T Zethof

Radboud University Medical Centre (Radboudumc), Nymegen, Gelderland, Netherlands

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Publications (27)49.12 Total impact

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    ABSTRACT: In mammals, stress exposure is frequently associated with an elevated body temperature ['emotional fever', stress-induced hyperthermia (SIH)]. Rectal measurement of body core temperature of the mouse induces a rise of 1-1.5 degrees C over a 10- to 15-min time interval. This phenomenon has been exploited to design a specific test for measuring stress-induced hyperthermia: the singly-housed SIH paradigm in mice. In the present experiments, changes in body temperature and corticosterone levels were studied 10, 30, 60, 90 and 120 min after the first insertion of the rectal probe. In addition, changes in patterns of neural activation, as observed after immunostaining for Fos-immunoreactivity (Fos-IR), were studied in the brains of animals perfused at times 0, 60 or 120 min. Our results show that SIH and corticosterone levels have their peak values between 10 and 30 min and are no longer different from control values after 60 min. Patterns of Fos-IR have been studied in 11 brain areas, of which 2 brain areas (anterodorsal preoptic and periolivary nuclei) showed a continuing rise in Fos-IR after 60 and 120 min, while six nuclei, mostly hypothalamic and septal, showed a peak induction of Fos-IR after 60 min. In three brain areas, no consistent changes in Fos-IR could be observed. The authors conclude that the changes observed in the patterns of Fos-IR, after application of the singly-housed SIH-test in mice, reflect the effects of both the stressor application and the ensuing thermoregulatory responses. The role of each activated brain area in either one of these effects is discussed in view of data available from the literature.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2004; 28(4):699-707. · 3.55 Impact Factor
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    ABSTRACT: When mammals, including man, are confronted with a stressful event, their core body temperature rises, stress-induced hyperthermia. In mice, the stress-induced hyperthermia procedure has been developed to measure antistress or anxiolytic-like effects of psychoactive drugs. Group-housed and singly housed versions of the stress-induced hyperthermia generate comparable results. Because the number of animals needed to perform an experiment is much lower in the singly housed versus the group-housed procedure, the former is the test of choice for pharmacological testing. A typical stress-induced hyperthermia test starts with an injection 60 min before the first rectal temperature measurement (T(1)), followed by a second temperature measurement (T(2)) 10-15 min later. The difference DeltaT (=T(2)-T(1)) is the stress-induced hyperthermia. The procedure also measures the intrinsic activity of drugs on the basal body temperature and DeltaT is relatively independent from the intrinsic temperature effects of drugs. Anxiolytic drugs (benzodiazepines, 5-HT(1A) receptor agonists, alcohol) reduce DeltaT suggestive of anxiolytic-like effects. Because the parameter measured for anxiety in the stress-induced hyperthermia procedure is not dependent on locomotor activity, like in almost all other anxiety tests, the stress-induced hyperthermia procedure is an attractive addition to tests in the anxiety field. Because the stress-induced hyperthermia is also present with a comparable pharmacological profile in females, this procedure has a wide species and gender validity. The procedure was applied in various genetically modified mice [5-HT(1A) and 5-HT(1B) receptor knockout (KO) mice and corticotropin-releasing hormone overexpressing (CRH-OE) mice] to study phenotypic influences of the various mutations on aspects of anxiety. The stress-induced hyperthermia test in singly housed male and female mice appears a useful and extremely simple test to measure effects of drugs on certain aspects of anxiety or to help to determine phenotypic differences in mutant mice.
