Acute rise in corticosterone facilitates 5-HT1A receptor-mediated behavioural responses

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Abstract

Corticosterone influences 5-HT1A receptor-mediated responses in the rat hippocampus in vitro: activation of the high affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated hyperpolarization, while subsequent activation of lower affinity glucocorticoid receptors enhances the effect of 5-HT. We have tested whether a similar effect of corticosterone exists in vivo. In intact rats, a systemic injection of the specific 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), led to increased locomotion and to a less persistent search strategy in the free swim trial of the Morris water maze test. Adrenalectomized rats with a corticosterone-pellet implanted as replacement received an injection of vehicle (predominant mineralocorticoid receptor occupation) or a high dose of corticosterone (both corticosteroid receptor types occupied) 1 h before injection of 8-OH-DPAT. The effect on search strategy, but not on locomotor activity, was less in animals with low corticosterone levels. The results suggest that hippocampal 5-HT1A receptor-mediated responses in vivo are attenuated during predominant activation of the mineralocorticoid receptor and increased after additional transient activation of the glucocorticoid receptor.

Introduction

The actions of corticosterone on the hippocampus are mediated by two types of corticosteroid receptors. The high-affinity mineralocorticoid receptor and the low affinity glucocorticoid receptor are co-localized in hippocampal neurons (Van Eekelen et al., 1988; Van Steensel et al., 1996). Mineralo- and glucocorticoid receptors are differentially occupied at different levels of circulating corticosterone. Around the circadian trough of corticosterone secretion, mineralocorticoid receptors are predominantly occupied; around the circadian peak and after stress, the output of the hypothalamic–pituitary–adrenal axis is increased and both corticosteroid receptor types are occupied by corticosterone (Reul et al., 1987; Spencer et al., 1993).

The 5-HT1A receptor is very highly expressed in the CA1 pyramidal cells and dentate granular neurons of the hippocampus (Chalmers and Watson, 1991; Pompeiano et al., 1992). The CA1 pyramidal neurons show 5-HT1A receptor-mediated hyperpolarization in response to 5-HT application (Andrade and Nicoll, 1987). In the hippocampal slice preparation, this response is suppressed by predominant occupation of mineralocorticoid receptors, e.g., after in vitro exposure to aldosterone (Joëls et al., 1991). Combined occupation of mineralo- and glucocorticoid receptors restores the responsiveness to 5-HT1A receptor stimulation as becomes apparent after combined administration of aldosterone, a mineralocorticoid receptor agonist, and the glucocorticoid receptor agonist, RU28362 (11β,17β-dihydroxy-6-methyl-17α(1-propynyl)-androsta-1,4,6-trione-3-one), to the hippocampal slice (Joëls and De Kloet, 1992).

In the present experiments, we tested the hypothesis that a similar mechanism of action of corticosterone, involving both receptor types, operates in vivo in rats. We used the Morris water maze, a spatial learning and memory task, the execution of which depends on the integrity of the hippocampus (Morris et al., 1982). Administration of the specific 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) (Arvidsson et al., 1981), interferes with the performance of rats in this task via activation of postsynaptic 5-HT1A receptors in the hippocampus (Hunter and Roberts, 1988; Carli and Samanin, 1992; Carli et al., 1992). We studied the effect of differential corticosteroid receptor occupation on the responsiveness to 8-OH-DPAT in the free swim trial of the Morris maze task, when the behaviour of trained animals is monitored in the absence of an escape platform in the pool.

We tested the effect of 8-OH-DPAT both in intact rats, and in adrenalectomized rats with corticosterone replacement rats. As the effect of corticosterone on 5-HT1A receptor responsiveness develops within an hour (Joëls and De Kloet, 1992), we looked for a design in which differential occupation of corticosteroid receptors could be obtained acutely before administration of 8-OH-DPAT. Because 8-OH-DPAT is a potent activator of the hypothalamic–pituitary–adrenal axis (Fuller, 1992), we used adrenalectomized rats subcutaneously implanted with a pellet containing 20 mg corticosterone. Injection of a high dose of corticosterone shortly before testing superimposed transient activation of both receptor types on the condition of constant predominant mineralocorticoid receptor occupancy maintained by low levels of corticosterone. We found that 5-HT1A receptor-mediated response involving search strategy was specifically sensitive to variations in corticosterone occupation. These responses were low in animals with a predominant mineralocorticoid receptor occupation, but enhanced in rats that had both corticosteroid receptors occupied.

Part of these data was reported previously in abstract form (Meijer et al., 1994).

Section snippets

Animals and surgery

Male Wistar rats, weighing 180–200 g at the time of surgery, were used. The animals were housed three per cage and had free access to food and water. Adrenalectomized rats had additional access to 0.9% saline. The rats were housed under a 12:12 h light–dark cycle, with lights on at 0700 h. All behavioural training took place between 0800 and 1400 h. The free swim trial (see below) took place between 0900 and 1200 h. Rats were sham-operated (experiment 1) or adrenalectomized (experiment 2) in

Intact rats

Fig. 2 shows that 8-OH-DPAT influences various parameters of the free swim trial. Significant main effects for intact rats were found for percentage of time spent in the former platform quadrant (F(2,24)=4.354; P=0.024) and total distance swum (F(2,24)=8.604; P=0.02). Number of crossings of the former platform location per travelled metre (F(2,24)=2.754; P=0.084) and the distance swum until the first crossing (F(2,24)=1.848; P=0.179) just exceeded statistical significance.

Injection of 100 μg/kg

Discussion

The results of these experiments showed that the responsiveness of distinct 5-HT1A receptor populations are under differential control by corticosterone in vivo. Animals with a predominant occupation of mineralocorticoid receptors by low, and constant, levels of corticosterone exhibited an attenuated 5-HT1A receptor-mediated response related to the spatial search strategy in the water maze. An injection of corticosterone which causes activation of both corticosteroid receptor types enhanced the

Acknowledgements

We would like to thank Marc Fluttert and Remon Van den Broek for the technical assistance.

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    Present address: Department of Physiology, University of California, San Francisco, CA 94143-0444, USA.

    2

    Present address: Department of Pharmacology, University of Bradford, Bradford, UK.

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