PubMed Health⌕ Search

Biomedical subjects

M S Oitzl

Publications and source records attributed to M S Oitzl.

At least 55 records · Page 3Linked to original sources
PubMed1995

Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis.

In this study we report a series of differences in brain and peripheral elements regulating the hypothalamic-pituitary-adrenal (HPA) axis between male LEW and Wistar rats. We found: (i) differential properties of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain (hippocampus, hypothalamus) and pituitary: LEW rats displayed an increased capacity of MRs in the hippocampus and hypothalamus and a decreased capacity of glucocorticoid receptors GRs in the pituitary. The binding affinity (Kd) for MRs and GRs in the hippocampus was comparable. (ii) Lower concentrations of corticotropin releasing hormone (CRH) mRNA were detected in the nucleus paraventricularis of the hypothalamus of LEW rats. (iii) Adrenal weight was similar in LEW and Wistar rats; however, LEW rats had about 30% less adrenocortical cells. Subjecting adrenocortical cells to increasing doses of ACTH1-24 in vitro resulted in about a 60% smaller release of corticosterone in LEW rats. (iv) LEW rats escaped dexamethasone suppression showing increased basal levels of endogenous ACTH, but responded with a comparable release of corticosterone to the IV injection of 5 ng ACTH1-24. (v) LEW rats responded to a variety of stimuli: adrenalectomy under ether anaesthesia, a novel environment, a tail nick and restraint or an immunological challenge, with lower circulating ACTH and corticosterone plasma levels than Wistar rats. (vi) Evening levels of ACTH and corticosterone were lower in LEW than Wistar rats but did not differ in the morning. Blockade of brain MRs in the evening by a central injection of the specific MR antagonist RU28318 in LEW rats resulted in increased circulating levels of ACTH and corticosterone. (vii) Levels of corticosteroid-binding proteins were lower in one-day adrenalectomized LEW rats, indicating higher levels of free corticosterone. (viii) LEW rats had a smaller thymus than Wistar rats. Taken together, the receptor binding data correspond to a decreased neuroendocrine responsiveness of LEW rats to stress. We suggest that the shift in the central MR/GR balance of LEW rats, i.e. augmented MR-mediated effects of corticosterone, is the central regulating mechanism of the hyporeactive HPA axis in this rat strain. Lower levels of CRH mRNA in the hypothalamus and lower levels of ACTH and corticosterone in response to various stimuli, as well as the hyporesponsive adrenals to exogenous ACTH, are apparently the consequences of the life-long suppressive action of corticosterone via central MRs.

Adrenocorticotropic Hormone↗
PubMed1995

Adrenocortical hyporesponsiveness and glucocorticoid feedback resistance in old male brown Norway rats.

This study was designed to examine adrenocortical function in old (30 months) and young (6 months) male Brown Norway rats. The following observations were made. First, stress induced a higher pituitary adrenocorticotropic hormone (ACTH) response in the aged male Brown Norway rats than in young rats, while peak circulating corticosterone (CORT) levels were not different. Moreover, this type of "repeated" stress involving subcutaneous injection and blood sampling at various time points by pinching the tail vein, evoked a prolonged ACTH and CORT response in the aged animal. Second, exogenous ACTH1-24 administered to dexamethasone-pretreated Brown Norway rats, used as an in vivo challenge test for adrenocortical function, resulted in a delayed CORT response in the aged rats. The termination of the CORT response to ACTH, however, was not different between young and old rats. Third, ACTH1-24 stimulation of adrenocortical cells in vitro showed a tendency to a reduced CORT output, when these cells were obtained from old animals. Fourth, adrenalectomy (ADX) differentially affected pituitary ACTH release at both ages. The initial post-ADX ACTH surge was more pronounced in the aged animals. Beyond 4 days post-ADX the old Brown Norway rats did not show the pronounced afternoon peak in circulating ACTH as was observed in the young animals. This study demonstrates that during the aging process a deficiency in adrenocortical function develops in the male Brown Norway rat. This deficiency involves a less efficient stress-induced activation of adrenocortical output of CORT having enhanced pituitary ACTH release as one of the consequences.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1994

The effect of corticosterone on reactivity to spatial novelty is mediated by central mineralocorticosteroid receptors.