    European Journal of Pharmacology 03/2003; 463(1-3):117-32. · 2.59 Impact Factor
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    ABSTRACT: When mammals, including man, are confronted with a stressful event, their core body temperature rises, stress-induced hyperthermia. In mice, the stress-induced hyperthermia procedure has been developed to measure antistress or anxiolytic-like effects of psychoactive drugs. Group-housed and singly housed versions of the stress-induced hyperthermia generate comparable results. Because the number of animals needed to perform an experiment is much lower in the singly housed versus the group-housed procedure, the former is the test of choice for pharmacological testing. A typical stress-induced hyperthermia test starts with an injection 60 min before the first rectal temperature measurement (T1), followed by a second temperature measurement (T2) 10–15 min later. The difference ΔT (=T2−T1) is the stress-induced hyperthermia. The procedure also measures the intrinsic activity of drugs on the basal body temperature and ΔT is relatively independent from the intrinsic temperature effects of drugs. Anxiolytic drugs (benzodiazepines, -HT1A receptor agonists, alcohol) reduce ΔT suggestive of anxiolytic-like effects. Because the parameter measured for anxiety in the stress-induced hyperthermia procedure is not dependent on locomotor activity, like in almost all other anxiety tests, the stress-induced hyperthermia procedure is an attractive addition to tests in the anxiety field. Because the stress-induced hyperthermia is also present with a comparable pharmacological profile in females, this procedure has a wide species and gender validity. The procedure was applied in various genetically modified mice [5-HT1A and 5-HT1B receptor knockout (KO) mice and corticotropin-releasing hormone overexpressing (CRH-OE) mice] to study phenotypic influences of the various mutations on aspects of anxiety. The stress-induced hyperthermia test in singly housed male and female mice appears a useful and extremely simple test to measure effects of drugs on certain aspects of anxiety or to help to determine phenotypic differences in mutant mice.
    European Journal of Pharmacology 01/2003; · 2.59 Impact Factor
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    ABSTRACT: Stress-induced hyperthermia (SIH) in singly housed mice, in which the rectal temperature of a mouse is measured twice with a 10-min interval, enables to study the effects of a drug on the basal (T1) and on the stress-enhanced temperature (T2), 10 min later, using the rectal procedure as stressor. SIH (T2-T1) reflects a stress-induced phenomenon sensitive to stress- or anxiety-modifying effects of drugs. Several benzodiazepine agonists (diazepam, chlordiazepoxide, oxazepam and alprazolam) dose-dependently antagonized SIH either in NMRI mice from two different breeders or in BALB/c mice. No major differences in the sensitivity for any of the drugs tested were found between strains or between substrains from different breeders. The selective BZ1 receptor agonists alpidem and zolpidem only at relatively high doses antagonized SIH, whereas flumazenil, FG7142, pentylenetetrazol and phenobarbital did not affect SIH. Alcohol antagonized SIH, and the effects of diazepam could be antagonized by flumazenil. The findings that full BZ receptor agonists have anxiolytic-like effects in the singly housed SIH paradigm are comparable to those previously found in the group-housed version. The singly housed SIH is proposed as a simple and reliable screen for detecting anxiety-like properties of drugs that is valid in every mouse strain tested so far.
    Pharmacology Biochemistry and Behavior 06/2002; 72(1-2):179-88. · 2.82 Impact Factor
  • Theo J.J. Zethof, Jan A.M. Heyden, Berend Olivier
    Current Protocols in Pharmacology, 04/2001: pages 5.16.1 - 5.16.11; , ISBN: 9780471141754
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    ABSTRACT: In the stress-induced hyperthermia paradigm in singly-housed male mice, two sequential rectal temperature measurements reveal the basal temperature (T1) and, 10 min later, an enhanced body temperature (T2), due to the stress of the first rectal measurement. The difference T2 - T1 (deltaT) is the stress-induced hyperthermia and putatively reflects a stress-induced anxiogenic response. The full 5-HT1A receptor agonist flesinoxan ((+)-enantiomer), its (-)-enantiomer and the racemic mixture reduced stress-induced hyperthermia effects, indicating putative anxiolytic properties. The ratio of their potencies to reduce stress-induced hyperthermia was similar to their potency in receptor binding affinities for 5-HT1A receptors, supporting that the anti-hyperthermia effects are mediated by the 5-HT1A receptor. This was further substantiated when the 5-HT1A receptor antagonists WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexane carboxamine trihydrochloride) and DU 125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, monomesylate) both were able to antagonize the anti-stress-induced hyperthermia effects of flesinoxan. The stress-induced hyperthermia paradigm in singly-housed mice represents a simple and robust paradigm to measure putative anxiolytic effects of drugs.
