Hypothalamic Temperature Research Articles

The treatment and management of neuroleptic malignant syndrome

Gratz, Silvia S., Douglas F. Levinson and George M. Simpson. The Treatment and Management of Neuroleptic Malignant Syndrome. Prog. Neuro. Psychopharmacol. & Biol. Psychiat. 1992, 16(4):425–443. 1. 1. The neuroleptic malignant syndrome was initially described as a disorder specifically related to neuroleptic usage with frequent fatal outcome. The observations of variant or mild cases of this syndrome as well as case reports on neuroleptlc-malignant-like syndromes in the absence of neuroloptics raises the issue of the usefulness of this terminology and highlights the potential for inappropriate management of this “malignant” syndrome. It has been suggested that hypothalamic thermoregulatory responses may involve an interplay among noradrenergic, cholinergic and serotonergic pathways. Out treatment strategy is based on the pharmacology of neuroleptics and empirical data, verified in our own clinical practice and considers that it is often difficult to determine whether certain physiologic states are a consequence to or specific triggering factors. 2. 2. If a patient's temperature is less than 101, we emphasize vigorous treatment with anticholinergic agents, while simultaneously assessing the psychiatric need for neuroleptics versus medical risks. Given that the severe rigidity of NMS represents severe extrapyramidal effects of dopamine blockade, there is no reason to withhold anticholinergics in the absence of higher temperatures. Neuroleptics can be stopped at the discretion of the clinician even during circumstances when there is fever below 101. 3. 3. In cases of severe EPS with fever greater than or equal to 101, we recommend stopping neuroleptlcs, treating with anticholinergics and starting with dopamine agonists. In the event of a poor response to dopamine agonists, a brief trial of dantrolene and/or benzodiazepines is recommended. Dantrolene should not be introduced for prolonged periods, since abnormal liver function studies have been observed in approximately 1.8% of patients. 4. 4. In cases of extreme hyperpyrexia (fever greater than 103), clinicians should consider transfer to an ICU or another medical support. Extreme temperatures have been associated with potentially irreversible cerebellar or other brain damage, if not aggressively treated. If neuroleptlcs are later indicated, a 2 week interval after resolution of symptoms should be maintained before reinstituting neuroleptics. 5. 5. In patients with severe EPS without fever, we emphasize aggressive use of anticholinergic therapy, while simultaneously considering the psychiatric need for neuroleptics versus medical risks. In an cases where a patient's swallowing, respirations or physical mobility is severely compromised, we suggest stopping neuroleptlcs. Anticholinergic agents should be continued for 7 days after neuroleptics are stopped. If anticholinergic agents are unsuccessful after 2–3 dosages, dopamine agonlsts may be added, while simultaneously monitoring vital signs. It should be emphasized that severe EPS sometimes takes days to improve even after neuroleptic cessation and the addition of anticholinergics. 6. 6. If EPSs are intense or of long enough duration and, particularly, in the presence of akathisia and agitation, then a combination of excess heat production and interference with the hypothalamic temperature control mechanisms can produce a syndrome of NMS. If EPSs are avoided, neuroleptlcs are used in low dosages and benzodiazepines are used concomitantly for agitation, then we should see very little of NMS.

Effects of selective brain cooling on mechanisms of respiratory heat loss.

Experiments (n = 36) in three conscious goats were performed at 35 degrees C air temperature and low (LH) or high (HH) humidity. Prior to the experiments the animals received carotid loops and an arteriovenous shunt, which made it possible to increase the temperature of the blood flowing to head and trunk (series A), or to increase the temperature of the trunk at constant carotid blood and hypothalamic temperature (Thyp), respectively (series B). Owing to the smaller cooling power of the inspired air in HH, the slope of respiratory evaporative heat loss versus aorta blood temperature (Taor) was reduced in series A and B. In series A the slopes of respiratory minute volume (VE) and respiratory frequency (RF) versus Taor were larger in HH than in LH. The effects were caused by a reduction of selective brain cooling in HH, which resulted in higher levels of Thyp. This is concluded from the results of series B, in which Thyp was equal in LH and HH, and the slopes of VE and RF over Taor showed no differences. Thus, selective brain cooling contributes to counteract the deterioration of the gain of the respiratory heat loss mechanism, which occurs during exposure to humid air.

