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Serum thyroxin levels during hyperthermia evoked in the monkey by intrahypothalamic injection of PGE1 5-HT or pyrogen
Brain Research Bulletin, Vol. 3, pp. 215-218.
Printed in the U.S.A.
BRIEF COMMUNICATION Serum Thyroxin Levels During Hyperthermia Evoked in the Monkey by Intrahypothalamic Injection of PGE,, S-HT or Pyrogen C. W. SIMPSON, W. D. RUWE, P. V. MALVEN AND R. D. MYERS Departments of Psychological, Biological and Animal Sciences, Purdue University West Lafayette, IN 47907 (Received 27 June 1977)
SIMPSON, C. W., W. D. RUWE, P. V. MALVEN AND R. D. MYERS. Serum thyroxin levels during hyperthermia evoked in by intrahypothalamic injection of PGE,, 5-HT or pyrogen. BRAIN RES. BULL. 3(3) 215-218, 1978. Serotonin (S-HT), prostaglandin E, (PGE, ) or a bacterial pyrogen (E. coli or S. typhosa) was microinjected in a volume of 1.0-1.5 ~1 into the hypothalamus of the unanesthetized monkey to evoke a long-term hyperthermia. Samples of venous blood collected every 15 min, before, during and after each fever were analyzed by radioimmunoassay for plasma thyroxin levels, There was no statistically significant correlation between plasma thyroxin values and a given phase of the hyperthermic episode induced by the microinjections of 5-HT, PGE, or bacteria. The possibility that an enhanced release of the thyroid hormone serves to sustain a long-term elevation in temperature evoked by a centrally acting pyrogenic substance is not supported. the monkey
Bacteria
Serotonin (5-HT) Prostaglandin E, Temperature regulation
Thyroxin
mulatta
and
two
Hypothalamus
Macaca
275 Copyright
0 1978 ANKHO
Fever
weighing 6.5 to 7.5 kg, were acclimated to primate restraining chairs, where water and food were available ad lib. The monkeys were maintained at an ambient temperature of 22-24°C and on a day-night cycle of approximately 15 hr light-9 hr dark. Employing surgical techniques described previously [lo], an array of six to eight guide cannulae, cut 50 mm in length from 22 ga stainless steel tubing, was implanted above the monkey’s hypothalamus [ 12,131. Ten days postoperatively, sites in the hypothalamus were tested for their sensitivity to 5-HT, PGE, or pyrogen. A single microinjection of 1.0-l .5 ~1, delivered over a 30 to 60 set interval, was made at successive 1 .O mm depths below the tip of a given guide according to procedures described previously [lo] . The concentration of 5-HT (5-hydroxytryptamine creatinine sulphate, Sigma) ranged from 3.0-7.5 pg/pl whereas PGE, (supplied by Dr. J. E. Pike of Upjohn) ranged from 100-150 ng PGE, /pl. A solution of either S. typhosa (Eli Lilly) or E. coli (supplied by Dr. R. L. Somerville, Purdue) was in a concentration of lo* organisms per ml. In a series of 146 experiments, specific sites in the hypothalamus were identified for subsequent testing at which the substances would reliably induce hyperthermia. A total of 20 reactive sites were then used as the test loci
METHOD
two Macaca
Axis
nemistrina,
IN THE CAT, primate and other species, an injection into the anterior hypothalamus of serotonin (S-HT), prostaglandin E, (PGE, ) or a bacterial pyrogen elicits an intense hyperthermia [5, 6, 9, 12, 13, 151. An unusual feature of the temperature rise produced by each substance is its prolonged duration, a fever lasting sometimes up to 30 hr [ 131. Since the pituitary-thyroid axis also parthermoregulation [ 1,4] a 5 - HT-hypot icipates in physeal-thyroxin link has been incorporated in one primate model of thermoregulation [ 111. When the baboon is cooled, the plasma concentration of T, rises [7] ; similarly, T, injected into the cerebral ventricle of the cat elevates body temperature in a dose-dependent manner [3] Further, when a fever associated with an acute pneumonia infection begins either in the human [8] or monkey [ 171, T, in plasma increases significantly. The present study was designed to determine whether these hyperthermic substances given centrally might also activate the pituitary-thyroid axis. Therefore, the concentration of T, in serum was analyzed before, during and after a rise in temperature was induced.
