Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test

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Abstract

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10–30 mg/kg, ip) or desipramine (30 mg/kg, ip) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10–100 mg/kg, po), however, had no affect on the performance of rats in the forced swim test. ACTH (100 μg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10–30 mg/kg, ip) or desipramine (30 mg/kg, ip) was blocked by chronic administration of ACTH for 3–14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, ip) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, po) was administered for 15 days concurrently with imipramine (10 mg/kg, ip), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.

Introduction

Psychoendocrinological studies of depressed patients focus on the disregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Abnormalities in the HPA axis have been noted in depressed patients Carpenter and Bunney, 1971, Carroll et al., 1976. Multiple neuroendocrinological abnormalities appear in depressive disorders, including increases in cortisol secretion and the attenuation of cortisol suppression in response to dexamethasone (Carroll et al., 1981). Cortisol hypersecretion in depression is believed to result from abnormalities in the HPA axis. Patients with Cushing's disease, a hyperadrenocorticism following a pituitary tumor, an adrenal tumor, or a tumor producing ectopic adrenocorticotropic hormone (ACTH), often exhibit mental changes including depression Kelly et al., 1980, Murphy et al., 1991. Tricyclic antidepressants are not effective for the treatment of depression in patients with Cushing's disease (Sonino et al., 1986). However, steroid-suppressive agents, such as metyrapone and aminogluethimide, are an effective treatment for such depression (Sonino et al., 1986), suggesting an etiological link between depressive illness and the disinhibition of the HPA axis observed in subjects with Cushing's disease. In addition, steroid-suppressive agents, such as metyrapone and ketoconazole, and a glucocorticoid receptor antagonist, RU486, are effective treatments for antidepressant treatment-resistant depression Murphy et al., 1991, Murphy et al., 1993, Wolkowitz et al., 1993. These results suggest that abnormal activation of the HPA axis correlates with treatment-resistant depression.

Kuroda et al. (1992) reported the effects of ACTH (ACTH (1–24)-zinc) on serotonin (5-HT2A) receptor binding in the rat forebrain. Chronic treatment with ACTH (50 μg/day, sc, 10 days) increases 5-HT2A receptor density within the neocortex of the rat forebrain. Up-regulation of 5-HT2A receptors has also been reported in platelets from depressed patients Biegon et al., 1987, Pandey et al., 1990 and in the frontal cortex of suicide victims Arora and Meltzer, 1989, Mann et al., 1986. An animal model of chronic ACTH treatment may increase our understanding of the pathophysiology and pathogenesis of depression.

Clinically, lithium is effective in the management of bipolar mood disorders and unipolar depression. In patients with treatment-resistant depression, lithium has been reported as an effective therapeutic agent de Montigny et al., 1983, Heninger et al., 1983. For instance, in imipramine-resistant depressive patients, the antidepressant effects of imipramine are potentiated by the addition of lithium (de Montigny et al., 1981). As lithium possesses broad therapeutic properties, we examined the efficacy of lithium in an ACTH-treated, treatment-resistant animal model of depression.

In rodents, the forced swim test is widely used as a predictor of antidepressant activity (Porsolt et al., 1978). Many antidepressants, screened in the forced swim test, reduce immobility of rodents in the forced swim test. Imipramine and desipramine are well-established tricyclic antidepressants clinically used for many years. Although these reports evaluate the effects of imipramine, desipramine, and lithium on immobility in the forced swim test in native rats, few attempts have been made to examine their effects on a model of abnormal HPA axis activation.

By administering ACTH to rats, we investigated the effects of imipramine, desipramine, and lithium in a model of abnormal HPA axis activation.

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Animals

Male Wistar rats (Charles River, Yokohama, Japan) weighing 180–230 g, kept on a constant light–dark cycle (light 07.00–19.00 h), were sustained with standard laboratory food and tap water in an air-conditioned room (23±1 °C with approximately 60% humidity).

Drugs

The following drugs were used in this study: imipramine hydrochloride (Wako Pure Chemical, Osaka, Japan), desipramine hydrochloride (Sigma, St. Louis, MO, USA), lithium carbonate (Taisho Pharmaceutical, Tokyo, Japan), and ACTH-(1–24)-zinc

Experiment 1: effects of a single administration of imipramine, desipramine, or lithium on immobility in normal rats

Following a single administration of imipramine, desipramine, or lithium to normal rats, we examined the effects on the duration of immobility in the forced swim test (Table 1). Both imipramine (3–30 mg/kg, ip) [F(3,39)=7.81, P<.01] and desipramine (3–30 mg/kg, ip) [F(3,28)=11.12, P<.01] potently decreased the duration of immobility in a dose-dependent manner. A single administration of lithium (10–100 mg/kg, po) did not alter the duration of immobility [F(3,20)=0.24, P=.79].

Experiment 2: effects of a 15-day chronic administration of either imipramine or lithium on immobility in normal rats

Following a 15-day

Discussion

We examined the influence of imipramine, desipramine, and lithium on the immobility of ACTH-treated rats when subjected to the forced swim test. A 14-day chronic administration of ACTH at doses ranging from 50 to 75 μg/day (sc) did not alter the duration of immobility induced by imipramine (30 mg/kg, ip). The immobility-decreasing effect of imipramine (30 mg/kg, ip), however, was inhibited by chronic ACTH treatment when given at 100 μg/day (sc) for 14 days; a single dose of ACTH could not exert

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