O

a Sal-Sal a Sal-LPS

C Imp-UPS

a Sal-Sal a Sal-LPS

C Imp-UPS

Saccharin

Water

Saccharin

Water

Saccharin

Water

Figure 3. Effects of acute and chronic treatment with imipramine on mean (+S.E.M.) consumption of saccharin solution or water measured 4 hours after LPS or saline (Sal) administration. A: The acute effects of imipramine (Imip) were examined by administering either imipramine or saline immediately before LPS,'Sal injection, B:The chronic effects of inipraminc were examined ill the same rats following daily injections of either imipramine or saline for 3 weeks.

6.2. Mechanisms of the Effects of Antidepressants on Immune Activation-Induced Depressive Symptoms

6.2.1. Alterations in Cytokine Production. The effects of antidepressants on immune functions, including cytokine production, have been assessed both in depressed patients, and in experimental animal models. In depressed patients, the effects of antidepressants seem to be related to the immune status of the patients at the initiation of the treatment. When depression was associated with immune activation, antidepressants suppressed immune function and cytokine secretion. For example, the increased plasma levels of IL-6 during acute depression were normalized by 8-week treatment with fluoxetin (Sluzewska et al., 1995), the increased monocyte counts in depressed patients were reduced following 6-weeks treatment with tricyclic antidepressants (Seidel et al., 1996), and the increased numbers of leukcytes and neutrophils were also reduced by antidepressant treatment (Maes, Vandoolaeghe, Van Hunsel, Bril, Demedts, Wauters, & Neels, 1997b). On the other hand, when immune functions were found to be normal, antidepressants had no effects, e.g., chronic moclobemide treatment had no effect on monocytes functions, TNFa production or IFNy levels (Landmann, Schaub, Link, & Wacker 1997). Moreover, in a study of depressed patients who exhibited immune suppression before treatment, the tricyclic antidepressant clomipramine increased the production of IL-lp, IL-2, and IL-3 (Weizman, Laor, Podliszewski, Notti, Djaldetti, & Bessler, 1994).

In experimental animals, antidepressants (both TCAs and SSRIs) produce mainly immune suppression and anti-inflammatory effects (Albrecht, Helderman, Schlesser, & Rush, 1985; Audus & Gordon, 1982; Eisen, Irwin, Quay, & Livnat, 1989; Miller, Asnis, van Praag, Norin, 1986; Xiao & Eneroth, 1996). Antidepressant treatment in vivo was found to reduce immune activation in several models: it inhibited the increased acute phase response in olfactory bulbectomized rats, a useful animal model of depression (Song & Leonard, 1994), reduced IL-1 and IL-2 production in a chronic mild stress model of depression (Kubera, Symbirtsev, Basta-Kaim, Borycz, Roman, Papp, & Claesson, 1996), and inhibited immune activation in rats with experimental allergic neuritis (Zhu, Bengtsson, Mix, Thorell, Olsson, & Link, 1994). Anti-inflammatory properties were demonstrated for both fluoxetin and clomipramine in carrageenin or brewer's yeast-induced inflammation (Bianchi, Rossoni, Sacerdote, Panerai, & Berti, 1995; Bianchi, Sacerdote, & Panerai, 1994a, b). Some of the effects of antidepressants are probably mediated by a direct action on immune cells; TCAs were found to inhibit spontaneous secretion of IL-2 and IFNy form T-cells, as well as spontaneous and LPS-induced secretion of IL-1 and IL-6 and TNFa from monocytes (Xia, DePierre, & Nassberger, 1996). Similarly, the antidepressant rolipram was found to suppress TNFa and (to a lesser extent) also IFNy secretion by human and rat auto-reactive T-cells (Sommer, Loschmann, Northoff, Weller, Steinbrecher, Steinbach, Lichtenfels, Meyermann, Riethmuller, Fontana, Dich-gans, & Martin, 1995).

These findings suggest that the effects of antidepressants on LPS-induced sickness behavior and corticosterone secretion, found in our studies, are mediated by changes in immune reactivity to LPS (particularly reduced production of cytokines). To elucidate these mechanisms we have recently examined the effects of chronic fluoxetin on the expression of TNFa and iNOS mRNA following LPS administration. Preliminary evidence suggests that LPS-induced TNFa mRNA in splenocytes was attenuated in fluoxetin-treated rats. Furthermore, LPS-induced expression of iNOS was saline rozac saline rozac

Figure 4. Effects of chronic treatment with fluoxetin on LPS-induced expression of iNOS and P-actin (as control) mRNA in the spleen.

P-actin iNOS

P-actin iNOS

Figure 4. Effects of chronic treatment with fluoxetin on LPS-induced expression of iNOS and P-actin (as control) mRNA in the spleen.

also markedly attenuated (Fig. 4), suggesting that the immune-suppressive effect of chronic fluoxetin treatment on splenocytes is general, and not specific to TNFa.

Following chronic treatment with either saline (Sal) or fluoxetin (Prozac, lOmg/kg injected daily for 5 weeks), rats were injected acutely with either saline or LPS (100pg/kg). Spleens were removed 2 hr post-injection and iNOS mRNA levels assessed by RT-PCR analysis. The results represent data from individual spleens, obtained during one replication of this experiment.

