
cool themselves. The remaining LDS rats were immediately removed from
the temperature boxes and sacrificed. LDS rats treated with low-dose
8-OH-DPAT at a hot ambient temperature did not differ in their core
temperature response from saline-treated rats or low-dose-treated HDS
rats. HDS and LDS rats showed a similar gradual increase in core
temperature following recovery from 8-OH-DPAT injection between the 4th
and 5th hour of experimentation. Unexpectedly, none of the LDS rats
treated with low-dose 8-OH-DPAT survived the full 5-h experiment at a
hot ambient temperature and were found dead in the temperature
chambers. In contrast, HDS rats that were run at the same time appeared
normal. Lethality at a hot ambient temperature was not observed for
low- or high-dose 8-OH-treated HDS rats or saline-treated HDS and LDS
rats (Fig. 2). The lethality observed in LDS rats suggests: 1) line
differences in compensatory thermoregulatory responses following
administration of 8-OH-DPAT in a hot environment and 2) some
life-sustaining process is more sensitive to the elevation of core
temperature in LDS than HDS rats.
Effects of Chronic 8-OH-DPAT.
HDS and LDS rats were treated
with chronic low- or high-dose 8-OH-DPAT at cool, neutral, warm, or hot
ambient temperatures for 13 days. An unexpected influence of ambient
temperature on the thermic response was observed in HDS
(P < 0.001) and LDS (P < 0.001) rats
following repeated treatment with 8-OH-DPAT (Fig. 2). A significant
decrease in the magnitude of the HDS thermic response to low- and
high-dose 8-OH-DPAT was observed on day 6 (P < 0.001)
and day 14 (P < 0.001) compared with day 1 of repeated injection at a cool ambient temperature (Fig. 2, C and D). At a neutral
ambient temperature, a decrease in the magnitude of the thermic
response was observed on treatment days 6 (P < 0.01) and 13 (P < 0.05) compared with day 1 in HDS rats
treated with low-dose 8-OH-DPAT (P < 0.01). No
significant change in response was observed for HDS rats treated at
warm or hot ambient temperatures. Unexpectedly, an increase in the
magnitude of the HDS thermic response to repeated injection of
high-dose 8-OH-DPAT was observed on treatment days 6 (P < 0.001) and 13 (P < 0.01) compared with day 1 for
HDS rats treated at a warm ambient temperature, as well as on treatment
days 6 (P < 0.001) and 13 (P < 0.05)
compared with day 1 for HDS rats treated at a hot ambient temperature
(Fig. 2D).
LDS rats treated with low-dose 8-OH-DPAT at a cool ambient temperature
showed a decrease in the magnitude of their thermic response on
treatment days 6 (P < 0.001) and 13 (P < 0.001) compared with day 1 (Fig. 2A). A similar decrease in the
magnitude of the thermic response on treatment days 6 (P < 0.01) and 13 (P < 0.05) compared
with day 1 was observed for LDS rats treated with high-dose 8-OH-DPAT
at a cool ambient temperature (Fig. 2B). No significant difference in
thermic response to repeated injection of high- or low-dose 8-OH-DPAT
was observed for LDS rats treated at neutral or warm ambient temperatures.
Influence of Pretreatment Ambient Temperature on Change in Core
Body Temperature following Challenge with 8-OH-DPAT at Neutral Ambient
Temperature.
HDS and LDS rats treated with chronic high-dose
8-OH-DPAT at cool, warm, or hot ambient temperatures were challenged
with 8-OH-DPAT at a neutral ambient temperature on treatment days 7 and
14. The change in core body temperature for these rats was then
compared with rats treated solely at neutral ambient temperature to
further characterize the influence of pretreatment temperature on the
thermic response to 8-OH-DPAT.
A clear effect of pretreatment ambient temperature (P = 0.02) was observed on the HDS responses to 8-OH-DPAT challenge at a
neutral ambient temperature (Fig. 3B). On
day 14, HDS rats treated at cool (P < 0.01) or neutral
(P < 0.05) ambient temperatures showed a significantly
smaller thermic response to 8-OH-DPAT than rats treated at a hot
ambient temperature. This reversal pattern suggests that changes in the
magnitude of thermic response observed at different pretreatment
ambient temperatures represent a learned thermoregulatory compensatory
change evoked by repeated exposure to cool, warm, and hot environments.
