Strain-dependent neurochemical and neuroendocrine effects of desipramine, but not fluoxetine or imipramine, in Spontaneously Hypertensive and Wistar–Kyoto rats
Introduction
There is growing evidence for a significant, albeit not unique, impact of genetics in both the aetiology of mood disorders (Bouchard, 1994; Plomin et al., 1994) and the efficacy of psychotropes (May, 1994; Rudorfer and Potter, 1997; Smeraldi et al., 1998). Although the functional impacts of allelic variations in relevant genes have been detected in mood disorders (Collier et al., 1996a, Collier et al., 1996b; Lesch et al., 1996) and drug efficacy (May, 1994; Rudorfer and Potter, 1997), mechanisms underlying the genetic variability in emotivity processes and responses to psychotropes have yet to be discovered. Among the animal models available so far to study such an impact of genetics, mice bearing a selective disruption of a gene encoding for a receptor protein or an enzyme have proved useful (Piciotto, 1999). However, the limits of these models (e.g. all-or-none response, genetic background, compensatory mechanisms; Piciotto, 1999) underline the need for complementary models, especially in rat research. Indeed, one such paradigm may be the comparison of inbred rat strains for their behavioral, neurochemical and/or neuroendocrine responses to stress and antidepressant/anxiolytic drugs. This approach first allows an analysis of the respective genetic impacts of candidate targets within complex and integrative systems, and also permits the recognition, through molecular genetic tools, of chromosomal loci associated with complex traits, including behavioral ones (Moisan et al., 1996; Ramos et al., 1999).
In this context, we have recently investigated the effects of a 3-week treatment with the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine (Wong et al., 1995) on anxiety-related behaviors, corticotropic activity and key direct (5-HT transporter) and indirect (hippocampal 5-HT1A and cortical 5-HT2A receptors) serotonergic targets of antidepressants in spontaneously hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats (Durand et al., 1999). Interestingly, it was observed that fluoxetine exerted anxiogenic effects and stimulated the corticotropic axis in WKY rats, a stress-sensitive strain (Paré and Tejani-Butt, 1996), but not in the hyperactive and hypoanxious SHR (Durand et al., 1999). This study thus suggested that the psychoneuroendocrine effects of SSRIs tightly depend on the genetic status of the individual. However, such a study left open the following questions. First, fluoxetine was administered i.p. instead of p.o., as in humans, thus questioning the clinical relevance of our results. Second, all rats were controls (i.e. left undisturbed), thus raising the possibility that fluoxetine would be endowed with opposite effects in stressed rats. Third, only fluoxetine was used, thereby impeding any conclusion as to whether other drugs acting on serotonergic systems, but also on other candidate systems (such as the noradrenergic ones; Ressler and Nemeroff, 1999), would exert behavioral and neuroendocrine effects similar to those exerted by fluoxetine.
With these questions in mind, we have set up different series of experiments in which SHRs and WKY rats were treated p.o. for 4 weeks with either fluoxetine, imipramine (which first acts on serotonergic and noradrenergic systems; Johnson, 1991), or desipramine (the main metabolite of imipramine, which first acts on noradrenergic systems; Johnson, 1991). Moreover, half of the animals were subjected to a daily restraint stress during the last 5 days of the final week of treatment. All rats were examined for (i) key serotonergic (5-HT transporters, hippocampal 5-HT1A and cortical 5-HT2A receptors) and noradrenergic (cortical β-adrenoceptors, midbrain and hypothalamic noradrenaline (NA) transporters) targets of antidepressants, (ii) adrenocorticotropin releasing hormone (ACTH) responses to an acute stressor (open field exposure), and (iii) behaviors in the elevated plus-maze (end of the third week of treatment) and open field (24 h after the end of the 4-week treatment).
Section snippets
Animals and housing conditions
Male SHRs and WKY rats (IFFA CREDO, Les Oncins, France), aged 4–5 weeks on arrival, were housed four per cage under constant temperature (22±1°C) and a 12-h light/dark cycle (lights on at 07:00 h), with food and water ad libitum. All rats were used at least 2 weeks after their arrival. The minimal number of animals was used in the present study, and all efforts were made to avoid suffering of the animals (the protocol followed the rules established by the French legislation on animal welfare;
Antidepressant and antidepressant metabolite levels in SHRs and WKY rats
Fig. 1 reports circulating antidepressant and antidepressant metabolite levels 22–24 h after a 28-day treatment with fluoxetine, imipramine or desipramine in SHRs and WKY rats. Norfluoxetine, the main metabolite of fluoxetine, accumulated to a much higher extent than the parent drug in fluoxetine-pretreated rats. With regard to tricyclics, imipramine was not detected in imipramine-pretreated rats, as opposed to its main metabolite, desipramine; on the other hand, the latter molecule was
Discussion
Numerous reports (McCarty, 1983; Gentsch et al., 1987; Söderpalm, 1989; Paré, 1989), including ours (Ramos et al., 1997; Durand et al., 1999), have indicated that WKY rats display high anxiety and low locomotor reactivity compared with SHRs. The present study partly confirmed these differences as strain-dependent behaviors in the elevated plus-maze, i.e. total arm visits (an index of activity and anxiety: Ramos et al., 1997) and percent time in open arms (an index of anxiety: Ramos et al., 1997
Acknowledgements
The authors thank the Direction of the CHS Charles Perrens for providing technical help with blood antidepressant analyses and Y. Mellerin for taking care of the animals. Financial support for this study was provided by INSERM, INRA and Le Conseil Régional d'Aquitaine. M.D. was supported by L'Association pour la Recherche Médicale en Aquitaine, La Société de Secours des Amis des Sciences, and La Fondation pour la Recherche Médicale.
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