Male monkeys,
Thyroid
International
Inc.-0361-9230/78/0303-0275$00.60
SIMPSON,
276 A thermistor probe for the subsequent T, experiments. (Yellow Springs Instrument) inserted into the colon and a skin thermistor attached to the pinna were utilized to measure body and skin temperatures, respectively, which were monitored continuously on a Honeywell recorder. Respiratory rate was also recorded throughout each experiment. After colonic temperature had stabilized, the saphenous vein was catheterized with a Butterfly-21 infusion set (Abbott). To maintain venous patency, the catheter was connected to a constant-infusion system (Sorenson, Abbott) which delivered sterile 0.9% saline at 20-40 ml/hr. To obtain a blood sample, the Sorenson stop-cock was opened so that 2 ml of blood could be collected rapidly. Each sample was kept on ice, centrifuged, the serum frozen, and assayed for T, 1-3 days later. A double-antibody radioimmunoassay technique (Pantex) was used to determine the amount of T, in each sample. The quantity of precipitated ’ 25 I-T, was decreased with increasing amounts of standard T, from 0.25 to 8 ng per assay tube, Non-specific binding of ’ 2 5I-T,, averaging 3.3 t 0.2 (N = 22), was determined in each assay in the absence of antiserum against T, . The amount of non-specific binding was substracted from each count, standards as well as unknowns, in order to obtain the amount of specific binding (%B). The %B for the zero standard tubes in all assays averaged 5 I * 1% (N = 22) as a percent of the total I2 *I-T, added. Then, the average count in the zero standard (B,) of each assay was set to equal 100% and all specifically bound counts for standards and unknowns were expressed as %B, . A standard curve, plotted using logit (%B, ) versus log (ng of standard) scales, was used to determine the amount of immunoreactive T, in each unknown sample which was converted to ng/ml of serum. Before a hypothalamic microinjection, 4 to 12 blood
samples were collected either 5-HT, PGE, or injected at the reactive Thereafter, samples were the experiment ended. RESULTS
at 15 min intervals. As soon as a bacterial pyrogen was microsite, a blood sample was taken. collected at 1.5 min intervals until
AND DISCUSSION
Overall, the activity of the thyroid axis as reflected in plasma concentrations of thyroxin was not significantly affected during the three phases of fever evoked by 5-HT, PGE, or the bacteria. Analyses of variance were performed on the thyroxin values [ 161 to compare the blood levels of thyroxin during the three phases of the fever irrespective of the compound microinjected into the hypothalamus: (1) rising temperature; (2) plateau hyperthermia (i.e., less than three consecutive changes of at least O.l”C per 15 min); and (3) defervescence. No significant differences were obtained, F(3.55) = 1.40; p>O.lO. An analysis of variance contrasting the average change in thyroxin level after each substance was given intrahypothalamically, again revealed that there were no significant alterations in plasma thyroxin concentrations, F(3.37) = 0.019; p>O.SO. Figure 1 presents the average ng/ml of plasma-bound thyroxin in blood samples collected during the rising phase of fever, at the plateau, and during defervescence. A representative experiment is shown in Fig. 2. After successive microinjections of E. coli into a hypothalamic site just
dorsal
to the optic
chiasm
(see histological
inset),
a
PRE-INJECT
RISE
CONTROL
RUWE,
MALVEN
PLATEAU FEVER
AND+MYERS
FALL
PHASE
FIG. 1. Mean thyroxin levels (ng/ml) in plasma during the preinjection control condition (N = 106) and the rising (N = 92), plateau (N = 92) and falling phases (N = 53) of a fever elicited by ~tracran~al injections of 5-HT, PGE, or bacteria. Standard errors indicated by vertical lines.
long-lasting
ensued.
