Elsevier

Neuropharmacology

Volume 39, Issue 12, November 2000, Pages 2464-2477
Neuropharmacology

Strain-dependent neurochemical and neuroendocrine effects of desipramine, but not fluoxetine or imipramine, in Spontaneously Hypertensive and Wistar–Kyoto rats

https://doi.org/10.1016/S0028-3908(00)00088-5Get rights and content

Abstract

Spontaneously Hypertensive rats (SHRs) and Wistar–Kyoto (WKY) rats differ in their emotional responses to stress and antidepressant administration. We have analysed different neurochemical and psychoneuroendocrine responses to repeated pretreatments with fluoxetine, imipramine or desipramine (10 mg/kg p.o. daily for 4 weeks) in SHRs and WKY rats exposed to a daily 2-h restraint episode for the last 5 days of antidepressant administration. Following a 24-h wash-out period, WKY rats displayed higher plasma antidepressant and antidepressant metabolite levels than SHRs. Fluoxetine pretreatment decreased [3H]citalopram binding at midbrain serotonin (5-HT) transporters, whereas tricyclic and/or fluoxetine decreased [3H]ketanserin binding at cortical 5-HT2A receptors, [3H]CGP-12177 binding at cortical ß-adrenoceptors, and [3H]nisoxetine binding at midbrain noradrenaline (NA) transporters in both strains. None of the antidepressants affected [3H]8-hydroxy-2-(di-N-propylamino)tetralin binding at hippocampal 5-HT1A receptors. In WKY rats, repeated restraint triggered a desipramine-sensitive 140% increase in hypothalamus [3H]nisoxetine binding; moreover, plasma adrenocorticotropin-releasing hormone responses to a 5-min open field test were amplified by prior repeated restraint in both strains, but desipramine prevented such an amplification in WKY rats only. However, neither elevated plus-maze nor open field behaviors of SHRs and WKY rats were affected by desipramine pretreatment. Thus, the SHR and WKY rat strains may prove useful in understanding how genetic differences in noradrenergic responses to repeated stress and desipramine treatment impact on adaptive processes.

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.

References (74)

  • G. Griebel et al.

    Behavioural effects of acute and chronic fluoxetine in Wistar–Kyoto rats

    Physiology and Behavior

    (1999)
  • J.P. Herman et al.

    Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis

    Trends in Neurosciences

    (1997)
  • O. Hoffmann et al.

    Genetic differences in morphine sensitivity, tolerance and withdrawal in rats

    Brain Research

    (1998)
  • G.A. Kennett et al.

    Female rats are more vulnerable than males in an animal model of depression: the possible role of serotonin

    Brain Research

    (1986)
  • G.A. Kennett et al.

    Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression

    European Journal of Pharmacology

    (1987)
  • A. Lahmame et al.

    Are Wistar Kyoto rats a genetic model of depression resistant to antidepressants?

    European Journal of Pharmacology

    (1997)
  • K.P. Lesch et al.

    Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants

    Molecular Brain Research

    (1993)
  • J.F. Lopez et al.

    Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression

    Biological Psychiatry

    (1998)
  • C. Lopez-Rubalcava et al.

    Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test

    Neuropsychopharmacology

    (2000)
  • W.C. Low et al.

    Genetically related rats with differences in hippocampal uptake of norepinephrine and maze performance

    Brain Research Bulletin

    (1984)
  • A. Maggi et al.

    Differential effects of antidepressant treatment on brain monoaminergic receptors

    European Journal of Pharmacology

    (1980)
  • R. McCarty

    Stress, behavior and experimental hypertension

    Neuroscience and Biobehavioral Reviews

    (1983)
  • T. Miyawaki et al.

    Altered basal firing pattern and postactivation inhibition of locus coeruleus neurons in spontaneously hypertensive rats

    Neuroscience Letters

    (1992)
  • R. Mongeau et al.

    The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments

    Brain Research Reviews

    (1997)
  • A.A. Palmer et al.

    Strain differences in Fos expression following airpuff startle in spontaneously hypertensive and Wistar Kyoto rats

    Neuroscience

    (1999)
  • W.P. Paré

    Stress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats

    Physiology and Behavior

    (1989)
  • S. Pellow et al.

    Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat

    Journal of Neuroscience Methods

    (1985)
  • F. Pollier et al.

    Serotonin reuptake inhibition by citalopram in rat strains differing for their emotionality

    Neuropsychopharmacology

    (2000)
  • A. Ramos et al.

    A multiple test study of anxiety related behaviours in six inbred rat strains

    Behavioral Brain Research

    (1997)
  • A. Ramos et al.

    A genetic and multifactorial analysis of anxiety-related behaviours in Lewis and SHR intercrosses

    Behavioral Brain Research

    (1998)
  • K.J. Ressler et al.

    Role of norepinephrine in the pathophysiology and treatment of mood disorders

    Biological Psychiatry

    (1999)
  • G. Spurlock et al.

    Lack of effect of antidepressant drugs on the levels of mRNAs encoding serotonergic receptors, synthetic enzymes and 5-HT transporter

    Neuropharmacology

    (1994)
  • S.M. Tejani-Butt et al.

    Effect of repeated novel stressors on depressive behavior and brain norepinephrine receptor system in Sprague-Dawley and Wistar Kyoto (WKY) rats

    Brain Research

    (1994)
  • D.T. Wong et al.

    Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication

    Life Science

    (1995)
  • H.M. Zafar et al.

    Effect of acute or repeated stress on behavior and brain norepinephrine system in Wistar–Kyoto (WKY) rats

    Brain Research Bulletin

    (1997)
  • S. Benmansour et al.

    Effects of chronic antidepressants treatments on serotonin transporter function, density, and mRNA level

    Journal of Neuroscience

    (1999)
  • L. Bertilsson et al.

    Polymorphic drug oxidation

    Clinical Concepts

    (1996)
  • Cited by (0)

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