Corticosterone, secreted by the adrenal glands, binds to central mineralocorticoid receptors with high affinity and to glucocorticoid receptors with a tenfold lower affinity. In previous studies we have shown that the selective activation of either mineralocorticoid receptors or glucocorticoid receptors exerts distinctly different behavioural effects. In this study we examined in particular the mineralocorticoid receptor-mediated effect of corticosterone on the control of the behavioural response of male Wistar rats to spatial novelty. This analysis was based on our observation that in adrenal-intact rats the presence of an object in the centre of an open field alters the time spent and distance walked in the centre compared to the peripheral area, i.e. the pattern of reactive locomotor activity is changed. Using this paradigm we found that 1 day after removal of the adrenals the rats increased their behavioural reactivity towards the object. Treatment of adrenalectomized rats with a low dose of corticosterone (50 micrograms/kg s.c.) 1 h prior to testing restored the behavioural reactivity to the level of sham-operated, intact rats. Surprisingly, a high dose of corticosterone (1000 micrograms/kg s.c.) also increased the rat's reactivity towards the object. The same high dose of corticosterone given to adrenal-intact rats also increased behavioural reactivity. Pretreatment of these rats with an intracerebroventricular injection of the selective mineralocorticoid receptor antagonist RU28318 (100 ng/microliters) prevented the corticosterone-induced increase in behavioural reactivity, while the blockade of glucocorticoid receptors with the antagonist RU38486 (100 ng/microliters) was not effective. Administration of the mineralocorticoid receptor antagonist without corticosterone to adrenal-intact rats also increased behavioural reactivity, but this increase did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1994

Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication.

Interleukin-1 (IL-1) and interleukin-6 (IL-6), and their cognate receptors, are expressed in hippocampal neurons, which are targets for corticosteroid hormones. Corticosteroids bind to intracellular receptors, that is, mineralocorticoid (MRs) and glucocorticoid receptors (GRs). MRs respond to low concentrations of the steroid, while higher concentrations are needed for additional activation of GRs. MR occupation appears relevant in hippocampal neurons for stability of ongoing transmission, for basal activity and sensitivity of the stress response system, and for behavioural reactivity and response selection. Additional transient GR activation suppresses excitability, facilitates recovery from the stress response, and promotes information storage. Thus, the balance of MR- and GR-mediated effects appears critical for the long-term control exerted by corticosteroids over specific aspects of neuronal activity, stress responsiveness, and behavioural adaptation. Administration of IL-1 produces a long-lasting increase in corticosterone. IL-1 also influences MR function in hippocampus and causes a shift in the MR/GR balance, which may underlie prolonged activation of the HPA axis during an immune response.

Animals↗
PubMed1993

Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning.

The effects of the cytokines interleukin-1 and -6 (IL1 beta, IL6; 100 ng) on spatial learning were examined in the Morris water maze. Intracerebroventricular injection of IL1 or IL6 before the training on day 1 did not influence the acquisition of spatial navigation. However, IL1 administered at 60 min, but not immediately before the training, resulted in impaired performance of spatial navigation the following day. In contrast, IL6 administered at both times had no effect. In a second experiment the same doses of IL1 and IL6 increased the body temperature of rats in a time-related fashion. The temperature effect of IL1 developed after a delay of 120 min, while the IL-6-effect was immediate. Comparable behavioral changes might accompany infections or inflammatory diseases and therapeutic cytokine administration.

Animals↗
PubMed1993

Functional implications of brain corticosteroid receptor diversity.