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Fig. 3.
Influence of pretreatment ambient temperature on
thermic response to high-dose 8-OH-DPAT challenge in a neutral
environment on days 7 and 14 of chronic treatment with high-dose
8-OH-DPAT. The bars for day 1 show the maximal change in core body
temperature for LDS (A) and HDS (B) rats in response to acute high-dose
8-OH-DPAT at cool, neutral, warm, and hot ambient temperatures. The
bars for day 7 and 14 show the maximal change in core body temperature
in response to challenge with high-dose 8-OH-DPAT at a neutral ambient
temperature for LDS and HDS rats pretreated at cool, warm, neutral, or
hot ambient temperatures. Data bars represent the mean ± S.E.M.
for n = 5-6. *, P < 0.05, **, P < 0.01, different from hot pretreatment
ambient temperature.
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Effect of WAY100635.
The hypothermic response to high-dose
8-OH-DPAT was blocked by the 5-HT1A antagonist
WAY100635 in HDS and LDS rats at all ambient temperatures on the day
following chronic treatment (Fig. 4).
Since chronic studies could not be completed for LDS rats at high
ambient temperatures, the thermic response to acute 8-OH-DPAT is shown
following pretreatment with WAY100635 (Fig. 4A). Following pretreatment
with WAY100635, HDS and LDS rats injected with high-dose 8-OH-DPAT did
not differ significantly from saline-treated rats in preinjection or
postinjection maximal change in core body temperature. WAY100635
effectively blocked the lethal response to acute 8-OH-DPAT observed in
LDS rats at a hot ambient temperature (Fig. 4). All LDS rats pretreated
with WAY100635 survived the hot ambient environment and did not differ
in appearance or behavior from HDS rats. This finding supports the idea
that the lethal increase in core body temperature observed in LDS rats
is caused by the action of 8-OH-DPAT on 5-HT1A
receptors.
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Fig. 4.
Pretreatment with WAY100635 antagonizes thermic
responses to 8-OH-DPAT in LDS (A) and HDS (B) rats. The graphs show the
thermic response to high (0.5 mg/kg)-dose 8-OH-DPAT (2nd arrow)
injected 25 to 27 min following pretreatment with 0.1 mg/kg WAY100635
(1st arrow). Data points represent the mean ± S.E.M. for
n = 5-6. Response data are given in 5-min
intervals.
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Discussion |
These findings suggest that the 8-OH-DPAT-induced decrease in core
body temperature is highly sensitive to ambient temperature and
represents a hypothermic event that does not involve a change in
temperature set point. The HDS and LDS rat lines differ in the
magnitude of their hypothermic responses to 8-OH-DPAT at several ambient temperatures. Administration of 8-OH-DPAT in a hot environment causes a lethal hyperthermia in the LDS, but not HDS, rat line. Ambient
temperature influences the magnitude of the thermic response following
repeated injection of 8-OH-DPAT. The changes in the hypothermic
response to 8-OH-DPAT in the HDS line, evoked by repeated injection,
may reflect a compensatory thermoregulatory response that is
independent of a change in 5-HT1A receptor sensitivity.
Baseline Thermoregulatory Function.
Naïve HDS and LDS
rats did not differ in their thermoregulatory ability to maintain core
body temperature at different ambient temperatures. Saline-treated HDS
and LDS rats displayed splayed body posture and salivation at a hot
ambient temperature, behaviors associated with heat loss (Gordon,
1993). At a cool ambient temperature, both lines displayed piloerection
and huddled body posture, behaviors associated with heat conservation
(Gordon, 1993). HDS and LDS rats maintained their core body temperature
at cool, neutral, and warm ambient temperatures. At a hot ambient
temperature, a significant increase in core body temperature that
reached a plateau within 30 min of exposure, was observed in
saline-treated HDS and LDS rats. This response was previously observed
in regular rats in a hot environment, suggesting that hot ambient
temperature challenges the ability of both HDS and LDS rats to maintain
core body temperature in a way that is similar to normal rats (Gordon, 1993).