    European Journal of Pharmacology 01/1998; 342(2-3):177-82. · 2.59 Impact Factor
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    ABSTRACT: In the stress-induced hyperthermia paradigm in singly-housed male mice, two sequential rectal temperature measurements reveal the basal temperature (T1) and, 10 min later, an enhanced body temperature (T2), due to the stress of the first rectal measurement. The difference T2−T1 (ΔT) is the stress-induced hyperthermia and putatively reflects a stress-induced anxiogenic response. The full 5-HT1A receptor agonist flesinoxan ((+)-enantiomer), its (−)-enantiomer and the racemic mixture reduced stress-induced hyperthermia effects, indicating putative anxiolytic properties. The ratio of their potencies to reduce stress-induced hyperthermia was similar to their potency in receptor binding affinities for 5-HT1A receptors, supporting that the anti-hyperthermia effects are mediated by the 5-HT1A receptor. This was further substantiated when the 5-HT1A receptor antagonists WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexane carboxamine trihydrochloride) and DU 125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, monomesylate) both were able to antagonize the anti-stress-induced hyperthermia effects of flesinoxan. The stress-induced hyperthermia paradigm in singly-housed mice represents a simple and robust paradigm to measure putative anxiolytic effects of drugs.
    European Journal of Pharmacology. 01/1998;
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    ABSTRACT: The stress-induced hyperthermia (SIH) paradigm in group-housed mice allows screening of putative anxiolytic drugs. The group-housed SIH was adapted to singly housed animals in order to drastically reduce the number of animals used. The effect of various stressors on rectal temperature was measured in order to find a simple and reliable test procedure. Repeated, but not single disturbance of animals resulted in a strong hyperthermia (deltaT) within 10 min. Similar hyperthermic responses were obtained after immobilization for 1 min or rectal temperature measurement itself. Neither a 120 dB acoustic stimulus, nor repeated 1 mA footshocks led to a temperature change, but 2 mA electric footshocks led to hyperthermia. The final test paradigm chosen involved repeated temperature measurement at a 10 min interval, thus providing both information on basal temperature and deltaT in each animal within a short time frame. Repeated temperature measurements at 10 min intervals revealed a maximum hyperthermia after approximately 30 min, but up to 70% of the hyperthermia is already present 10 min after the first measurement. Repeated use of animals at successive daily or weekly intervals resulted in a gradual increase of both the basal temperature and the temperature 10 min later. At short inter-test intervals (one day) deltaT also decreased, whereas weekly intervals did not affect the amplitude of deltaT. Prior injection of the animals resulted in modest hyperthermia, that returned to baseline after 60 min. The anxiolytics diazepam and 5-HT1A receptor agonist flesinoxan dose-dependently suppressed SIH. The antidepressant amitriptyline lowered temperature levels but did not affect deltaT. The SIH model in singly housed mice appears a fast and reproducible screening test for anxiolytic activity. Compared to the group-housed version, the singly-housed SIH enabled a drastic reduction in the number of animals used.
    Physiology & Behavior 10/1997; 62(3):463-70. · 3.16 Impact Factor
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    ABSTRACT: In the stress-induced hyperthermia (SIH) paradigm in mice, both a benzodiazepine receptor agonist, diazepam, and a 5-HT1A receptor agonist, flesinoxan, reduced the stress-induced increase in rectal temperature. The SIH procedure itself enhanced plasma ACTH and corticosterone levels but not plasma glucose levels. Diazepam (3, 6, and 12 mg/kg p.o.) did neither affect basal plasma ACTH, corticosterone, or glucose levels, nor did it suppress the stress-induced rises in these parameters. Flesinoxan (1, 3, and 10 mg/kg p.o.) enhanced plasma ACTH and corticosterone concentrations under nonstress conditions but did not affect the stress-induced increases in ACTH and corticosterone secretion. No clear effects of flesinoxan on plasma glucose levels were found. Our results indicate that in mice the anxiolytic effects of diazepam and flesinoxan in the SIH paradigm are not paralleled by a blockade of stress-induced increases in plasma ACTH, corticosterone, and glucose levels.
    Pharmacology Biochemistry and Behavior 06/1996; 54(1):249-54. · 2.82 Impact Factor
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    ABSTRACT: In the stress-induced hyperthermia (SIH) paradigm in mice, both a benzodiazepine receptor agonist, diazepam, and a 5-HT1A receptor agonist, flesinoxan, reduced the stress-induced increase in rectal temperature. The SIH procedure itself enhanced plasma ACTH and corticosterone levels but not plasma glucose levels. Diazepam (3, 6, and 12 mg/kg PO) did neither affect basal plasma ACTH, corticosterone, or glucose levels, nor did it suppress the stress-induced rises in these parameters. Flesinoxan (1, 3, and 10 mg/kg PO) enhanced plasma ACTH and corticosterone concentrations under nonstress conditions but did not affect the stress-induced increases in ACTH and corticosterone secretion. No clear effects of flesinoxan on plasma glucose levels were found. Our results indicate that in mice the anxiolytic effects of diazepam and flesinoxan in the SIH paradigm are not paralleled by a blockade of stress-induced increases in plasma ACTH, corticosterone, and glucose levels.