rise
When
in the 200 mg/kg
monkey’s colonic of acetaminophen
temperature (ACET) was
given intraperitoneally to ameliorate the pyrexia, the body temperature of the monkey declined toward the preinjection baseline. Although individual levels of plasma thyroxin varied considerably from sample to sample, a with the rise in colonic slight increase in T, concurrent
temperature was noted. Little change in respiratory rate or in vasomotor response was observed during the fever, although the monkey tended to vasodilate after the bacte~a-induced fever was underway. Although on several occasions a number of thyroxin values were well above preinjection control levels observed during a fever produced by 5-HT, PGE, or E. colz’ microinjected into the monkey’s hypothalamus, no consistent pattern of change in thyroxin activity emerged. Thus, these results generally do not support the hypothesis that enhanced thyroid activity underlies a long-term aspect of the hyperpyrexia induced by an endogenous substance acting on the anterior hypothalamus [ 1 I]. Although somewhat unexpected, the rapid short-term fluctuations in plasma thyroxin measured at 15-min intervals, have been observed in the human patient [ 21. Possibly, changes in plasma protein concentration due to hemodynamic responses arise from an alteration in posture or physical activity rather than from an episodic secretion of thyroxin. A significant increase in plasma thyroxin accompanying either a bacterial or viral infection and a rise in body temperature reportedly does occur in the human [8], rat [ 141 and monkey [ 171, when the pathogens are acting systemically. In the present study, hyperthermia was elicited by a hypothalamic injection of the substance. In addition, the monkey did not exhibit gastrointestinal disturbances such as vomiting or diarrhea, nor develop tolerance to repeated microinjections of E. coli which is
THYROXIN
211
AND FEVER
z
32
\ g
24
i
16
OC a 35 E W
32
+
cf a W
29
z
x
6o
0
E
II
50 -
& lF40& 4
30 -
Kl 20 -
OC 39
a 2 k
38 1 I
2
3
4
5
6
7
8
9
IO
HOURS FIG. 2. A representative example of a fever (bottom trace) following successive microinjections of E. coli (lo* organisms/ml in 1.5 ~1) at a site in the preoptic area of the hypothalamus shown in the inset. Thyroxin values are expressed in terms of ng/ml in plasma. Respiratory rate, ear and colonic temperatures are plotted at 15 min intervals before and after microinjection. Acetaminophen was given systemically in a dose of 200 mg/kg at the arrow.
is administered peripherally that systemically acting bacteria affect plasma thyroxin concentrations directly by altering the binding characteristics or turnover rate of the hormone during a prolonged infectious process. Finally, the present results do not rule out a possible involvement of triiodothyronine (T, ), adrenocorticotropin often
seen
when
[ 13 ] . It is likely
an endotoxin
(ACTH) or other hormone systems in the genesis and maintenance of a febrile response. However, since a change in plasma thyroxin does not correlate with the centrally elicited fever, the prolonged hyperthermia is likely due to an alteration in the local neuronal activity of the mechanism involved in the modification of body temperature.
hormone
SIMPSON, RUWE, MALVEN AND MYERS ACKNOWLEDGMENTS
This research was supported in part by U.S.A. Office of Naval Research Contract N-00014-75--C-0203 and by Grant BMS-18441 National Science Foundation. W.D.R. is a Pre-
Doctoral Fellow in Neurobiology. We would like to gratefully acknowledge the technical and other assistance provided by Elizabeth L. Myers, Diane Higgins, Marlene M. Bunch, R. A. Nattermann, M. I.. McCaIeb and Dr. M. Wailer.
REFERENCES 1.
2.
3.
4. 5. 6. 7. 8.
Andersson, B. Central nervous and hormonal interaction in temperature regulation of the goat. in: P~~S~~OgjCQz QBd ~~~~~~a1 Te~~ra~re Relation, edited by J. D. Hardy, A. P. Gagge and J. A. J. Stoiwijk. Springfield: Thomas, 1970, pp. 634-647. Azukizawa, M., A. E. Pekary, J. M. Hershman and D. C. Parker. thyroxine and triiodothyronine rePlasma thyrotropin, lationshivs in man. J. clin. Endocr. Metab. 43: 533-542.1976. Beleslin,-D. B. and R. Samardzic. Effect of thyroxine on the body temperature after its intraventricular injection into conscious cats. J. Physiol. 238: 27-28P, 1973. Chaffee. R. R. J. and J. C. Roberts. Temoerature acclimation in birds’and mammals. Ann. Rev. Physiol. -33: 155-202, 1971. Feldberg, W. and R. D. Myers. Effects on temperature of amines injected into the cerebral ventricles: a new concept of temperature regulation. A Physiol. 173: 226-237,1964. Feldberg, W.- and P. N. Saxena. Fever produced by orostanlandin E.. J. Physjo~. 217: 547-556.1971. bale, “c. C. Endocrine and metabolic responses to coId in baboons. Fedn Proc. 34: 1685-1691,1975. Gregerman, R. I. and N. Solomon. Acceleration of thyroxine and triiodothyronine turnover during bacterial pulmonary infections and fever: implications for the functional state of the thyroid during stress and in senescence. J. clin. Endocr. 27: 93-105,1967.