Induction of adrenocorticotropic hormone release by interleukin-6 in vivo and in vitro.

Recent reports show that cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and intravenously administered interleukin-6 (IL-6) stimulate adrenocorticotropic hormone (ACTH) release. Both IL-1 and TNF are known to be potent inducers of IL-6, a monokine produced by activated monocytes and folliculo-stellate cells of the pituitary gland and released from the hypothalamus. To determine the site(s) of action of IL-6 in the control of ACTH release, we injected human recombinant IL-6 into the third brain ventricle (3V) of freely moving, conscious male rats and measured ACTH by RIA. Both 0.05 pmole and 0.25 pmole doses of IL-6 were ineffective to change plasma ACTH in comparison to the values in controls. The maximal IL-6 dose tested of 1.25 pmole increased plasma ACTH within 15 min and the response lasted over 180 min. The effects of IL-6 on plasma ACTH were only partially paralleled by increased rectal temperature which suggests that hypothalamic temperature regulating centers were independent of these actions. To evaluate a possible direct effect on the pituitary, IL-6 was incubated in vitro with hemipituitaries under an atmosphere of 95% O2/5% CO2. After 1 hr of incubation IL-6 failed to cause any change in the secretion of ACTH throughout a concentration range of 10(-15) to 10(-9) M. Increased ACTH secretion into the incubation medium was found only with 10(-13) M IL-6 after a 2-hr incubation. The results support a possible role for IL-6 at both hypothalamic and/or pituitary levels to stimulate ACTH release.

Fluoxetine decreases brain temperature and REM sleep in Syrian hamsters.

The antidepressant drug, fluoxetine (FLX), a selective serotonin reuptake inhibitor, was administered to Syrian hamsters, and its acute and chronic effects on EEG sleep and hypothalamic temperature were recorded. Acute fluoxetine treatment at doses of 5, 10, 20 and 40 mg/kg decreased REM sleep and hypothalamic temperature in a dose-dependent manner. It increased NREM sleep, and, at doses of 20 and 40 mg/kg, it increased wakefulness. At 40 mg/kg, it decreased motor activity. During chronic treatment, tolerance developed to FLX's REM sleep-inhibiting effects, but tolerance did not develop to FLX's hypothalamic temperature-decreasing effects. Chronic FLX treatment produced circadian phase-dependent decreases in temperature beyond those that were observed during acute treatment. The apparent dissociation during chronic treatment between FLX's temperature-lowering effects and its REM-decreasing effects might be related to long-term changes in 5HT receptor function or FLX pharmacokinetics.

Exercise performance of normothermic and hyperthermic rats: Effect of warm rearing

1. 1.|Hypothalamic and rectal temperatures were recorded in 8 warm-reared (wr) and 12 control rats. Rats ran to exhaustion at a constant speed of 1.5 km h −1 but at a variable ambient temperature adjusted to stabilize their hypothalamic temperature at 38.0°C (normothermia) or 41.0°C (hyperthermia). Blood lactate concentrations were determined before and after exercise. 2. 2.|Exercise caused exhaustion in normothermic control rats after 62.08 ± 5.43 min and in wr rats after 29.64 ± 2.09 min. 3. 3.|Hyperthermia shortened to one half (to 12.24 ± 1.36 min) and to one fourth (to 16.15 ± 1.20 min) the endurance time in wr and control rats, respectively. 4. 4.|There were no correlations between lactate concentraion and hyperthermia or endurance time. 5. 5.|In conclusion, in rats and other animals which have safe refuges, hyperthermia interferes with the ability to continue exercising.

