Strain and line differences in the HPA axis Fischer 344 and Lewis rats

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Fischer 344 (F344) rats were originally bred at Columbia University in 1920 by Curtiss and Dunning. Lewis (LEW) rats were originally developed by Margaret Lewis from the Wistar strain. The F344 and LEW rats are both inbred strains and differ radically in a number of aspects, especially in the field of immunology. Thus, LEW rats are highly susceptible to many inflammatory agents (Sternberg et al., 1989a,b). However, these animals differ in many other respects as well, especially in relation to the dopaminergic system. Thus, LEW rats self-administer opiates, cocaine and alcohol to a much greater extent than F344 rats (Suzuki et al., 1988; George and Goldberg, 1989), show a stronger locomotor response to methamphetamine and cocaine (Camp et al., 1994), and a stronger stereotyped gnawing response to apomorphine (Ellenbroek and Cools, 2002). In addition, LEW rats show a stronger dopamine release in the accumbens after methamphetamine or cocaine administration than F344 rats (Camp et al., 1994). Interestingly, under baseline conditions, LEW rats have significantly smaller number of dopaminergic cells within the ventral tegmental area than the F344 rats (Harris and Nestler, 1996), as well as lower levels of dopamine D3 receptors (in the nucleus accumbens shell) and dopamine transporter (throughout the dopaminergic terminal fields (Flores et al., 1998)). In other words, compared to F344 rats, LEW rats are characterised by a dopaminergic system, which is relatively inactive at baseline, but much more reactive after dopaminergic manipulations.

It is not surprising that F344 and LEW rats also show clear differences in stress responsiveness since dopamine, and especially the mesolimbic and mesocortical dopaminergic systems are intimately involved in the regulation of the stress response. There is general agreement that F344 and LEW rats do not differ in baseline HPA parameters. Thus baseline plasma levels of ACTH and corticosterone are similar in young and adult, F344 and LEW rats (Chaouloff et al., 1995; Armario et al., 1995; Stohr et al., 2000). However, LEW rats have been reported to show less diurnal variation in plasma corticosterone, with levels rising less in the late afternoon, just prior to the onset of activity (Dhabhar et al., 1993). However, compared to F344 rats, LEW rats show a blunted ACTH and/or corticosterone response after stressful events such as restraint stress (Stohr et al., 2000), forced swimming (Armario et al., 1995), footshock (Rivest and Rivier, 1994) or tailshock (Gomez et al., 1998). Typically, the ACTH and corticosterone response is not only smaller but also shorter in duration (Stohr et al., 2000). This is suggestive of a disturbance in the central feedback mechanism. However, recent studies using dexamethasone to probe the negative feedback mechanism showed that there were no differences between F344 and LEW rats (Gomez et al., 1998). In agreement with this, no differences were found in glucocorticoid receptors (GR) or mineralocorti-coid receptor (MR) numbers in the hypothalamus between F344 and LEW rats, though F344 had higher levels of both receptors in the hippocampal formation (Gomez et al., 1998). F344 and LEW rats also showed similar increase in c-fos mRNA activity in the PVN of the hypothalamus after footshock (Rivest and Rivier, 1994), and normal CRF gene expression under basal conditions and after stress (Gomez et al., 1996). One possible factor involved in the reduced HPA axis response of LEW rats may be the reduced content of AVP in the hypothalamus (Whitnall et al., 1994). Since AVP plays a permissive role in the pituitary gland, this would lead to a reduced ACTH release. Attractive as this hypothesis may be, it is important to realise that AVP is thought to primarily play a role under chronic stressful situations. Alternatively, the fundamental difference between F344 and LEW rats may be related to a reduced CRF production at the level of the PVN (Million et al., 2000; Opp and Imeri, 2001; Tonelli et al., 2002; Michaud et al., 2003). One possible mechanism for this reduced PVN functioning was recently proposed by Chikada and colleagues. They showed that after a lipopolysaccharide challenge not only the CRF production was significantly lower in LEW than in F344 rats, but the LEW rats also did not show an increase in neuronal nitric oxide synthase (nNOS) mRNA expression. This suggests that the reduced activity of the PVN neurons of LEW rats after stress may be (in part) due to an inability to increase NO production. In addition, there is some evidence that LEW rats also have a disturbance at the level of the adrenal cortex. Thus the corticosterone release to a standard dose of ACTH is significantly lower in LEW than in F344 rats (Grota et al., 1997). This hypo-sensitivity might be due to reduced numbers of ACTH receptors, though this has not been investigated to the best of our knowledge.

In summary, although the F344 and LEW rats do not differ very much in baseline HPA axis activity, LEW rats show a blunted HPA axis response to a variety of stressors. F344, on the other hand show a strong HPA axis response.

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