Antiglucocorticoid RU 38486 Attenuates Retention of a Behaviour and Disinhibits the Hypothalamic-Pituitary Adrenal Axis at Different Brain Sites

Abstract

Adrenalectomized rats displayed a deficiency in retention of an immobility response acquired during an initial 15-min forced swimming procedure (Porsolt swimming test) and measured 24 h later in a 5-min retest session. The deficit could be restored dose dependently with the glucocorticoid dexamethasone (µg range) administered 15 min after the initial test. The antiglucocorticoid RU 38486 administered subcutaneously (1 and 10 mg/kg) inhibited the dexamethasone effect and caused a parallel shift in the dose-response curve of dexamethasone. Intracerebroventricular administration of RU 38486 to intact rats immediately before the initial test attenuated retention of acquired immobility over a 100,000-fold lower dose range (ng) and increased the plasma corticosterone level. Local administration of 1 ng RU 38486 in the dentate gyrus of the hippocampus also diminished the percentage immobility, but did not influence the adrenocortical response. Injections of RU 38486 in parafascicular and paraventricular nucleus were ineffective on behaviour. In the latter nucleus the antiglucocorticoid disinhibited the activity of the hypothalamus-pituitary-adrenal axis. Intracerebroventricular pretreatment with promegestone did not interfere with RU 38486 action, ruling out involvement of its antiprogestin properties. Intracerebroventricular or subcutaneous treatment of intact rats with the antimineralocorticoid RU 28318 was not effective. Finally, adrenalectomized rats replaced with corticosterone delivered via subcutaneously implanted 100-mg corticosterone pellets showed normal behavioural performance, while a 25-mg implant did not. The present study with local infusions of RU 38486 indicates that glucocorticoid feedback via type 2 receptors exerts a long-term influence on behaviour in the hippocampus and controls the activity of the hypothalamus-pituitary-adrenal axis in the paraventricular nucleus.

Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

“…Jefferys and colleagues (Jefferys et al, 1983;Jefferys and Funder, 1987) were the first to show that the presence of glucocorticoids and opioid peptides after the initial test is necessary for the retention of the acquired immobility response in the retest. This finding was confirmed by De Kloet et al (1988) who have shown that local administration of the glucocorticoid receptor antagonist, RU38486, into the dentate gyrus of the hippocampus directly after the initial test disrupted this retention. Recently, however, it has been shown that inhibition of the synthesis of corticosterone with metyrapone reduced the immobility time during both initial test and retest (Bfiez and Volosin, 1994).…”

“…Low circulating levels of corticosterone predominantly occupy mineralocorticoid receptors, whereas after stress and during the circadian peak both mineralocorticoid receptors and gluco-corticoid receptors are activated (Reul et al, 1987). Behavioural effects of the synthetic glucocorticoid receptor antagonist and the mineralocorticoid receptor antagonist have been measured in animal models designed to examine anxiety (Korte et al, 1995), learning and memory (De Kloet et al, 1988;Jefferys et al, 1983;Jefferys and Funder, 1987;Oitzl and De Kloet, 1992;Oitzl et al, 1994) and learned helplessness (Papolos et ai., 1993). One of the behaviours sensitive to corticosterone (the principle glucocorticoid in the rat) is immobility in the Porsolt forced swim test.…”

Biphasic Effects of Adrenal Steroids on Learned Helplessness Behavior Induced by Inescapable Shock

“…Adrenal steroids play an important role in regulating both learned and unlearned fear and anxiety (Korte 2001;Calvo et al, 1998;Calvo and Volosin, 2001) and alterations in the balance between Type I or mineralocorticoid receptors (MR) and Type II or glucocorticoid receptors (GR) in the brain appear to play a role in these behaviors as well as in the etiology of depression and anxiety (de Kloet et al, 1988;Korte, 2001). MR and GR are expressed throughout the central nervous system, with GR showing a more widespread distribution and MR showing a discrete localization, such as in neurons of the hippocampus, regions of the amygdala, and brain stem (Ahima and Harlan, 1990;Ahima et al, 1991).…”

“…MR and GR mediate different aspects of corticosterone (CS) action: for example, hippocampal MR is responsible for the maintenance of stability in the stress response system throughout the circadian cycle (Ratka et al, 1989;Dallman et al, 1992), whereas GR facilitates the recovery of the system after the exposure to a stressful stimulus (de Kloet et al, 1988). Moreover, the activation of MR in neurons from the hippocampal CA1 region stabilizes local excitability while it is reduced by GR activation .…”

“…For example, CS has been shown to facilitate the acquisition and retention of the immobility acquired in a forced-swim paradigm (de Kloet et al, 1988;Báez and Volosin, 1994). CS has also been implicated in the acquisition of inactivity during the exposure to inescapable shock (IS) and in the expression of inactivity and escape failures in a subsequent shuttle-box task (Báez et al, 1996).…”