Previous studies have clearly demonstrated that TNFa is involved in mediating the effects of various immune challenges on food consumption, body weight and HPA axis activation. Exogenous administration of TNFa produced anorexia, body weight loss, and pituitary-adrenal activation (Plata-Salaman, 1998; Sonti et al., 1996; Van der Meer, Fred Sweep, Pesman, Borm, & Hermus, 1995; Warren, Finck, Arkins, Kelley, Scamurra, Murtaugh, & Johnson, 1997). Moreover, TNFa synthesis blockers or antibodies to TNFa suppressed the anorexia, body weight loss, and adrenocortical activation produced by various immune challenges (Breuille, Farge, Rose, Arnel, Attaix, & Obled, 1993; Smith, & Kluger, 1993; Wohlman, Gallily, Yirmiya, & Weidenfeld, 1997). Thus, the attenuation of LPS-induced TNFa expression in fluoxetin-treated rats may explain at least some of the reduction of anorexia, body-weight loss, and adrenocortical activation in these rats.

6.2.2. Alteration in Monoaminergic Systems. In addition to their direct effects on cytokines, antidepressants may suppress the behavioral and neuroendocrine effects of LPS by modulating monoaminergic neurotransmission.

Both imipramine and fluoxetin are monoamine reuptake inhibitors (imipramine inhibits the reuptake of both norepinephrine and serotonin, whereas fluoxetin is an SSRI) (Montgomery, 1994). The basis for the therapeutic effects of these drugs is not clear. Chronic, but not acute, treatment produces adaptive changes in several neural systems, particularly monoaminergic systems and the HPA axis. For example, animal studies demonstrated that chronic imipramine reduces the number and function of (3-adrenergic and serotonergic (5-HT2) receptors (Burnet, Michelson, Smith, Gold, & Sternberg, 1994), and decreases tyrosine hydroxylase and CRH mRNA levels (Brady, Whitfield, Fox, Gold, & Herkenham, 1991). Chronic administration of fluoxetin was also found to down regulate serotonergic receptors functions (Leonard, 1994; Newman, Shapira, & Lerer, 1992). These changes may be relevant to the effects of LPS observed in our study, since LPS administration has been found to increase the turnover of norepinephrine and serotonin in several brain areas (Dunn & Welch, 1991; Dunn & Wang, 1995; Linthorst, Flachskamm, Holsboer, & Reul, 1995a; Linthorst, Flackskmann, Muller-Preuss, Holsboer, & Reul, 1995b). Although there is no direct evidence for the involvement of monoamines in mediating LPS-induced sickness behavior symptoms, we have recently found that pretreatment with the al adrenoreceptor antagonists prazosin and urapidil significantly attenuated IL-1-induced sickness behavior (Pollak, Avitsur, Canaan, & Yirmiya, 1998). Similarly, pretreatment with the serotonin "synthesis blocker PCPA attenuated several sickness behavior symptoms (Zubareva, Abdurasulova, Bluthe, Dantzer, & Klimenko, 1998). Thus, it is possible that following chronic treatment with antidepressants, the activation of monoaminergic systems by LPS is reduced, and this reduction may be responsible for the attenuation of the behavioral anhedonia and sickness behavior.

6.3.3. Alterations in the HPA Axis. Chronic treatment with antidepressants also alters the functioning and regulation of the HPA axis (Holsboer & Barden, 1996). Chronic, but not acute, administration of imipramine (Barden, Reul & Holsboer, 1995) or fiuoxetin (Brady, Gold, Herkenham, Lynn, & Whitfield, 1992) were found to increase the levels of glucocorticoids receptors in the hippocampus (Brady et al., 1992), which normally mediate the negative feedback response to LPS-induced activation of the HPA axis (e.g., Weidenfeld & Yirmiya, 1996). In experimental animals, long term administration of fiuoxetin, as well as tricyclic antidepressants, inhibits the pituitary-adrenal response to various challenges (Li, Levy, Cabrera, Brownfield, Battaglia, & Van de Kar, 1993; Reul, Stec, Soder, & Holsboer, 1993). Similarly, chronic imipramine treatment was found to normalize the hyperactive HPA axis in successfully treated depressed patients (Holsboer, Liebel, & Hofschuster, 1982). Finally, following long (8 weeks), but not short (2 weeks) treatment with Fiuoxetin, CRH mRNA was decreased by 30-48% in the hypothalamic PVN (Brady et al., 1992).

CRH within the brain mediates many of the behavioral and neuroendocrine effects of immune challenges (e.g., Bluthe, Crestani, Kelley, & Dantzer, 1992; Uehara, Sekiya,Takasugi, Namiki, & Arimura, 1989;Tilders et al., 1994;Turnbull & Rivier, 1995). Thus, it may be suggested that the attenuation of CRH system induced by antidepressants is also involved in the reduction of the behavioral and neuroendocrine depressive-like symptoms induced by immune activation.

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