1. Corticosteroids readily enter the brain and control gene expression in nerve cells via binding to intracellular receptors, which act as gene transcription factors. In the rat brain corticosterone binds to mineralocorticoid receptors (MRs) with a 10-fold higher affinity than to glucocorticoid receptors (GRs). As a consequence, these MRs are extensively occupied under basal resting conditions, while substantial GR occupation occurs at the circadian peak and following stress. Both receptors are colocalized in most, but not all, hippocampal neurons. In addition, some neurons contain aldosterone-selective MRs, if corticosterone is enzymatically inactivated. These aldosterone target neurons are presumably localized in the anterior hypothalamus, where they underlie central control of salt appetite and cardiovascular regulation. 2. The data show that MR- and GR-mediated effects proceed in a coordinate and often antagonistic mode of action: (i) in hippocampus MR activation maintains excitability, while GR occupancy suppresses excitability, which is transiently raised by excitatory stimuli; (ii) central MRs participate in control of the sensitivity of the neuroendocrine stress response system, while GRs are involved in termination of the stress response; (iii) MRs in the hippocampus have a role in regulation of behavioral reactivity and response selection. GR-mediated effects facilitate storage of information. 3. On the basis of these data, we propose that a relative deficiency or excess of MR- over GR-mediated neuronal effects may lead to a condition of enhanced or reduced responsiveness to environmental influences, alter behavioral adaptation, and promote susceptibility to stress. The findings may serve development of novel therapeutic strategies for treatment of stress-related brain diseases.

Animals↗
PubMed1993

An ACTH/MSH(4-9) analog counteracts the behavioral effects of a mineralocorticoid receptor antagonist.

The ACTH/MSH(4-9) analog Org2766 has been demonstrated to counteract age-related behavioral and morphological parameters especially those related to hippocampal functioning. Hippocampal mineralocorticoid receptors (MRs) are known to decline in the senescent rat. This decrease can be also counteracted by a chronic treatment with an ACTH(4-9) analog. The apparent effect of the peptide on hippocampal functioning prompted us to study a possible interaction between ACTH and MRs at a behavioral level. A chronic treatment with the ACTH(4-9) analog prevented the behavioral alteration induced by a specific MR antagonist (RU28318; 100 ng/microliters, ICV) in the Morris water maze and a step-through avoidance task. A possible role for neuronal excitation, involving MR activation, in peptide-facilitated behavioral recovery as seen in lesion studies and aging is discussed.

Adrenocorticotropic Hormone↗
PubMed1993

Brain mineralocorticoid receptor diversity: functional implications.

Mineralocorticoid receptors (MRs) in neurons of the anterior hypothalamus and the periventricular brain regions mediate aldosterone-selective actions on sodium homeostasis, salt appetite and cardiovascular regulation. Corticosterone is not effective in these neurons, possibly because it is enzymatically inactivated. However, MRs in limbic brain regions, notably in the hippocampal neurons, do already respond to very low concentrations of both corticosterone and aldosterone. The MR-mediated effects stabilize neuronal transmission and appear critical for neuronal integrity of a sub-region of the hippocampus: the dentate gyrus. Higher concentrations of corticosterone induced by stress and the circadian rise progressively activate the lower affinity glucocorticoid receptors (GRs), which in coordination with MR-mediated actions then facilitate adaptive processes required for recovery of homeostasis. It is postulated that this balanced MR- and GR-mediated action of corticosterone is of critical importance for regulation of the stress response and behavioural adaptation.

Aldosterone↗
PubMed1992

Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning.

Receptors for mineralocorticoids (MRs) and glucocorticoids (GRs) display a high concentration and distinct distribution in the hippocampus. The effects of corticosteroids on behavior mediated by central MRs and GRs were assessed in rats. Spatial navigation is considered to be a sensitive measure for hippocampal functioning. Removal of circulating corticosteroids (via adrenalectomy) impaired spatial learning. In intact rats, blockade of central MRs and GRs by intracerebroventricular injection of selective MR and GR antagonists influenced different aspects of spatial learning. The analysis of the behavioral pattern revealed that treatment with the MR antagonist altered search-escape strategies in the water maze. The injection of the GR antagonist after training resulted in increased latencies to find the platform, which reflects the disturbed consolidation of spatial information. Corticosteroids affect in a differential and coordinated manner behavioral strategies and storage of spatial information.