9.
10.
11. 12.
13. 14. 15.
16. 17.
Milton, A. S. and S. Wendlandt. A possible role for prostaglandin E as a modulator for temperature regulation in the centraf nervous system of the cat. J. Physiol. 207: 76-77, 1970. Myers, R. D. Methods of chemical stimulation of the brain. In: Methods in Psychobiology, Vol. I, edited by R. D. Myers. London: Academic Press, 1971, pp. 247-280. Myers, R. D. Handbook of Drug and Chemical Stimui&ion of the Brain. New York: Van Nostrand, 1974. Myers, R. D. and T. L. Yaksh. Control of body temperature in the unanaesthetized monkey by cholinergic and aminergic systems in the hypothalamus. J. Physiol. 202: 483-500, 1969. Myers, R. D., T. A. Rudy and T. L. Yaksh. Fever produced by endotoxin injected into the hypothalamus of the monkey and its antagonism by salicylate. J. Physiol. 243: 167-193, 1974. Shambaugh, G. E. and W. R. Beisel. Alterations in thyroid physiology during pneumococcal septicemia in the rat. Endocriprology‘79: Sll-523,1966. Walbr, M. B. and R. D. Myers. Hy~rthermia and operant responding for heat evoked in the monkey by intrahypothalamic prostaglandin. Sot. Neurosci. 118: 1973. Winer, B. J. Statistical Principles in Experimental Desigrt. Second edition. New York: McGraw-Hi& 1971, pp. 261-308. Woeber, K. S. and W. A. Harrison. Alterations in thyroid hormone economy during acute infection with Diplococcus pneumoniae in the rhesus monkey. J. din. Invest. 50: 378-387.1971.
Printed in the U.S.A.
BRIEF COMMUNICATION Serum Thyroxin Levels During Hyperthermia Evoked in the Monkey by Intrahypothalamic Injection of PGE,, S-HT or Pyrogen C. W. SIMPSON, W. D. RUWE, P. V. MALVEN AND R. D. MYERS Departments of Psychological, Biological and Animal Sciences, Purdue University West Lafayette, IN 47907 (Received 27 June 1977)
SIMPSON, C. W., W. D. RUWE, P. V. MALVEN AND R. D. MYERS. Serum thyroxin levels during hyperthermia evoked in by intrahypothalamic injection of PGE,, 5-HT or pyrogen. BRAIN RES. BULL. 3(3) 215-218, 1978. Serotonin (S-HT), prostaglandin E, (PGE, ) or a bacterial pyrogen (E. coli or S. typhosa) was microinjected in a volume of 1.0-1.5 ~1 into the hypothalamus of the unanesthetized monkey to evoke a long-term hyperthermia. Samples of venous blood collected every 15 min, before, during and after each fever were analyzed by radioimmunoassay for plasma thyroxin levels, There was no statistically significant correlation between plasma thyroxin values and a given phase of the hyperthermic episode induced by the microinjections of 5-HT, PGE, or bacteria. The possibility that an enhanced release of the thyroid hormone serves to sustain a long-term elevation in temperature evoked by a centrally acting pyrogenic substance is not supported. the monkey
Bacteria
Serotonin (5-HT) Prostaglandin E, Temperature regulation
Thyroxin
mulatta
and
two
Hypothalamus
Macaca
275 Copyright
0 1978 ANKHO
Fever
weighing 6.5 to 7.5 kg, were acclimated to primate restraining chairs, where water and food were available ad lib. The monkeys were maintained at an ambient temperature of 22-24°C and on a day-night cycle of approximately 15 hr light-9 hr dark. Employing surgical techniques described previously [lo], an array of six to eight guide cannulae, cut 50 mm in length from 22 ga stainless steel tubing, was implanted above the monkey’s hypothalamus [ 12,131. Ten days postoperatively, sites in the hypothalamus were tested for their sensitivity to 5-HT, PGE, or pyrogen. A single microinjection of 1.0-l .5 ~1, delivered over a 30 to 60 set interval, was made at successive 1 .O mm depths below the tip of a given guide according to procedures described previously [lo] . The concentration of 5-HT (5-hydroxytryptamine creatinine sulphate, Sigma) ranged from 3.0-7.5 pg/pl whereas PGE, (supplied by Dr. J. E. Pike of Upjohn) ranged from 100-150 ng PGE, /pl. A solution of either S. typhosa (Eli Lilly) or E. coli (supplied by Dr. R. L. Somerville, Purdue) was in a concentration of lo* organisms per ml. In a series of 146 experiments, specific sites in the hypothalamus were identified for subsequent testing at which the substances would reliably induce hyperthermia. A total of 20 reactive sites were then used as the test loci