Shifts in the hypothalamic temperature of rats acclimated to direct internal heat load with different schedules

1. 1.|The hypothalamic temperature ( T hy) of rats was recorded every 5 min, before, during and after a 10-day period of direct internal heating (1.2 W per rat) through an i.p. electric heater at an ambient temperature of 24°C under a 12:12 h L:D cycle. 2. 2.|The rats were divided into 4 groups: the control without heat load (Cn) and heat acclimated groups with continuous heating (HC) and groups with intermittent heatings for 6 h during the last half of the dark phase (NI) or during the last half of the light phase (DI). 3. 3.|During heat load, the daily mean T hy rose in the HC but decreased in the NI, with no changes in the Cn and DI. 4. 4.|After the heating period, the T hy of the HC did not change markedly except that a transient hypothermia was observed for several hours just after terminating the heat load. 5. 5.|The mean T hy during the light and dark phases of the NI significantly decreased after the heating schedule. 6. 6.|The T hy fell markedly for about 1–h during the period of previous heating and T hy formed a characteristic trough during the dark phase. 7. 7.|No significant changes in daily mean T hy were observed in the DI and Cn. 8. 8.|These results suggest that changes in body temperature after acclimation to direct internal heat load depend on the heating schedule. 9. 9.|It is also assumed that a time memory of internal heat load is formed in rats after acclimation to intermittent heat stress.

Sleep Deprivation in the Rat: XIV. Comparison of Waking Hypothalamic and Peritoneal Temperatures

Earlier studies of rats subjected to total sleep deprivation (TSD) by the disk-over-water method had shown an initial increase in waking peritoneal temperature (T(ip)) followed by an even greater decrease as deprivation proceeded. In the present study, hypothalamic temperature (T(hy)), as well as T(ip), were recorded continuously. As in the earlier studies, TSD rats showed an increase in energy expenditure and an initial increase followed by a decrease in T(ip). Waking T(hy) showed a more prolonged initial rise and a smaller late decline than waking T(ip) Assuming that, as the literature suggests, T(hy) is held closer to temperature setpoint (TSET) than is T(ip), the present results suggest an elevated waking TSET during deprivation. T(ip) became progressively lower than T(hy) over the course of deprivation, indicating a decreased ability to maintain the whole body near TSET. This decreased ability could result from insufficient thermogenesis or excessive heat loss. Because thermogenesis rose progressively throughout deprivation, heat loss must have increased even more than heat production. Thus, the results are consistent with other data which indicate that TSD in the rat produces two opposing effects on waking temperature, an elevation of setpoint and excessive heat loss, which together increase the demand for energy expenditure.

Prostaglandin E 2 accelerates sexual behavior in male rats

Sexual behavior in male rats is accompanied by an increase in body temperature of 1°C. It has been suggested that this increase may be, at least in part, a febrile response mediated by the endogenous central release of prostaglandins of the E series (PGE). This putative release of PGE could also affect the expression of sexual behavior, a possibility that was tested in the present experiment. PGE 2 was infused into the cerebral aqueduct and sexual behavior and hypothalamic temperature were monitored. PGE 2 infusion raised hypothalamic temperature and decreased the postejaculatory interval and ejaculation latency. The exact cause of this acceleration of sexual behavior cannot as yet be determined.

Hypothalamic Cooling Elicits Eating: Differential Effects on Motivation and Pleasure

The perceived attractiveness of stimuli to humans has been modulated by changes in cephalic blood temperature. Can similar effects be produced in animals by manipulation of hypothalamic temperature? This study examined the attractiveness and pleasure of food to rats during hypothalamic cooling or hypothalamic heating, by measuring feeding and hedonic and aversive facial reactions to taste. Hypothalamic cooling administered through a permanently implanted thermode elicited feeding. Hypothalamic heating did not. Hedonic and aversive reactions to taste were unaltered by hypothalamic cooling or heating, even for rats that ate during cooling. Hypothalamic cooling may thus potentiate the attractive quality of food without modulating basic taste pleasure.

Lateral distribution of hypothalamic signals controlling thermoregulatory vasomotor activity and shivering in rats

The present study explored the laterality of central nervous thermoregulatory control in anesthetized rats by measuring paw skin vasomotor activity and cold-induced shivering in hind leg muscles during unilateral preoptic area and anterior hypothalamus (POAH) warming and electrical stimulation or during unilateral thermal stimulation of abdominal skin. Unilateral POAH warming produced vasodilation on both sides of the body, but vasodilation on the ipsilateral side always either occurred at a lower threshold hypothalamic temperature or was stronger than on the contralateral side. In a cold environment (5 degrees C), shivering was suppressed simultaneously in both hind legs when one side of the POAH was warmed, and shivering reappeared simultaneously on both sides when POAH warming stopped. These results suggest that different thermoregulatory effectors are regulated in a different way by each side of the POAH. Unilateral thermal stimulation of the abdominal skin, on the other hand, affected vasomotor activity and shivering equally on both sides of the body, as previously reported for its influence on salivary secretion. Skin thermal signals from both sides of the body therefore seem to converge before they act on different thermoregulatory effector systems.

