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. 2023 Jan 9:16:1064369.
doi: 10.3389/fnins.2022.1064369. eCollection 2022.

Disturbed relationship between glucocorticoid receptor and 5-HT1AR/5-HT2AR in ADHD rats: A correlation study

Xiaoxia Lin  1 , Liang Huang  1 , Huifang Huang  1 , Zhongling Ke  1 , Yanhui Chen  1
Affiliations

Disturbed relationship between glucocorticoid receptor and 5-HT1AR/5-HT2AR in ADHD rats: A correlation study

Xiaoxia Lin et al. Front Neurosci. .

Abstract

Objective: This work is to investigate the alterations of the central 5-hydroxytryptamine (5-HT) system in spontaneously hypertensive rats (SHR) and the correlation with the behaviors of SHR, and to explore the effects of glucocorticoid intervention on the central 5-HT system and SHR behaviors.

Materials and methods: Three weeks old SHR were chosen as the attention-deficit hyperactivity disorder (ADHD) model and treated with glucocorticoid receptor (GR) agonist or inhibitor, whereas Wista Kyoto rats (WKY) were chosen as the normal control group. Open-field test and Làt maze test were used to evaluate the spontaneous activities and non-selective attention. The levels of 5-HT in the extracellular fluid specimens of the prefrontal cortex of rats were analyzed by high-performance liquid chromatography. The expressions of GR, 5-HT1A receptor (5-HT1AR), and 5-HT2A receptor (5-HT2AR) in the prefrontal cortex were analyzed through immunohistochemistry.

Results: Our study demonstrated that the 5-HT level was lower in the prefrontal cortex of SHR compared to that of WKY. The Open-field test and Làt maze test showed that GR agonist (dexamethasone, DEX) intervention ameliorated attention deficit and hyperactive behavior, whereas GR inhibitor (RU486) aggravated the disorders. With DEX, the expression levels of 5-HT and 5-HT2AR in the prefrontal cortex of SHR were significantly higher than those in the control group, whereas the expression level of 5-HT1AR was lower. However, the expression levels of 5-HT and 5-HT2AR were significantly decreased after the intervention with RU486, while the expression level of 5-HT1AR increased. Results showed that glucocorticoid was negatively correlated with 5-HT1AR and positively correlated with 5-HT2AR.

Conclusion: In the prefrontal cortex of ADHD rats, the down-regulation of 5-HT and 5-HT2AR expressions and the up-regulation of 5-HT1AR, compared with WYK rats, suggested a dysfunctional central 5-HT system in ADHD rats. The GR agonist can upregulate the expression of 5-HT and 5-HT2AR and downregulate the expression of 5-HT1AR in the prefrontal cortex of SHR as well as reduce the hyperactivity and attention deficit behavior in SHR, while the opposite was true for the GR inhibitor. It is suggested that the dysfunction of the 5-HT system in ADHD rats is closely related to glucocorticoid receptor activity.

Keywords: 5-HT; 5-HT1A receptor; 5-HT2A receptor; attention deficit hyperactivity disorder; glucocorticoid receptor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of experimental procedures.
FIGURE 2
FIGURE 2
Behavioral performance in open field test (OFT) (n = 15 in each group). (A) The number of line crossings before drug intervention, (B) the number of rearing before drug intervention, (C) the number of line crossing after drug intervention for 2 weeks, (D) the number of rearing after drug intervention for 2 weeks, (E) representative pathways of each group before and after drug intervention. One-way analysis of variance (ANOVA) with repeated measures followed by post hoc with Tukey test. All data are presented as mean ± SEM. ***p < 0.001, compared to Wista Kyoto rats (WKY) group; ##p < 0.01, ###p < 0.001, compared to spontaneously hypertensive rats (SHR) group.
FIGURE 3
FIGURE 3
Behavioral performance in Làt maze (n = 15 in each group). (A) The number of corner crossings before drug intervention, (B) the number of rearings before drug intervention, (C) the number of corner crossings after drug intervention for 2 weeks, (D) the number of rearings after drug intervention for 2 weeks. One-way analysis of variance (ANOVA) with repeated measures followed by post hoc with Tukey test. All data are presented as mean ± SEM. ***p < 0.001, compared to Wista Kyoto rats (WKY) group; ##p < 0.01, ###p < 0.001, compared to spontaneously hypertensive rats (SHR) group.
FIGURE 4
FIGURE 4
Levels of 5-hydroxytryptamine (5-HT) in the prefrontal cortex of rats in four groups (n = 15 in each group) before and after drug intervention. (A) Pre-intervention and (B) post-intervention content of 5-HT in the extracellular liquids of the rat prefrontal cortex, respectively. One-way analysis of variance (ANOVA) with repeated measures followed by post hoc with Tukey test. All data are presented as mean ± SEM. ***p < 0.001, compared to Wista Kyoto rats (WKY) group; ###p < 0.001, compared to spontaneously hypertensive rats (SHR) group.
FIGURE 5
FIGURE 5
The immunohistochemical images for the measurements of glucocorticoid receptor (GR) levels in the prefrontal cortex of rats in four groups (× 400) [(A) Wista Kyoto rats (WKY) group; (B) spontaneously hypertensive rats (SHR) group; (C) SHR + dexamethasone (DEX) group; (D) SHR + RU486 group); Comparison of GR levels in the prefrontal cortex of rats in four groups (E). One-way analysis of variance (ANOVA) with repeated measures followed by post hoc with Tukey test. All data are presented as mean ± SEM. ***p < 0.001, compared to WKY group; ###p < 0.001, compared to SHR group.
FIGURE 6
FIGURE 6
Comparison of 5-HT1A receptor (5-HT1AR) levels in the prefrontal cortex of rats in four groups (× 400) [(A) Wista Kyoto rats (WKY) group; (B) spontaneously hypertensive rats (SHR) group; (C) SHR + dexamethasone (DEX) group; (D) SHR + RU486 group]; Comparison of 5-HT1AR levels in the prefrontal cortex of rats in four groups (E). One-way analysis of variance (ANOVA) with repeated measures followed by post hoc with Tukey test. All data are presented as mean ± SEM. ***p < 0.001, **p < 0.01, compared to WKY group; ###p < 0.001, compared to SHR group.
FIGURE 7
FIGURE 7
Comparison of 5-HT1A receptor (5-HT2AR) levels in the prefrontal cortex of rats in four groups (× 400) [(A) Wista Kyoto rats (WKY) group; (B) spontaneously hypertensive rats (SHR) group; (C) SHR + dexamethasone (DEX) group; (D) SHR + RU486 group]; Comparison of 5-HT2AR levels in the prefrontal cortex of rats in four groups (E). One-way analysis of variance (ANOVA) with repeated measures followed by post hoc with Tukey test. All data are presented as mean ± SEM. ***p < 0.001, compared to WKY group; ###p < 0.001, compared to SHR group.
FIGURE 8
FIGURE 8
Scatter plots for the correlation between glucocorticoid receptor (GR) and 5-HT1A receptor (5-HT1AR) or 5-HT2AR in spontaneously hypertensive rats (SHR) or Wista Kyoto (WKY) rats: Correlation between GR and 5-HT1AR in WKY (A) or SHR (B); Correlation between GR and 5-HT2AR in WKY (C) or SHR (D).
See this image and copyright information in PMC

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