Adrenal Medulla↗
PubMed1992

Corticosteroid receptor plasticity in the central nervous system of various rat models.

The action of corticosteroids in the central nervous system (CNS) is mediated by two distinct corticosteroid receptors: the mineralocorticoid and glucocorticoid receptors (MR and GR respectively). Using an established in vitro binding assay system, MR and GR binding parameters were determined in the hippocampal, hypothalamic and pituitary cytosol of various rat models. In the (pharmaco-)genetically selected rat lines, the apomorphine susceptible (APO-SUS) rats showed a significant increase in the hippocampal and pituitary MR binding capacities (but not affinity) compared to those in the apomorphine-unsusceptible (APO-UNSUS) rats. In immunologically-altered Lewis (LEW/N) rats and in spontaneously hypertensive rats (SHR), increased hippocampal MR capacity (but not affinity) and hypothalamic MR capacity were observed compared to their respective control, Wistar (WIST) and Wistar Kyoto (WKY) rats. In addition, compared to WKY rats, SHR rats also showed a much greater pituitary but lesser hypothalamic GR binding capacity. In rats subjected to alteration in environmental conditions, the long-term effects of a short inescapable stress resulted in a significant increase in both hippocampal MR and GR while the pituitary and hypothalamic MR and GR do not differ in the stress and control groups. In rats subjected to a defeat test, a decrease in hippocampal MR and GR was observed 3 weeks (but not 1 week) later.

Animals↗
PubMed1991

Brain corticosteroid receptor gene expression and neuroendocrine dynamics during aging.

The present study examined the stress responsiveness of the hypothalamic-pituitary-adrenal axis in relation to the properties of corticosteroid receptors in the brain and pituitary in old (30 months) and young (3 months) male Brown Norway rats. The data demonstrate that circulating ACTH rather than the corticosteroid plasma level was elevated under basal conditions and following stress. Furthermore, a reduction of mineralocorticoid receptor (MR) number in the hippocampus and of glucocorticoid receptor (GR) number in the hypothalamus and the pituitary correspond to increased neuroendocrine responsiveness and negative feedback following stress. The changes in receptor binding do not parallel the changes in the amount of MR and GR mRNA measured with in situ hybridization. This suggests that the processing rather than the receptor gene expression is affected in senescence.

Aging↗
PubMed1990

Reinforcing effects of peripherally administered substance P and its C-terminal sequence pGlu6-SP6-11 in the rat.

Reinforcing effects of intraperitoneally (IP) administered substance P (SP1-11), its amino-terminal fragment SP1-7 (SPN) and an analog of the carboxy terminus (pGlu6-SP6-11: SPC) were studied in rats. Two conditioned place preference paradigms were used. After three pairings of the drug with a certain environment the effect of the treatment was evaluated in the drug-free state during a test trial. The reinforcing effects of SP (37 nmol) and the equimolar dose of SPC were expressed by a significant increase in the amount of time the animals spent in the treatment environment. Other doses of SP (3.7 and 185 nmol) and SPC (7.4 and 185 nmol) and none of the doses of SPN (37, 185, 370 nmol) influenced the place preference behavior of the rats. The reinforcing effects of SP parallel the known facilitating effects of peripherally administered SP on memory. The amino acids that encode the reinforcing effects of SP may lie within the C-terminal sequence of the SP molecule.

Animals↗
PubMed1989

Conditioned place preference in the corral: a procedure for measuring reinforcing properties of drugs.