Effect of heat acclimation on diurnal changes in body temperature and locomotor activity in rats.

1. The present study was performed to examine the effects of heat exposure hours hours at a fixed time once a day on diurnal variations of deep body temperature, heat balance and locomotor activity in rats. 2. The heat-exposed group (HE) was subjected to an ambient temperature of 33.5 degrees C for about 5 h in the last half of the dark phase daily for at least 10 consecutive days, while the control rats were constantly kept at 24 degrees C. 3. After the completion of the heat exposure schedule, hypothalamic temperature (Thy), heat loss, heat production and locomotor activity of HE rats significantly decreased for 3-4 h during the period of previous heat exposure time and formed a characteristic trough in the dark phase, which was never observed in the control rats or in the HE rats before the start of the heat exposure schedule. 4. The troughs of Thy, heat loss and heat production in the dark phase were persistent for at least 2 days after the end of the heat exposure schedule. The reductions of locomotor activity in this period were, however, observed only on the first day after stopping the heat exposure schedule. 5. These results suggest that the time memory for heat exposure was formed in heat-acclimated rats and was persistent for at least 2 days after the removal of heat exposure. It is also concluded that the reduction in metabolic heat production contributed to the fall of Thy during the period of heat exposure.

Selective brain cooling in rats resting in heat and during exercise

1. 1.|Hypothalamic, sagittal sinus venous blood and rectal temperatures were recorded in 8 rats during resting in heat (40°C) and during running at 31°C. 2. 2.|In normothermic animals the brain was warmer than rectal temperature. In hyperthermic animals, both resting and running, it became cooler than rectal temperature. This selective brain cooling response to hyperthermia was highly significant ( P < 0.001). 3. 3.|Sagittal sinus was always cooler than the hypothalamus. Thermal changes in sagittal sinus reflected thermolytic responses and were followed by parallel shifts in hypothalamic temperature which were independent of trunk temperature changes. 4. 4.|The basis of selective brain cooling in rats may be collecting cool blood from the head skin by the system of dural venous sinuses.

The effect of interleukin-6 on pituitary hormone release in vivo and in vitro.

Intravenously administered interleukin-6 (IL-6), a monokine produced by activated monocytes and folliculostellate cells of the pituitary gland, has been recently reported to elevate plasma ACTH level and to stimulate PRL, GH and LH release from cultured pituitary cells. To determine the site(s) of action of IL-6 in the control of pituitary hormone release, we injected human recombinant IL-6 into the third brain ventricle (3V) of freely moving, conscious male rats. Both 0.05 and 0.25 pmol doses of IL-6 were ineffective to change plasma ACTH in comparison to the values in controls. The maximal IL-6 dose tested of 1.25 pmol increased plasma ACTH within 15 min and the response lasted over 180 min. Plasma TSH levels were significantly lowered by a dose of 0.25 pmol IL-6, but neither the lower dose of 0.05 pmol nor the higher dose of 1.25 pmol altered plasma TSH levels throughout the 180 min of the experiment. Plasma PRL and GH levels were not changed by any IL-6 dose tested. In ovariectomized rats plasma LH and FSH levels were also unaltered by IL-6. The effects of IL-6 on plasma ACTH and TSH were only partially paralleled by increased rectal temperature which suggests that hypothalamic temperature regulating centers were independent of these actions. To evaluate a possible direct effect on the pituitary, IL-6 was incubated in vitro with hemipituitaries under an atmosphere of 95% O2/5% CO2. After 1 h of incubation IL-6 failed to cause any change in the secretion of pituitary hormones throughout a concentration range of 10(-15)-10(-9) M.(ABSTRACT TRUNCATED AT 250 WORDS)

Cold-induced changes in breathing pattern as a strategy to reduce respiratory heat loss

