Effects of corticosterone on 5-HT1A and 5-HT2 receptor binding and on the receptor-mediated behavioral responses of rats

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Abstract

The effects of corticosterone after binding to 5-HT1A and 5-HT2 receptors were studied in rats. Binding of [3H]8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) to 5-HT1A receptors in the hippocampus decreased 24 h after both acute and chronic (14 day) administration of CORT (50 mg/kg, s.c.). Chronic, but not acute, CORT treatment increased [3H]ketanserin binding to 5-HT2 receptors in the frontal cortex. Receptor-mediated behavioral responses were also examined following acute and chronic CORT treatment. Flat body posture and hypothermia induced by 8-OH-DPAT, a 5-HT1A receptor agonist, were attenuated following chronic, but not acute, CORT administration. (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, induced wet-dog shakes, but not hyperthermia and this response was increased 24 h after the chronic administration of CORT. These findings indicate that both 5-HT1A and 5-HT2 receptor functions were changed following chronic exposure to high levels of CORT. Such changes in these receptor systems may play an important role in the etiology of affective disorders.

Introduction

We previously reported that chronic, but not acute, forced swim stress in rats increased frontal cortical 5-HT2 receptor levels and the severity of the wet-dog shakes that they mediate (Takao et al., 1995). Since chronic forced swim stress did not alter 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations, the up-regulation of 5-HT2 receptors does not seem to be due to lower presynaptic serotonergic activity following stress. In our previous paper, we could not explain the precise mechanisms of the up-regulation of 5-HT2 receptors.

Stress has been shown to alter endocrine functions in the hypothalamic–pituitary–adrenal axis. Forced swim stress results in increased serum corticosterone levels in rats (Abel and Hannigan, 1992). One possible mechanism by which chronic forced swim stress up-regulates 5-HT2 receptors is that increased plasma corticosterone levels after stress may change 5-HT2 receptor function. In our previous study (Takao et al., 1995), we concluded that 5-HT2 receptors may be closely related to responses to chronic forced swim stress in rats, which may be a model of some depressive conditions in animals.

The recent discovery of multiple biochemical and functional subtypes of 5-HT receptors has given new impetus to studies investigating the function of 5-HT in affective disorders (Cowen, 1991; Peroutka, 1988). The 5-HT receptor subtypes, particularly 5-HT1A and 5-HT2 receptors, have been postulated to play an important role in the pathogenesis of depression. Additionally, the 5-HT2 receptor partial agonists, ipsapirone and gepirone (Heller et al., 1990; Jenkins et al., 1990) and the 5-HT2 receptor antagonist, ritanserin (Reyntjens et al., 1986), are proposed to have antidepressant activity. These findings suggest that there is a malfunction in serotonergic neural transmission, particularly that mediated by 5-HT1A and 5-HT2 receptors, in patients with affective disorders.

The action of steroid hormones in the regulation of 5-HT function is of continuing psychoneuroendocrine interest in view of the hypercortisolism typical of affective disorders (Christie et al., 1986) and the marked effect of tricyclic antidepressants on hippocampal glucocorticoid receptors (Seckl and Frick, 1992).

This study was designed to investigate the effect of acute and prolonged exposure to elevated levels of corticosterone on the binding capacity of 5-HT1A and 5-HT2 receptors and on their receptor-mediated behavioral responses in rats.

Section snippets

Animals

Male Wistar rats, weighing 150–200 g (Charles River Japan, Yokohama), were used. They were housed in groups of 5 under controlled temperature (23±3°C) and lighting conditions (dark period 20.00–8.00 h), with free access to food and water.

Corticosterone administration

Corticosterone-21 acetate was suspended in 0.5% methylcellulose. The suspension at a dose of 50 mg/kg was injected subcutaneously in rats for 1 day or 14 days. Control animals only received the 0.5% methylcellulose vehicle. 24 h after administration of the last

Changes in plasma CORT

Both acute and chronic CORT (50 mg/kg) treatment significantly increased the plasma CORT levels (intact control=17.9±4.8 μg/dl, acute CORT=46.4±4.1 μg/dl, chronic CORT=45.7±3.6 μg/dl).

Changes in 5-HT1A and 5-HT2 receptor binding

Both acute and chronic CORT treatment significantly decreased the binding of [3H]8-OH-DPAT to 5-HT1A receptors in hippocampal membranes (Fig. 1). The binding of [3H]ketanserin to 5-HT2 receptors in the frontal cortex was significantly increased following chronic, but not acute, CORT administration.

Changes in 5-HT1A and 5-HT2 receptor-mediated behavioral responses

Chronic

Discussion

In this study, we demonstrated that hypercorticism, which raises circulating corticosterone levels, produced changes in brain serotonergic neural function, affecting the 5-HT1A and 5-HT2 receptor systems, in rats.

In binding assay studies, hypercortisolism decreased 5-HT1A receptor binding in hippocampal membranes, while it increased 5-HT2 receptor binding in the frontal cortex. CORT has been shown to alter presynaptic serotonergic neurotransmission, which may affect postsynaptic 5-HT1A and 5-HT2

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