A novel conditioned place preference (CPP) method is described. The behavioral testing apparatus is a circular open field consisting of 4 uniform quadrants that are equally preferred by the rats prior to drug treatment. In an illustrative experiment, rats received an i.p. injection of either morphine (10 mg/kg), substance P (50 micrograms/kg) or vehicle (phosphate-buffered 0.01 M acetic acid in saline) on 3 consecutive days and were placed into their assigned treatment quadrant. Four animals were simultaneously treated with the aid of barriers, which restricted each rat to its treatment quadrant. On the test for CPPs, when provided a choice between the 4 quadrants, rats treated with morphine and substance P exhibited preferences for the quadrant which had been paired with the drugs, illustrating the usefulness of this procedure for assessing the reinforcing properties of the two drugs. Gross locomotor activity was not influenced by either treatment. The advantages of this version of the CPP method over the conventional shuttle-box procedures are discussed.

Animals↗
PubMed1985

D-ala2-Metenkephalinamide blocks the synaptically elicited cortical spreading depression in rats.

Spreading depression (SD) was elicited in rats anesthetized with pentobarbital by a train of 8 electrical pulses (0.1 ms, 10 Hz) applied to parietal cortex. Local application of 50 micrograms of D-ala2-metenkephalinamide (DAME) on the stimulated area evoked one or two SD waves followed by an increase of SD threshold from 40 V to 90 V. This effect could be partly prevented by naloxone (1 mg/kg i.p.) and reversed by local application of 4-aminopyridine (10(-3) M, 2 microliters), which reduced SD threshold to 5 and 20 V in normal and DAME-treated cortex, respectively. It is argued that DAME exerts an inhibitory effect on cortical neurons and that the initial SD facilitation is due to initial blockade of inhibitory neurons in the superficial cortical layers.

Aminopyridines↗
PubMed1985

Threshold of synaptically elicited cortical spreading depression: drug-induced changes in rats.

The role played by synaptic phenomena in the initiation of Leão's spreading depression (SD) was examined in 30 rats anaesthetized with pentobarbital. SD was elicited by a train of 8 electrical pulses (0.1-0.3 msec, 10 Hz) applied through bipolar electrodes to the exposed cortical surface. The slow potential waves of SD were recorded from the stimulated site and from a remote cortical area. Threshold stimulus intensity (40 V) was increased above 80 V when low frequency stimulation (0.3 Hz, 10 V) was applied through the same electrodes. SD penetration into the stimulated area was blocked with higher stimulus rates (3-10 Hz) and intensities (20 V). Systemic application of the pyrrolopyrimidine drug BE 58-271 decreased SD threshold from 40 V to 7 V and reduced also the intensity and frequency of stimulation inducing the SD blockade. Similar effects were obtained with local application of 2 microliters of 10(-3) M 4-amino-pyridine to the stimulated cortex. The SD threshold was reduced from 40 V to 5 V, probably by prolonged depolarization of axon terminals and increased output of transmitters. Estimation of SD threshold revealed a biphasic effect of locally applied penicillin: an initial threshold decrease which gradually changed with the development of regular interictal discharge into a threshold increase and eventual SD blockade. It is concluded that sudden synaptic activation of cerebral cortex elicits SD whereas prolonged continuous stimulation decreases SD susceptibility, probably by enhancing the K+ clearance.

4-Aminopyridine↗
PubMed1985

Radial maze in the water tank: an aversively motivated spatial working memory task.

An 8-arm radial maze with 40 X 40 X 12 cm channels was inserted into a circular tank (120 cm in diameter, 60 cm high) filled 30 cm deep with 25 degrees C opaque water. Rats (n = 13) had to escape from the central area of the maze (30 cm in diameter) onto an invisible bench (1 cm below water surface) at the far end of each channel. Twenty sec after each choice the bench was collapsed and the animal was forced to choose again until all 8 channels had been visited. From the very beginning rats performed better than chance. The acquisition and performance of this aversively motivated radial maze test is similar as in conventional elevated 8-arm radial mazes.

Animals↗