Elsevier

Hormones and Behavior

Volume 65, Issue 1, January 2014, Pages 6-13
Hormones and Behavior

The effect of chronic administration of corticosterone on anxiety- and depression-like behavior and the expression of GABA-A receptor alpha-2 subunits in brain structures of low- and high-anxiety rats

https://doi.org/10.1016/j.yhbeh.2013.10.011Get rights and content

Highlights

  • Chronic corticosterone (CORT) treatment decreased activity in the forced swim test.

  • CORT increased anxiety in the elevated plus maze test.

  • In high-anxiety rats (HR) CORT increased anxiety in the open field test.

  • In HR CORT increased alpha-2 subunit GABA-A receptor density in the basolateral amygdala.

  • In HR CORT decreased alpha-2 subunit GABA-A receptor density in the prefrontal cortex.

Abstract

The aim of this study was to examine changes in rat emotional behavior and determine differences in the expression of GABA-A receptor alpha-2 subunits in brain structures of low- (LR) and high-anxiety (HR) rats after the repeated corticosterone administration. The animals were divided into LR and HR groups based on the duration of their conditioned freezing in a contextual fear test. Repeated daily administration of corticosterone (20 mg/kg) for 21 days decreased activity in a forced swim test, reduced body weight and decreased prefrontal cortex corticosterone concentration in both the LR and HR groups. These effects of corticosterone administration were stronger in the HR group in comparison with the appropriate control group, and compared to LR treated and LR control animals. Moreover, in the HR group, chronic corticosterone administration increased anxiety-like behavior in the open field and elevated plus maze tests. The behavioral effects in HR rats were accompanied by a decrease in alpha-2 subunit density in the medial prefrontal cortex (prelimbic cortex and frontal association cortex) and by an increase in the expression of alpha-2 subunits in the basolateral amygdala. These studies have shown that HR rats are more susceptible to anxiogenic and depressive effects of chronic corticosterone administration, which are associated with modification of GABA-A receptor function in the medial prefrontal cortex and basolateral amygdala. The current data may help to better understand the neurobiological mechanisms responsible for individual differences in changes in mood and emotions induced by repeated administration of high doses of glucocorticoids or by elevated levels of these hormones associated with chronic stress or affective pathology.

Introduction

Glucocorticoids are released in response to physical, emotional and/or metabolic stressors, and many of the effects of glucocorticoids are thought to serve as adaptive responses to stressful events (Levy and Tasker, 2012). The chronic stress or repeated corticosterone administration may lead to profound maladaptive changes in emotional behavior, thereby mimicking human mental disorders such as anxiety and depression (Erickson et al., 2003, Korte, 2001, McEwen, 2005, Mitchell and O'Keane, 1998, Swaab et al., 2005). We previously found that chronic corticosterone administration decreased plasma corticosterone concentration, inhibited exploratory behavior, enhanced freezing behavior on a retest of fear conditioning (with the final injection being given 90 min before contextual fear conditioning training), and produced complex changes in c-Fos expression: a decrease in the magnocellular neurons of the paraventricular hypothalamic nucleus, and an increase in the secondary motor cortex and in the central nucleus of amygdala (CeA) (Skórzewska et al., 2006).

Preclinical findings indicate reciprocal regulation of emotional behavior by GABA-A receptors and glucocorticoids (Lussier et al., 2013, Mody and Maguire, 2012, Orchinik et al., 1995, Verkuyl et al., 2005). The structure of GABA-A receptors causes differences in their pharmacological and functional characteristics. It seems that the effect of GABA on emotional behavior depends on activation of specific GABA-A receptor subunits. For example, it has been shown that activation of alpha-2 subunits of GABA-A receptors is involved in the regulation of anxiety and depression-like behavior (Lussier et al., 2013; cf. Smith and Rudolph, 2012). In this context it is noteworthy that glucocorticoids can alter the uptake and release of GABA and can also decrease benzodiazepine receptor binding in the hippocampus and amygdala (Drugan et al., 1989, Miller et al., 1988, Orchinik et al., 1995, Wilson and Biscardi, 1994).