    Pharmacology Biochemistry and Behavior. 05/1996;
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    ABSTRACT: In group-housed mice (ten per cage), mice removed last from their home cage always have higher rectal temperatures than mice removed first from this cage. Stress-induced hyperthermia is calculated as the difference (delta T) between the basal temperature (mouse number 1) and the end temperature (mouse number 10) when the temperature of the ten mice is sequentially measured using a 1-min interval between rectal measurements. Using this protocol, various drugs, belonging to different pharmacological classes, were tested in order to investigate their putative anxiolytic effect, measured as a decrease in delta T. Benzodiazepines (diazepam, alprazolam), alcohol, and some (flesinoxan, buspirone), but not all (ipsapirone) 5-HT1A receptor agonists had anxiolytic properties with this protocol. Clonidine (alpha 2-adrenoceptor agonist) and prazosine (alpha 1-adrenoceptor antagonist) had, but at high doses, some anxiolytic actions. Antidepressants (desipramine, fluvoxamine, nomifensine, tianeptine, amitriptyline, clomipramine, imipramine), serotonergic ligands (ondansetron, ketanserin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), fenfluramine, metachlorophenylpiperazine (mCPP), eltoprazine) and various other drugs (phenobarbital, pentetrazol, haloperidol, apomorphine, amphetamine, (+)-N-[1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3( R)-yl]- N'-(3-methylphenyl)urea (MSD 365260), dizocilpine and acetyl salicylic acid) had no anxiolytic activity. The stress-induced hyperthermia protocol used was unable to detect anxiogenic properties of drugs, probably due to a (physiological) ceiling in the maximal end temperature. The stress-induced hyperthermia protocol with mice can be used to measure anxiolytic properties of drugs and is a fast and robust model which does not need extensive training of animals.
    European Journal of Pharmacology 01/1996; 294(1):125-35. · 2.59 Impact Factor
  • Annals of the New York Academy of Sciences 01/1996; 771:252-6. · 4.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In group-housed mice (ten per cage), mice removed last from their home cage always have higher rectal temperatures than mice removed first from this cage. Stress-induced hyperthermia is calculated as the difference (ΔT) between the basal temperature (mouse number 1) and the end temperature (mouse number 10) when the temperature of the ten mice is sequentially measured using a 1-min interval between rectal measurements. Using this protocol, various drugs, belonging to different pharmacological classes, were tested in order to investigate their putative anxiolytic effect, measured as a decrease in ΔT. Benzodiazepines (diazepam, alprazolam), alcohol, and some (flesinoxan, buspirone), but not all (ipsapirone) 5-HT1A receptor agonists had anxiolytic properties with this protocol. Clonidine (α2-adrenoceptor agonist) and prazosine (α1-adrenoceptor antagonist) had, but at high doses, some anxiolytic actions. Antidepressants (desipramine, fluvoxamine, nomifensine, tianeptine. amitriptyline, clomipramine, imipramine), serotonergic ligands (ondansetron, ketanserin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), fenfluramine, metachlorophenylpiperazine (mCPP), eltoprazine) and various other drugs (phenobarbital, pentetrazol, haloperidol, apomorphine, amphetamine, (+)-N-[1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3(R)-yl]-N′-(3-methylphenyl)urea (MSD 365260), dizocilpine and acetyl salicylic acid) had no anxiolytic activity. The stress-induced hyperthermia protocol used was unable to detect anxiogenic properties of drugs, probably due to a (physiological) ceiling in the maximal end temperature. The stress-induced hyperthermia protocol with mice can be used to measure anxiolytic properties of drugs and is a fast and robust model which does not need extensive training of animals.
    European Journal of Pharmacology 12/1995; · 2.59 Impact Factor
  • Annals of the New York Academy of Sciences 01/1995; 771:252-256. · 4.38 Impact Factor
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    ABSTRACT: In the stress-induced hyperthermia (SIH) paradigm in group-housed male mice, the rectal temperature of last measured mice is approximately 1.5 degrees C higher than the first measured one when the temperature of each mouse is measured sequentially with an interval of 1 min. In the present study it is demonstrated that SIH is accompanied by increases in plasma ACTH, corticosterone, and glucose levels that return to baseline more or less parallel to the temperature. The simultaneous increases in temperature and plasma stress hormones strongly support the use of the SIH paradigm in mice as an animal model to study putative anti-stress or anxiolytic properties of drugs.