METHOD
two Macaca
Axis
nemistrina,
IN THE CAT, primate and other species, an injection into the anterior hypothalamus of serotonin (S-HT), prostaglandin E, (PGE, ) or a bacterial pyrogen elicits an intense hyperthermia [5, 6, 9, 12, 13, 151. An unusual feature of the temperature rise produced by each substance is its prolonged duration, a fever lasting sometimes up to 30 hr [ 131. Since the pituitary-thyroid axis also parthermoregulation [ 1,4] a 5 - HT-hypot icipates in physeal-thyroxin link has been incorporated in one primate model of thermoregulation [ 111. When the baboon is cooled, the plasma concentration of T, rises [7] ; similarly, T, injected into the cerebral ventricle of the cat elevates body temperature in a dose-dependent manner [3] Further, when a fever associated with an acute pneumonia infection begins either in the human [8] or monkey [ 171, T, in plasma increases significantly. The present study was designed to determine whether these hyperthermic substances given centrally might also activate the pituitary-thyroid axis. Therefore, the concentration of T, in serum was analyzed before, during and after a rise in temperature was induced.
Male monkeys,
Thyroid
International
Inc.-0361-9230/78/0303-0275$00.60
SIMPSON,
276 A thermistor probe for the subsequent T, experiments. (Yellow Springs Instrument) inserted into the colon and a skin thermistor attached to the pinna were utilized to measure body and skin temperatures, respectively, which were monitored continuously on a Honeywell recorder. Respiratory rate was also recorded throughout each experiment. After colonic temperature had stabilized, the saphenous vein was catheterized with a Butterfly-21 infusion set (Abbott). To maintain venous patency, the catheter was connected to a constant-infusion system (Sorenson, Abbott) which delivered sterile 0.9% saline at 20-40 ml/hr. To obtain a blood sample, the Sorenson stop-cock was opened so that 2 ml of blood could be collected rapidly. Each sample was kept on ice, centrifuged, the serum frozen, and assayed for T, 1-3 days later. A double-antibody radioimmunoassay technique (Pantex) was used to determine the amount of T, in each sample. The quantity of precipitated ’ 25 I-T, was decreased with increasing amounts of standard T, from 0.25 to 8 ng per assay tube, Non-specific binding of ’ 2 5I-T,, averaging 3.3 t 0.2 (N = 22), was determined in each assay in the absence of antiserum against T, . The amount of non-specific binding was substracted from each count, standards as well as unknowns, in order to obtain the amount of specific binding (%B). The %B for the zero standard tubes in all assays averaged 5 I * 1% (N = 22) as a percent of the total I2 *I-T, added. Then, the average count in the zero standard (B,) of each assay was set to equal 100% and all specifically bound counts for standards and unknowns were expressed as %B, . A standard curve, plotted using logit (%B, ) versus log (ng of standard) scales, was used to determine the amount of immunoreactive T, in each unknown sample which was converted to ng/ml of serum. Before a hypothalamic microinjection, 4 to 12 blood
samples were collected either 5-HT, PGE, or injected at the reactive Thereafter, samples were the experiment ended. RESULTS
at 15 min intervals. As soon as a bacterial pyrogen was microsite, a blood sample was taken. collected at 1.5 min intervals until
AND DISCUSSION