8-OH-DPAT-Evoked Hypothermia.
A significant effect of ambient
temperature on 8-OH-DPAT-induced decrease in core body temperature,
consistent with a hypothermic event, was observed in HDS and LDS rat
lines. For both HDS and LDS rats, a cool ambient temperature enhanced
the decrease in core body temperature elicited by 8-OH-DPAT injection.
As ambient temperatures increased, the magnitude of the thermic
response to 8-OH-DPAT decreased. This was true with the exception of an unexpected and lethal increase in core body temperature in response to
high-dose 8-OH-DPAT observed in LDS rats at a hot ambient temperature. Previous studies have shown that 8-OH-DPAT causes heat loss through cutaneous vasodilation and decreased metabolism, effects that interfere
with the normal thermoregulatory responses activated by environmental
temperature (Lin et al., 1998). Cutaneous vasodilation would have a
greater cooling effect in a cold environment relative to a neutral
environment. In a hot environment, it is difficult to lose heat via
cutaneous vasodilation compared with a neutral environment. Therefore,
we would expect a cold environment to facilitate and a hot environment
to attenuate 8-OH-DPAT-induced heat loss. This explains the observed
effect of ambient temperature on 8-OH-DPAT-mediated heat loss in HDS
rats and is consistent with a hypothermic event.
The line differences observed for the thermic response to 8-OH-DPAT
could be attributable to a stronger compensatory mechanism or thermal
sensitivity to environmental temperature in the LDS compared with the
HDS rat. The blunted hypothermic response to 8-OH-DPAT and decreased
influence of cool, neutral, and warm ambient temperature observed for
LDS rats compared with HDS rats suggests that compensatory responses to
skin temperature are increased in the LDS rat. In a cool environment,
blood flow to the skin is decreased in an attempt to conserve heat
(Gordon, 1993; Nagashima et al., 2000). Cutaneous vasoconstriction in
response to a cool environment may counteract the cutaneous
vasodilation induced by 8-OH-DPAT. Therefore, if LDS rats have a
greater compensatory response to skin temperature than HDS rats, we
would expect increased cutaneous vasoconstriction in LDS rats exposed
to a cool environment, resulting in decreased 8-OH-DPAT-induced
cutaneous vasodilation and a subsequent blunted hypothermic response.
The magnitude of the line difference in the hypothermic response to
8-OH-DPAT should therefore decrease as ambient temperature increases,
which is what we have observed.
It is well established that acute treatment with 8-OH-DPAT decreases
core body temperature (Hjorth, 1985; Hutson et al., 1987; Larsson et
al., 1990; Uphouse et al., 1991; Millan et al., 1993). Therefore, it
was surprising to find that acute systemic treatment with high-dose
8-OH-DPAT at a hot ambient temperature causes a lethal increase in core
body temperature in the LDS rat line. This response is effectively
blocked by the 5-HT1A receptor antagonist WAY100635, showing that the lethality is caused by the
5-HT1A receptor agonist properties of 8-OH-DPAT.
It is possible that the hyperthermia observed in LDS rats represents an
extreme example of a rat gaining heat from the environment. At hot
ambient temperatures, cutaneous blood flow increases in an attempt to
cool body temperature. However, if ambient temperatures are extremely
hot, this increase in cutaneous blood flow is reversed to prevent a
situation in which more heat is picked up from the environment than
lost to it (Gordon, 1993). The increase in cutaneous blood flow in
response to treatment with 8-OH-DPAT would cause an initial rise in
skin temperature that, for the LDS rat in a hot environment, may result in a reversal of cutaneous blood flow and subsequent acute lethal hyperthermia. Cutaneous vasodilation in response to low-dose 8-OH-DPAT is not enough to cause immediate lethal hyperthermia in the LDS line.
The delayed lethality observed following low-dose 8-OH-DPAT may occur
as a result of physiological line differences in compensatory response
to heat exposure elicited by 5-HT1A receptor activation.