Thermoregulatory benefits of cold-induced changes in breathing pattern and mechanism(s) by which cold induces hypoventilation were investigated using male Holstein calves (1-3 mo old). Effects of ambient temperatures (Ta) between 4 and 18 degrees C on ventilatory parameters and respiratory heat loss (RHL) were determined in four calves. As Ta decreased, respiratory frequency decreased 29%, tidal volume increased 35%, total ventilation and RHL did not change, and the percentage of metabolic rate attributed to RHL decreased 26%. Total ventilation was stimulated by increasing inspired CO2 in six calves (Ta 4-6 degrees C), and a positive relationship existed between respiratory frequency and expired air temperature. Therefore, cold-exposed calves conserve respiratory heat by decreasing expired air temperature and dead space ventilation. Compared with thermoneutral exposure (16-18 degrees C), hypoventilation was induced by airway cold exposure (4-6 degrees C) alone and by exposing the body but not the airways to cold. Blocking nasal thermoreceptors with topical lidocaine during airway cold exposure prevented the ventilatory response but did not lower hypothalamic temperature. Hypothalamic cooling (Ta 16-18 degrees C) did not produce a ventilatory response. Thus, airway temperature but not hypothalamic temperature appears to control ventilation in cold-exposed calves.

Selective brain cooling after bilateral superior cervical sympathectomy in sheep (Ovis aries)

We have investigated the role of the sympathetic innervation of the vasculature of the head in the control of selective brain cooling of sheep, during exposure to high and low ambient temperatures and during endotoxin-induced fever. Bilateral removal of the superior cervical ganglia resulted in a significant reduction of hypothalamic temperature during all procedures. Respiratory rate was also depressed by the sympathectomy, apparently mainly as a result of a decrease in nasal airway patency. Rectal temperature changes after sympathectomy were dependent on the experimental conditions, and the rectal - hypothalamic temperature difference was enhanced during heat exposure and fever. Our results support the contention that sympathetically mediated changes in nasal blood flow and in venous return from the nasal cavity, via the angularis oculi and facial veins, may be involved in the control of selective brain cooling in sheep.

Heat loss responses in rats acclimated to heat loaded intermittently

The present study examined the heat loss response of heat-acclimated rats to direct body heating with an intraperitoneal heater or to indirect warming by elevating the ambient temperature (Ta). The heat acclimation of the rats was attained through exposure to Ta of 33 or 36 degrees C for 5 h daily during 15 consecutive days. Control rats were kept at Ta of 24 degrees C for the same acclimation period. Heat acclimation lowered the body core temperature at Ta of 24 degrees C, and the core temperature level was lowered as acclimation temperature increased. When heat was applied by direct body heating, the threshold hypothalamic temperature (Thy) for the tail skin vasodilation was also lower in heat-acclimated rats than in the control rats. However, the amount of increase in Thy from the resting level to the threshold was the same in all three groups. When heat was applied by indirect warming, threshold Thy was slightly higher in heat-acclimated than in control rats. The amount of increase in Thy from the resting level to the threshold was significantly greater in heat-acclimated rats. In addition, Ta and the skin temperature at the onset of skin vasodilation were significantly higher in heat-acclimated rats. The results indicate that heat-acclimated rats were less sensitive to the increase in skin temperature in terms of threshold Thy. The gain constant of nonevaporative heat loss response was assessed by plotting total thermal conductance against Thy.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in body temperature of rats acclimated to heat with different acclimation schedules.

Male Wistar rats, initially maintained at an ambient temperature (Ta) of 23.8 degrees C, were subjected to one of seven different heat acclimation schedules under a 12:12-h light-dark cycle (lights on at 0600 h). Two groups of rats were exposed to Ta of 32.4 degrees C all day for 5 (HC5) or 10 (HC10) days. The other four groups were exposed to Ta of 32.8 degrees C for 5 h/day during the last half of the dark phase for 5 (NI5) or 10 (NI10) consecutive days or during the last half of the light phase for 5 (DI5) or 10 (DI10) consecutive days. Control rats (C) were kept at 23.8 degrees C throughout the experiment. Hypothalamic temperature (Thy) was measured every 5 min with a chronically implanted thermocouple from 1 day before the beginning to 2 days after the end of the heat acclimation periods. During the heat acclimation periods, daily mean Thy rose significantly in HC5 and HC10 rats but decreased significantly in NI5 and NI10 rats. Daily mean Thy did not change in C, DI5, and DI10 rats. Thy in HC10 rats sharply decreased at the end of the heat acclimation periods and remained at low levels for approximately 3 h. On the 2nd postacclimation day, however, mean Thy returned and remained at a significantly higher level. In NI10 rats, the mean Thy in the postacclimation period was significantly lower than the preacclimation values. No such changes in mean Thy were observed in DI10 rats. Five-days of heat exposure had little effect on the postacclimation Thy.(ABSTRACT TRUNCATED AT 250 WORDS)

