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Vol. 305, Issue 1, 368-374, April 2003
Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, Illinois
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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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 |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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 |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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 |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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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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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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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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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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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.
; 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.
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Acknowledgments |
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We thank David Overstreet for providing the HDS and LDS rats, Peggy Mason, Georgetta Vosmer, and Iwao Tanaka for their assistance.
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Footnotes |
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Accepted for publication December 6, 2002.
Received for publication October 3, 2002.
This study was supported by a grant from the National Institute of Mental Health (MH-11191).
DOI: 10.1124/jpet.102.045088
Address correspondence to: Andrea C. Nicholas, Department of Neurobiology, Pharmacology and Physiology, University of Chicago, 947 E. 58th Street, Chicago, IL 60637. E-mail: acnichol{at}midway.uchicago.edu
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Abbreviations |
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5-HT1A, 5-hydroxytryptamine 1A; 8-OH-DPAT, (±) 8-hydroxy-dipropylaminotetralin HBr; HDS, high 8-OH-DPAT-sensitive; LDS, low 8-OH-DPAT-sensitive; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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, P < 0.05, 