We have recently been studying the central mechanisms responsible for individual vulnerability to stress by employing a model that divides rats into high- (HR) and low-anxiety (LR) groups based on the duration of their conditioned freezing response in a contextual fear test. We found that HR rats had deficits in activity of the brain structures that control the cognition necessary to cope with stress (i.e., the prefrontal cortex, as measured by c-Fos expression) and increased activity of the amygdalar nuclei that enhance the stress response (c-Fos/glucocorticoid receptors-ir) (Lehner et al., 2009a). The HR rats additionally showed enhanced concentrations of CRF-positive cells in the basolateral amygdala (BLA) and parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN) and had higher basal concentrations of GABA-A receptor alpha-2 subunits in the amygdala (compared with an unconditioned control group) (Lehner et al., 2008, Lehner et al., 2010a). We also observed that some behavioral interventions (extinction and relearning of a conditioned fear response) and pharmacological interventions (d-cycloserine, midazolam, corticosterone) attenuated the increased fear responses of HR rats (Lehner et al., 2009b, Lehner et al., 2010a, Lehner et al., 2010b).

The aim of this study was to test the hypothesis that animals more vulnerable to stress are more likely to develop anxiety- and depression-like behavior following chronic corticosterone exposure. Thus, in the present study, we sought to determine if there are individual differences in rat emotional behavior and expression of GABA-A receptor alpha-2 subunits in the brain structures of low- (LR) and high-anxiety (HR) rats after repeated administration of corticosterone. We concentrated particularly on the medial prefrontal cortex and amygdalar nuclei to verify and extend previous findings that emphasized the role of these areas in mediating the central effects of stress in HR animals.

Section snippets

Animals

The experiments were performed on 30 male Wistar rats (280–300 g body weight), purchased from a licensed breeder (The Center for Experimental Medicine of the Medical University, 24A Skłodowskiej-Curie Str., Białystok, Poland) and housed under standard laboratory conditions with a 12 h light/dark cycle (lights on at 7 a.m.) at a constant temperature (21 ± 2 °C). The experiments were performed in accordance with the European Communities Council Directive of 24 November 1986 (86/609 EEC). The Local

Body weight gain

One-way ANOVA with repeated measures revealed significant differences among experimental groups (HRveh, LRveh, HRcort, LRcort): group effect [F(3,24) = 8.13, (P < 0.01)], time effect [F(4,96) = 220.12, (P < 0.01)], and group and time interaction effect [F(12,96) = 35.98, (P < 0.01)]. The HRcort rats were gaining weight significantly less than HRveh rats on day 15 (P < 0.05), 22, and 29 (P < 0.01) of the treatment (Tukey's post hoc test). The LRcort rats weighed significantly less than the LRveh rats on day 29

Discussion

We found that repeated treatment with corticosterone (20 mg/kg) attenuated rat activity in the forced swim test, reduced body weight gain and decreased prefrontal cortex corticosterone concentration both in the LR and HR groups. Behavioral changes were stronger in the HRcort group in comparison with the appropriate control rats, and compared to LRcort as well as LR control groups. Additionally, chronic corticosterone administration increased anxiety-like behavior in the HR group in the open

Conclusion

This study shows that HR rats are more susceptible to the anxiogenic and, to some extent to depressive-like effects of chronic corticosterone administration. Given the different changes in the expression of alpha-2 subunits in HR and LR animals in the prefrontal cortex and the BLA, it appears that innate, individual differences in local GABAergic activity may be causally related to the described behavioral effects. However, other studies using different experimental approaches are required to

Acknowledgments

The study was supported by Grant No. 501-003-13043 from the Institute of Psychiatry and Neurology in Warsaw and Grant No. 2012/05/B/NZ7/02460 from the National Science Centre, Poland. The authors thank Mrs. Ala Biegaj and Mrs. Maria Cissowska-Wiencław for the excellent technical assistance.

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