    Physiology & Behavior 11/1994; 56(4):747-9. · 3.16 Impact Factor
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    ABSTRACT: In an attempt to develop new animal models of anxiety with face and predictive validity for the spectrum of human anxiety disorders, two new animal paradigms have been described, stress-induced hyperthermia (SIH) in mice and ultrasonic pup vocalizations (UV) in rats. In SIH mice develop enhanced body temperature in anticipation of an aversive event. This SIH can be antagonized by benzodiazepines, alcohol and 5-HT1A receptor agonists, but not by specific 5-HT reuptake inhibitors (SSRIs) or 5-HT3 receptor antagonists. When rat pups are separated from their mother and littermates they produce ultrasonic sounds, indicative of a separation distress. Benzodiazepines, 5-HT1A receptor agonists and SSRIs decrease this calling, whereas 5-HT3 receptor antagonists have no effect. Antidepressants in general do not decrease pup calling because in contrast to the SSRIs, noradrenergic uptake blockers enhance calling. These two animal models of anxiety can be added to the range of anxiety models and will be of help in predicting new putative anxiolytic drugs.
    European Neuropsychopharmacology 07/1994; 4(2):93-102. · 4.60 Impact Factor
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    ABSTRACT: When the rectal temperature of group-housed mice is measured sequentially, the temperature of the last measured mouse is higher than that of the first mouse. This phenomenon is called stress-induced hyperthermia (SIH). We varied several experimental parameters to elucidate the mechanism behind this SIH. SIH was stable and found by all technicians performing the experiments. The large intertechnician difference in the mean rectal temperature could be eliminated by training in an identical fixation and handling technique. SIH was both independent of the number of handling days preceding the experiment and of the number of disturbances (0, 1, 2, or 5) implied on the mice per minute. The percentage of hyperthermic mice in 10-mice cages increased when the time interval between the individual measurements increased from 1 to 2, 5 or 10 min. In all groups the maximum increase was reached after an interval of approximately 10 min. SIH of mouse 10 returned time dependently in approximately 60 min to basal temperature. When SIH was tested on 2 or 5 successive days no tolerance developed. When animals were reused after 7 or 14 days SIH did not differ from day 1, implying that animals can be reused. When the number of mice was decreased from 10 to 5 mice per cage, the SIH of vehicle-treated mice was slightly lower in 5-mice cages compared to 10-mice cages. The blocking effects on SIH by anxiolytics was also less clear in 5-mice cages compared to 10-mice cages.(ABSTRACT TRUNCATED AT 250 WORDS)
    Physiology & Behavior 02/1994; 55(1):109-15. · 3.16 Impact Factor
  • International Journal of Clinical Pharmacy 01/1993; 15:I1-I15. · 1.27 Impact Factor
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    ABSTRACT: Female Wistar rats were tested for aggressive behaviour induced by electrical brain stimulation (EBS) in the lateral hypothalamus. Threshold currents for the induction of aggression were determined on several days before the females were paired with experienced breeder males. Beginning in the second week of pregnancy threshold current values were measured once or twice weekly. No change in thresholds was observed either during pregnancy, the early postpartum period or after weaning. Lactation was the only period during which the females were spontaneously aggressive towards male intruders in their home cage, but not in the EBS cage. Analysis of bite targets revealed no difference between the bite patterns in the postpartum maternal aggression test and the EBS-induced attacks. The results demonstrate that the change in physiological and hormonal status in pregnant and lactating females has no influence on the propensity to attack during EBS. The similarity in wound patterns does not advocate a major difference in the types of aggression studied. We speculate upon the nature of EBS-induced attacks as the activation of a rigid, final pathway of aggression which is rather insensitive to mild modulations.
    Brain Research 03/1987; 404(1-2):263-6. · 2.88 Impact Factor
  • Progress in clinical and biological research 02/1984; 167:137-56.

Publication Stats

594 Citations
49.12 Total Impact Points

Institutions

  • 2004
    • Radboud University Medical Centre (Radboudumc)
      • Department of Anatomy
      Nymegen, Gelderland, Netherlands
  • 1994–2002
    • Universiteit Utrecht
      • Division of Pharmacology and Pathofysiology
      Utrecht, Provincie Utrecht, Netherlands