Lewis/Fischer rat strain differences in endocrine and behavioural responses to environmental challenge.

The Lewis (LEW) and Fischer (F344) rat strains provide a comparative model of hypothalamic-pituitary-adrenal (HPA) function in which LEW is relatively hypoactive at homeostasis and hyporeactive to environmental challenge. The present study describes a comparison of LEW and F344 rats, males and females, in terms of their corticosterone (CORT) or behavioural responses to a range of behavioural tasks, where each of the tasks used contains a stressor component and has been demonstrated to be sensitive to corticotropin releasing factor (CRF) and/or CORT manipulation: acoustic startle response (ASR), elevated plus maze, schedule-induced polydipsia, and fear-conditioned suppression of drinking. Our aim was to determine to what extent the LEW trait of HPA axis hyporesponsiveness is associated with strain differences in behavioural responsiveness to environmental challenge. As expected, young (2-3 months)-mature (5-10 months) LEW males and females exhibited a lesser CORT response to restraint and novel confinement than did F344 males and females, although in old adulthood (18 months) the CORT stress response was equable in LEW/F344 males and actually higher in LEW than in F344 females. In young-mature adults, the ASR was greater in LEW males than in the other groups; all groups spent a low proportion of time on the open arms of the elevated plus maze; polydipsia was greater in F344 females than in the other groups; and fear-conditioned suppression of drinking was greater in F344 males and females than in LEW males and females. Therefore, relative hyporeactivity of the HPA axis in LEW rats is clearly not associated with uniform behavioural hyporeactivity, including CRF-dependent behaviours. Rather, this study suggests further evidence that environmental reactivity reflects a number of distinct emotional states and underlying neural circuits.

Prenatal stress in rats: effects on plasma corticosterone, hippocampal glucocorticoid receptors, and maze performance.

The present experiments were designed to investigate the effects of maternal stress on cognitive and endocrine parameters in the adult offspring. Pregnant rats were stressed daily during the last week of pregnancy (days 15-19) by restraint, and the performance of their offspring in the Morris water maze was recorded. Plasma corticosterone levels after swimming and the status of hippocampal glucocorticoid receptors (GRs) were determined. During acquisition of the task, prenatally stressed (PS) males - but not females - showed longer escape latencies than non-stressed controls when swimming in cold (10 degrees C) but not in warm (20 degrees C) water. This sex- and prenatal stress-specific difference was even more pronounced during reversal learning of the task. In contrast, PS females - but not males - had higher basal corticosterone levels and a lower density of hippocampal corticosteroid receptors than non-stressed controls. In all animals irrespective of treatment, swimming in the water maze causes an increase of corticosterone that was smaller on day 8 of swimming than on day 1. After swimming in cold water, the rise in corticosterone levels in females was steeper and returned faster to baseline values than after swimming in warm water. A similar pattern could be seen in PS females when compared to their non-stressed controls. The data suggest that prenatal stress impairs spatial learning in males but not in females. Basal and stress-induced increases in corticosterone levels, however, were altered in PS females and not in PS males; i.e., prenatal stress-induced changes in corticosterone secretion were not paralleled by prenatal stress-induced deficits in spatial learning.

Behavioural and hormonal differences between two Lewis rat lines.

Lewis (LEW) is an inbred strain of rats frequently used as an animal model of autoimmune diseases. However, there is evidence that some lines of LEW rats develop autoimmune diseases more readily than do other LEW rat lines. Because the hypothalamus-pituitary-adrenal system is involved in the pathophysiology of these diseases, we compared two LEW lines (SsNHsd and HANRijHsd) in their behavioural and neuroendocrine response to stress. In addition, we studied the psychostimulant effects of acute and repeated amphetamine in these two LEW rat lines. HAN rats were less active in the open field test and showed faster habituation of novelty-induced locomotion. The acoustic startle response was lower in HAN than in SSN rats, whereas prepulse inhibition of the startle response was greater in the HAN than in the SSN LEW subline. Moreover, HAN rats showed impaired acquisition of the two-way active avoidance response relative to SSN rats. The psychostimulant effects of acute amphetamine were smaller in HAN rats. Following repeated injections of amphetamine, behavioural sensitization to the psychostimulant effects of amphetamine was more pronounced in HAN than in SSN rats. Basal concentrations of serum corticosterone did not differ between the two rat lines. Following stress, however, HAN rats showed slightly higher corticosterone secretion than SSN rats. Our results show that two sublines of the LEW inbred strain of rats show profound behavioural differences which are only marginally paralleled by differences at the level of the HPA system.