Functional Implications.
As described above, HDS rats appear
to make less compensatory thermoregulatory adjustments than LDS rats
following acute treatment with 8-OH-DPAT, perhaps because they are less
sensitive to changes in skin temperature. With repeated exposure to hot
and cool ambient temperature over days, a secondary compensatory
response to environment appears to develop in HDS rats. This is shown
as a decrease in the magnitude of 8-OH-DPAT induced hypothermia at a
cold ambient temperature and increase in the magnitude of
8-OH-DPAT-induced hypothermia at a hot ambient temperature following
chronic daily treatment. This effect of pretreatment at different
ambient temperatures is readily observed following 8-OH-DPAT challenge
at a neutral ambient temperature. HDS rats pretreated in a cool
environment show a smaller hypothermic response to 8-OH-DPAT challenge
at a neutral ambient temperature compared with HDS rats pretreated in
warm and hot environments. These results are strong evidence that the
developed compensatory response is not solely dependent on thermal
information from cutaneous receptors but reflects a central change in
the sensitivity and/or function of thermoregulatory neurons.
Furthermore, the HDS rats do not show tolerance or desensitization following 14 days of treatment with high-dose 8-OH-DPAT at a neutral ambient temperature, suggesting that the changes in response to repeated injection at cool and hot ambient temperatures do not reflect
a change in 5-HT1A receptor sensitivity to
8-OH-DPAT.
If the observed line differences in the thermic response to 8-OH-DPAT
represent differences in compensatory thermoregulatory mechanisms, then
there may not be line differences in 5-HT1A
receptor function. Similarly, the blunted thermic response to
5-HT1A receptor agonists observed in patients
with depression and panic disorder may also represent a difference in
thermoregulatory sensitivity (Lesch et al., 1990a, 1991).
Because the partial 5-HT1A agonist buspirone has
proven to be an effective anxiolytic medication, drug company research
has focused on the development of specific full
5-HT1A receptor agonists to further improve the
treatment of anxiety and as an adjunct treatment for depression.
Increasingly, emergency medical facilities are faced with cases of
hyperthermia associated with serotonin syndrome caused by the
interaction of medications prescribed for mood disorder (McGugan,
2001). Interestingly, lethal hyperthermia is known to be a leading
cause of death in patients taking monoamine oxidase inhibitors in
response to the accumulation of high levels of serotonin in the synapse
(Sporer, 1995). The decrease in core body temperature evoked by
ipsapirone, a 5-HT1A receptor agonist, is
significantly blunted in older subjects, as is the 8-OH-DPAT-induced hypothermia observed in LDS rats (Gelfin et al., 1995). The lethal hyperthermic response of LDS rats to 5-HT1A
receptor stimulation serves to caution the use of specific full
5-HT1A receptor agonists for the treatment of
anxiety and depression, especially for patients whose thermoregulatory
responses to environmental temperature are compromised by age or
disease (Epstein et al., 1997).
Pindolol, a 5-HT1A receptor antagonist, has been
effectively used to enhance the antidepressant response to selective
serotonin reuptake inhibitors (Blier, 2001). The ability of WAY100635
to block the lethal hyperthermic response to 8-OH-DPAT in the LDS line
suggests that the combined administration of
5-HT1A receptor antagonists with antidepressant
medications that enhance serotonergic transmission may provide, in
addition to rapid onset of efficacy, protection against drug-induced hyperthermia.
It is clear that drugs influencing serotonergic transmission can
perturb normal thermoregulatory responses to environmental temperature
(Wappler et al., 2001; Hojer et al., 2002; Parrott, 2002). However, the
mechanisms by which this occurs are not well understood. Further
research regarding the influence of serotonin on thermoregulatory
processes is necessary to ensure that the growing number of patients
identified with mood disorder receive safe treatment.
We thank David Overstreet for providing the HDS and LDS rats,
Peggy Mason, Georgetta Vosmer, and Iwao Tanaka for their assistance.
This study was supported by a grant from the National Institute
of Mental Health (MH-11191).
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Abstract
Introduction