Do medial preoptic lesions interfere with the set-point of temperature regulation?

Rats with lesions in the medial preoptic area were placed in a thermocline where they could choose ambient temperatures (T a) ranging from 17 to 31°C. The hypothalamic temperature (T hy) and the selected T a were continuously recorded. Amplitude of T hy circadian oscillations was exaggerated in 23 out of 27 lesioned animals. Only in 6 circadian cycles out of the 158 recorded, the rats chose a higher T a during the night. In 55% of the recordings the preferred T a was significantly lower during the night than during the day and out of phase with T hy. In the other 36% of the recorded cycles no significant difference was found between the night and day preferred T a. Therefore in 91% of the recorded cycles the preferred T a oscillations did not support the idea that the exaggerated circadian oscillations of T hy in lesioned rats would be due to exaggerated cyclical shifts of the set-point temperature. The lesions induced many sporadic anomalies in the behavior of the rats in choosing a preferred T a. Short episodes of almost parallel variations in T hyand T a in phase with each other suggest that some lesions induce an instability of the set-point mechanism.

Responses of thalamic neurons in rats to skin cooling and hypothalamic temperature.

The responses of rat thalamic neurons to skin cooling were electrophysiologically examined. The responses of cold-excited neurons were classified into two types. One is a steplike response in which the activity abruptly increases with skin cooling, and the other is a graded response in which the activity gradually increases with skin cooling. The sites of these neurons were histologically identified in the ventrobasal complex of the thalamus, ventrolateral thalamus, and posterior thalamus. Two-thirds of them were found in a marginal region of the ventrobasal complex. There is no specific localization between the sites of thalamic neurons showing the steplike response and those showing the graded response. Furthermore, the effects of hypothalamic temperature on the thalamic neurons responding to skin cooling were observed. The response of thalamic neurons to cold stimulation of the skin was markedly suppressed during the hypothalamic warming. These results show that the steplike response is related to converting thermal analog signals to digital signals and that the graded response is related to relaying analog patterns of cold signals. Thermal afferent signals are modulated by hypothalamic temperature and subsequently cold sensation is modulated.

Effects of tracheostomy breathing on brain and body temperatures in hyperthermic sheep.

1. We measured rectal and hypothalamic temperature in sheep breathing nasally and via a tracheostomy, during hyperthermia resulting from exposure to a hot environment, exercise and fever. 2. In normothermic and hyperthermic sheep hypothalamic temperature was up to 1.0 degree C lower than rectal temperature when the sheep breathed nasally. Tracheostomy breathing abolished the rectal-hypothalamic temperature difference. 3. In sheep breathing via the tracheostomy and exposed to a dry-bulb temperature of 45-50 degrees C for 2 h, hypothalamic temperature exceeded rectal temperature by about 0.4 degrees C, and was significantly higher than that in sheep breathing nasally in the same environment. 4. During exercise on a treadmill and in the post-exercise period, the difference between hypothalamic and rectal temperature was abolished in the sheep while breathing through the tracheostomy, and rectal temperature rose to higher levels compared to those evident in the same activity while breathing nasally. 5. After an I.V. injection of 0.4 micrograms/kg lipopolysaccharide (LPS), the difference between hypothalamic and rectal temperature again was abolished in the sheep when breathing through the tracheostomy, but rectal temperature rose significantly less compared to when breathing nasally. 6. Our results indicate that selective brain cooling depends on upper respiratory tract cooling in normo- and hyperthermic states in sheep.