Overall, the activity of the thyroid axis as reflected in plasma concentrations of thyroxin was not significantly affected during the three phases of fever evoked by 5-HT, PGE, or the bacteria. Analyses of variance were performed on the thyroxin values [ 161 to compare the blood levels of thyroxin during the three phases of the fever irrespective of the compound microinjected into the hypothalamus: (1) rising temperature; (2) plateau hyperthermia (i.e., less than three consecutive changes of at least O.l”C per 15 min); and (3) defervescence. No significant differences were obtained, F(3.55) = 1.40; p>O.lO. An analysis of variance contrasting the average change in thyroxin level after each substance was given intrahypothalamically, again revealed that there were no significant alterations in plasma thyroxin concentrations, F(3.37) = 0.019; p>O.SO. Figure 1 presents the average ng/ml of plasma-bound thyroxin in blood samples collected during the rising phase of fever, at the plateau, and during defervescence. A representative experiment is shown in Fig. 2. After successive microinjections of E. coli into a hypothalamic site just
dorsal
to the optic
chiasm
(see histological
inset),
a
PRE-INJECT
RISE
CONTROL
RUWE,
MALVEN
PLATEAU FEVER
AND+MYERS
FALL
PHASE
FIG. 1. Mean thyroxin levels (ng/ml) in plasma during the preinjection control condition (N = 106) and the rising (N = 92), plateau (N = 92) and falling phases (N = 53) of a fever elicited by ~tracran~al injections of 5-HT, PGE, or bacteria. Standard errors indicated by vertical lines.
long-lasting
ensued.
rise
When
in the 200 mg/kg
monkey’s colonic of acetaminophen
temperature (ACET) was
given intraperitoneally to ameliorate the pyrexia, the body temperature of the monkey declined toward the preinjection baseline. Although individual levels of plasma thyroxin varied considerably from sample to sample, a with the rise in colonic slight increase in T, concurrent
temperature was noted. Little change in respiratory rate or in vasomotor response was observed during the fever, although the monkey tended to vasodilate after the bacte~a-induced fever was underway. Although on several occasions a number of thyroxin values were well above preinjection control levels observed during a fever produced by 5-HT, PGE, or E. colz’ microinjected into the monkey’s hypothalamus, no consistent pattern of change in thyroxin activity emerged. Thus, these results generally do not support the hypothesis that enhanced thyroid activity underlies a long-term aspect of the hyperpyrexia induced by an endogenous substance acting on the anterior hypothalamus [ 1 I]. Although somewhat unexpected, the rapid short-term fluctuations in plasma thyroxin measured at 15-min intervals, have been observed in the human patient [ 21. Possibly, changes in plasma protein concentration due to hemodynamic responses arise from an alteration in posture or physical activity rather than from an episodic secretion of thyroxin. A significant increase in plasma thyroxin accompanying either a bacterial or viral infection and a rise in body temperature reportedly does occur in the human [8], rat [ 141 and monkey [ 171, when the pathogens are acting systemically. In the present study, hyperthermia was elicited by a hypothalamic injection of the substance. In addition, the monkey did not exhibit gastrointestinal disturbances such as vomiting or diarrhea, nor develop tolerance to repeated microinjections of E. coli which is
THYROXIN
211
AND FEVER
z
32
\ g
24
i
16
OC a 35 E W
32
+
cf a W
29
z
x
6o
0
E
II
50 -
& lF40& 4
30 -
Kl 20 -
OC 39
a 2 k
38 1 I
2
3
4
5
6
7
8
9
IO
HOURS FIG. 2. A representative example of a fever (bottom trace) following successive microinjections of E. coli (lo* organisms/ml in 1.5 ~1) at a site in the preoptic area of the hypothalamus shown in the inset. Thyroxin values are expressed in terms of ng/ml in plasma. Respiratory rate, ear and colonic temperatures are plotted at 15 min intervals before and after microinjection. Acetaminophen was given systemically in a dose of 200 mg/kg at the arrow.