Differential effects of prenatal stress in two inbred strains of rats.

The long-term effects of prenatal stress (three times daily restraint stress during the last week of gestation) on the behavioral response to stress, as assessed by novelty-induced locomotion, performance in the forced swim test, and the acquisition of a two-way active avoidance, were investigated in two inbred strains of rats, Fischer 344 (F344/NHsd/Zur) and Lewis (LEW/SsNHsd/Zur). Additional measures included birth weights, pain threshold on the hot plate, and basal and stress-induced corticosterone secretion. In all of the behavioral paradigms strain differences were found: LEW rats showed poorer acquisition of avoidance conditioning, displayed higher levels of activity on the open plate, less immobility time in the forced swim test, and lower pain thresholds in the hot-plate test compared with F344 rats. LEW rats had higher birth weights after prenatal stress, whereas F344 rats were lighter. Following prenatal stress the pattern of behavioral effects obtained in LEW rats in stress-related tests could be interpreted as improved coping abilities with stress, i.e., improved acquisition of active avoidance, less immobility in the forced swim test, and reduced novelty-induced locomotion. Prenatal stress was much less effective in inducing long-term behavioral changes in F344 rats, yielding only one effect, namely, enhanced novelty-induced locomotion in female F344 rats. Pain thresholds were increased as a consequence of prenatal stress, irrespective of strain and gender. Basal and stress-induced corticosterone release differed in the two strains, with LEW rats showing less stress-induced corticosterone release. Prenatal stress did not, however, affect basal or stress-induced corticosterone release. The results suggest that prenatal stress exerts long-term effects on behavior, which depend on the genetic background.

Steroid receptors in the rat hippocampus: a note to the methodology of their binding assay.

Mineralocorticoid (MR) and glucocorticoid (GR) receptors in the rat hippocampus are linked to several cognitive functions of the animal and seem to play an important role in the response to various stressors. Their assessment by binding experiments brings about problems associated with their intracellular compartmentalization, and in particular with the separation of the bound and free ligands. Adrenalectomy 24 h before sacrificing is commonly used to clear the circulating adrenal steroids, and to facilitate their dissociation from hippocampal MR and GR. We have successful attempted to use dialysis to these purposes and thus, to avoid a potential surgical stress. Without dialysis, only GR can be measured in the cytosol from intact rats, while the corresponding pellet contains MR as a component of the cell nuclei. The bound ligand fraction was separated by filtration on polyethyleneimine pretreated glass fiber filters as suggested earlier. The method has clear-cut preferences compared to any alternative used up to now. Discrimination between the two receptor types can be optimally achieved in a cross-displacement experiment in which two labeled ligands possessing various affinities to individual receptors (in our case: corticosterone and aldosterone, or their synthetic analogs) are displaced with the two corresponding nonlabelled ligands from their receptors. Computations can be carried out with LIGAND software which yield accurate values of binding parameters.

Water maze performance and hippocampal weight of prenatally stressed rats.

Prenatally stressed rats were tested for water maze performance with the water temperature kept at 18 degrees C (low stress) or cooled down to 12 degrees C (high stress). When the platform had been removed from the pool and the water was kept at 12 degrees C, prenatally stressed males--but not females--spent more time searching for the platform in the correct quadrant of the pool than their controls. Prenatal stress reduced hippocampal weight in both sexes.

Prenatal stress effects on exploratory activity and stress-induced analgesia in rats.

Pregnant rats were exposed three times daily to immobilization stress during gestational Days 15-19. The behavior of their offspring was compared with the behavior of offspring from unstressed control mothers. Although the stress procedure decreased the weight gain of mothers during pregnancy, it slightly but significantly increased the weight of their offspring at birth and at weaning. On postnatal Day 10, prenatally stressed pups returned to their home cage more quickly than did prenatally unstressed control pups during a nest odor discrimination task, but no differences between groups in the number of correct responses were found. On postnatal Days 70-72, prenatally stressed offspring showed increased exploratory activity in a complex tunnel maze compared with control offspring. On postnatal Day 80, analgesia induced by stress (swimming for 3 min in cold water) was determined (tail flick latency). The degree of stress-induced analgesia was smaller in prenatally stressed rats than in control rats. These data suggest that the effects of prenatal stress on behavior are most clearly discernable when such animals are confronted with a novel or stressful situation.