Antidepressants have been used successfully in treating depressive symptoms associated with various medical conditions (Katon & Sullivan, 1990). Both tricyclic antidepressants (TCAs) (Schiffer & Wineman, 1990) and selective serotonin reuptake inhibitors (SSRIs) (Scott, Nussbaum, McConnell, & Brill, 1995) have been used successfully in the treatment of depression associated with multiple sclerosis, stroke (Lauritzen, Bjerg Bendsen, Vilmar, Bjerg Bendsen, Lunde, & Bech, 1994), Alzheimer's disease (Gottfries, 1997;Tueth, 1995), HIV infection (Ayuso, 1994; Rabkin, Wagner, & Rabkin, 1994), and depression induced by IFN administration (e.g., in hepatitis C or multiple sclerosis patients) (Levenson & Fallon, 1993; Mohr, Goodkin, Likosky, Gatto, Baumann, & Rudick, 1997).
To further elucidate the relationship between immune activation and depression, and explore the mechanisms underlying the therapeutic action of antidepressants, we employed an experimental animal model. Specifically, we examined the effects of antidepressants on LPS- or IL-1-induced behavioral and neuroendocrine alterations in rats.
6.1. Effects of Imipramine and Fluoxetin on LPS- and IL-l-Induced Sickness Behavior and Adrenocortical Activation
We first tested the effects of the tricyclic antidepressant imipramine on LPS-induced anhedonia, using the saccharin preference paradigm. Rats were habituated to a drinking deprivation schedule and to the taste of saccharin for several days before the experiment. On the first experiment day, rats were injected acutely with either imipramine or saline, immediately followed by an injection of either LPS or saline. Four hours later, animals were presented with two tubes containing either saccharin or water, and fluid consumption was measured over a priod of 20 minutes. For 3 weeks following this test, rats received only water, along with a daily injection of either imipramine or saline according to their respective group assignment during the first drinking test. On the last injection day (chronic imipramine test), the rats received either LPS or saline, according to their group assignment during the acute imipramine test, and the consumption of saccharin and water was measured 4 hours later. In the first expeimenal day, LPS significantly suppressed the consumption of saccharin, but not water, and this suppression was not attenuated by acute administration of imipramine. However, chronic imipraminetreatment, completely abolished the suppressive effect of LPS on saccharine consumption (Yirmiya, 1996).
Chronic administration of imipramine (daily injection for 5 weeks) attenuated many other behavioral effects of LPS. Imipramine-treated rats exhibited facilitated recovery from LPS-induced anorexia, body-weight loss, and reduced social activity. In addition, they did not demonstrate LPS-induced suppression of locomotor and exploratory behavior in the open field test. In another experiment, we showed that acute administration of imipramine did not have such effects, i.e., there was no effect of acute imipramine on LPS-induced reduction in food consumption, body weight, social exploration, and open-field activity. The dissociation between the effects of acute and chronic imipramine treatment is important, since in clinical settings, imipramine is also effective in alleviating depression only following chronic, but not acute administration (Montgomery, 1994).
In subsequent experiments we showed that chronic administration (daily injections, 5 weeks) of fluoxetin also affected some, but not all the alterations produced by LPS. Fluoxetin significantly attenuated LPS-induced reduction in food consumption and body weight, but did not affect LPS-induced decrease in social interaction and activity in the open-field test. Chronic fluoxetin treatment also attenuated LPS-induced secretion of corticosterone (Yirmiya, Weidenfeld, Pollak, Avitsur, Barak, & Ovadia, unpublished observation).
In contrast to the effects of antidepressants on the responsiveness to LPS, we found no evidence for an effect of imipramine on the behavioral and neuroendocrine changes induced by IL-1. Chronic treatment with imipramine had no significant effect on IL-l-induced reduction in food consumption, body weight, social exploration, open-field activity, and corticosterone secretion. This finding indicates that the behavioral response to IL-1 in imipramine-treated rats is normal. Thus, the effects of imipramine on LPS-induced behavioral changes are at least partly mediated by changes in immune reactivity to LPS (particularly reduced production of cytokines), and not by down-stream effects on IL-l-induced sickness behavior.
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