is administered peripherally that systemically acting bacteria affect plasma thyroxin concentrations directly by altering the binding characteristics or turnover rate of the hormone during a prolonged infectious process. Finally, the present results do not rule out a possible involvement of triiodothyronine (T, ), adrenocorticotropin often
seen
when
[ 13 ] . It is likely
an endotoxin
(ACTH) or other hormone systems in the genesis and maintenance of a febrile response. However, since a change in plasma thyroxin does not correlate with the centrally elicited fever, the prolonged hyperthermia is likely due to an alteration in the local neuronal activity of the mechanism involved in the modification of body temperature.
hormone
SIMPSON, RUWE, MALVEN AND MYERS ACKNOWLEDGMENTS
This research was supported in part by U.S.A. Office of Naval Research Contract N-00014-75--C-0203 and by Grant BMS-18441 National Science Foundation. W.D.R. is a Pre-
Doctoral Fellow in Neurobiology. We would like to gratefully acknowledge the technical and other assistance provided by Elizabeth L. Myers, Diane Higgins, Marlene M. Bunch, R. A. Nattermann, M. I.. McCaIeb and Dr. M. Wailer.
REFERENCES 1.
2.
3.
4. 5. 6. 7. 8.
Andersson, B. Central nervous and hormonal interaction in temperature regulation of the goat. in: P~~S~~OgjCQz QBd ~~~~~~a1 Te~~ra~re Relation, edited by J. D. Hardy, A. P. Gagge and J. A. J. Stoiwijk. Springfield: Thomas, 1970, pp. 634-647. Azukizawa, M., A. E. Pekary, J. M. Hershman and D. C. Parker. thyroxine and triiodothyronine rePlasma thyrotropin, lationshivs in man. J. clin. Endocr. Metab. 43: 533-542.1976. Beleslin,-D. B. and R. Samardzic. Effect of thyroxine on the body temperature after its intraventricular injection into conscious cats. J. Physiol. 238: 27-28P, 1973. Chaffee. R. R. J. and J. C. Roberts. Temoerature acclimation in birds’and mammals. Ann. Rev. Physiol. -33: 155-202, 1971. Feldberg, W. and R. D. Myers. Effects on temperature of amines injected into the cerebral ventricles: a new concept of temperature regulation. A Physiol. 173: 226-237,1964. Feldberg, W.- and P. N. Saxena. Fever produced by orostanlandin E.. J. Physjo~. 217: 547-556.1971. bale, “c. C. Endocrine and metabolic responses to coId in baboons. Fedn Proc. 34: 1685-1691,1975. Gregerman, R. I. and N. Solomon. Acceleration of thyroxine and triiodothyronine turnover during bacterial pulmonary infections and fever: implications for the functional state of the thyroid during stress and in senescence. J. clin. Endocr. 27: 93-105,1967.
9.
10.
11. 12.
13. 14. 15.
16. 17.
Milton, A. S. and S. Wendlandt. A possible role for prostaglandin E as a modulator for temperature regulation in the centraf nervous system of the cat. J. Physiol. 207: 76-77, 1970. Myers, R. D. Methods of chemical stimulation of the brain. In: Methods in Psychobiology, Vol. I, edited by R. D. Myers. London: Academic Press, 1971, pp. 247-280. Myers, R. D. Handbook of Drug and Chemical Stimui&ion of the Brain. New York: Van Nostrand, 1974. Myers, R. D. and T. L. Yaksh. Control of body temperature in the unanaesthetized monkey by cholinergic and aminergic systems in the hypothalamus. J. Physiol. 202: 483-500, 1969. Myers, R. D., T. A. Rudy and T. L. Yaksh. Fever produced by endotoxin injected into the hypothalamus of the monkey and its antagonism by salicylate. J. Physiol. 243: 167-193, 1974. Shambaugh, G. E. and W. R. Beisel. Alterations in thyroid physiology during pneumococcal septicemia in the rat. Endocriprology‘79: Sll-523,1966. Walbr, M. B. and R. D. Myers. Hy~rthermia and operant responding for heat evoked in the monkey by intrahypothalamic prostaglandin. Sot. Neurosci. 118: 1973. Winer, B. J. Statistical Principles in Experimental Desigrt. Second edition. New York: McGraw-Hi& 1971, pp. 261-308. Woeber, K. S. and W. A. Harrison. Alterations in thyroid hormone economy during acute infection with Diplococcus pneumoniae in the rhesus monkey. J. din. Invest. 50: 378-387.1971.