For F344 and LEW rats have been studied in such great detail, they have also been compared to other inbred and outbred strains. In a series of experiments, Armario and his colleagues investigated the HPA axis sensitivity of F344, LEW, Brown Norway (BN), spontaneous hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, using the forced swim test. They studied both behaviour (struggling and immobility times) and various biochemical parameters. At the behavioural level, WKY and BN showed low levels of struggling, LEW and SHR showed intermediate levels and F344 were the most active during the first exposure (Armario et al, 1995). A similar pattern was observed during the actual test (re-exposure 24 h after the first exposure), with WKY and BN being least active and LEW, SHR and F344 being the most. The reverse pattern was seen with the immobility patterns: WKY showed the longest immobility time, closely followed by the BN rats, while F344, LEW and SHR showed significantly lower levels of immobility. Since immobility scores are often considered to be related to depression, it has been suggested that the WKY might represent an interesting model for depression (Lahmame and Armario, 1996). Endocrinologically, a somewhat different pattern emerges. After stress, F344 and WKY rats showed the highest corticosterone response and LEW rats the lowest. A comparable picture emerges for the stress-induced ACTH release: highest in F344, lowest in LEW and with intermediate levels in BN, WKY and SHR. A similar pattern occurred after novelty stress, with BN (and Dark Agouti, DA) showing a more pronounced stress-induced increase in ACTH and corticosterone than LEW rats (Stefferl et al, 1999). Although these data suggest that the BN, WKY and SHR show an intermediate HPA axis response to stress, the actual situation is more complex. Analysis of the brain CRF content showed that BN showed the highest CRF binding in the hippocampal area and the prefrontal cortex. Moreover, BN rats also have the highest levels of CRF in the prefrontal cortex (Lahmame et al,
1997). Together with the finding that the dexametha-sone suppression test was less effective (Gomez et al,
1998), this indicates that BN rats show clearcut differences in the HPA axis activity compared to most other strains. In agreement with this, BN rats have larger adrenal glands but lower novelty stress-induced corticosterone levels than normal Wistar or F344 rats (Sarrieau et al, 1998). Strangely enough, although it did not reach significance, BN rats showed the strongest ACTH response to novelty. Finally, BN rats appear to have a disturbance in the normal diurnal rhythm. Although BN and F344 rats showed a steady rise in corticosterone levels during the day, BN rats showed a large drop after 20.00 h leading to very low levels at 24.00 h and 4.00 h, lower than the levels at 12.00 (Sarrieau et al, 1998).
In an extensive study, Oitzl et al. (1995) compared the HPA axis between LEW and Wistar (WIS) rats. Since WIS rats represent an outbred strain, the data should be interpreted with some care, and cannot be considered to be representative for all WIS rats. As discussed below, there is a lot of heterogeneity within the WIS population. Moreover, as was shown by many authors, there are clear differences between WIS from different breeders (Kinney et al, 1999; Swerdlow et al, 2000). According to this study LEW rats have significantly lower levels of ACTH and corticosterone than WIS rats, both in basal levels (only in the evening) and after exposure to novelty. Interestingly, exposure to ether did not differentially affect the stress response in both strains of animals (Oitzl et al, 1995). This differential response seems to be due to alterations at different levels of the HPA axis. Thus, LEW rats have significantly fewer adrenocortical cells, and the ACTH-induced release of corticosterone is also significantly smaller in LEW rats when compared to WIS rats (even when corrected for the total number of cells). Moreover compared to LEW rats, WIS rats have a reduced number of MR in the hippocampus and the hypothalamus, and an increased number of GR in the pituitary gland (Oitzl et al, 1995). Finally, the mRNA levels for CRF in the PVN are significantly lower in LEW rats, which is in line with the increased MR levels in the hypothalamus, since MR inhibit the synthesis and release of CRF from the PVN. MR also play a pivotal role in regulating the HPA axis both under basal and stress conditions. Since MR are largely occupied by corticosterone under baseline conditions (Reul and de Kloet, 1985) and reduce the baseline release of CRF and ACTH, the increase in MR in LEW rats is in line with the lower basal corticosterone release. However, MR may also be involved in the sensitivity of the feedback mechanism (Reul et al., 2000). Overall then, the disturbances in the HPA axis of the LEW rats appear to be due to abnormalities at all levels in the system.
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