While I am not an expert and it is possible that it could indicate adrenal disorder, I think the greater possibility is that corticosterone is binding to stress sensitive mineralocorticoid and glucocorticoid receptors. Based on a quick PubMed search I found an article (see below) which indicates differences in rat species MR and GR expression and how this may affect serum corticosterone levels. I think it may be helpful to look at adrenal hypertrophy in addition to corticosterone levels as well as MR and GR expression/binding to figure out what exactly is going on in these animals. I hope this helps.

1. Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis.

Oitzl MS1, van Haarst AD, Sutanto W, de Kloet ER.

2. Adrenal gland enlargement in major depression. A computed tomographic study.

Nemeroff CB1, Krishnan KR, Reed D, Leder R, Beam C, Dunnick NR.

~ Hi, thanks for the respond and suggestion. Will really looking into it. Maybe it's too presumptive of me to relate it to adrenal disorder without doing further test.

Dear Qamarul,

on what time and by which method did you measure it?

Several factors are important to consider like circadian rhythm and cross-reactivity of immunoassays.

But most important: chronic stress can cause a blunted HPA-axis, due to receptor overstimulation.

Kind regards,

Bibian van der Voorn

PhD-student VUMC, Amsterdam, the Netherlands

Dtar Qamarul Hafiz Zainol Abidin,

chronic stress you describe the reaction may occur (unfortunately , I do not know how you cause chronic stress reaction ) .Chronic stress ends exhaustion , reducing corticosterone synthesis , wherein the level of ACTH remains higher than in the control. But the high level of ACTH is not able to provide an increase in the synthesis of corticosterone .  It is likely that the continuing stress exposure in rats happen reduction as corticosterone and ACTH.

Can you give us some more details on your methods for CORT collection and analysis? I agree with the other thoughts here, but I think that would also help refine our answers. Was there a higher baseline of resting CORT post-chronic stress, or was it unchanged from before the experiment?

~ Hi, I am using Chronic Unpredictable Mild Stress method induced for 28-days. My previous CUMS animal experiment show high corticosterone in CUMS-rats 3-days after CUMS regime end. However, corticosterone result  were different when i repeat the experiment (low CORT but high ACTH). CORT was analysed using ELISA kit and the sample was rats' plasma. Blood was collected between 10am - 12 pm through cardiac puncture and plasma was stored in -80 celcius fridge only to be taken out when im going to use the ELISA kit.

Dear Qamarul Hafiz Zainol Abidin,

probably , high level of ACTH - a temporary ( compensatory , physiological ) response to low levels of corticosterone .

Elevated ACTH but low CORT is sometimes seen in rodent models of post-traumatic stress disorder (only in males though, are you using males? There are significant sex differences in the HPA axis response to stress). Diminished CORT release in response to stress could be due to a sensitization (or increase in number) of glucocorticoid receptors (GR) in the pituitary, and if all GR are saturated with ligand, no more suppression of ACTH can occur so that's where you can get high ACTH and low CORT. Due to this, the adrenal glands can become insensitive to ACTH--you can quantify ACTH receptors or just give them an ACTH injection and measure their CORT response to see.

I use the single prolonged stress paradigm (a PTSD model), which is a single exposure to 2.5 hours of intense stress. These stressed rats show a 50% increase in glucorcorticoid receptor expression in the PVN of the hypothalamus and exaggerated negative feedback of the HPA axis which drives their CORT levels down. As you pointed out though, CUMS doesn't usually result in this phenotype. It sounds like maybe something was different between your experiments, but it's hard to tell what (light cycle, handling, housing?)

If you want to explore further what's going on in your rats I suggest looking at the dexamathasone suppression test to measure HPA negative feedback (see attached paper). It would also be helpful to quantify glucocorticoid receptor expression in the hypothalamus and pituitary. Baseline CORT levels can vary a lot between individuals, so I take a baseline blood sample and expose them to a mild stress (30 minutes  in a restraint tube), take another blood sample at 30 minutes, and then look at the CORT released. Good luck!

~ hi..thanks for all of your respond..I will conduct dexa suppression test in future batch and if the observation still the same maybe test for GC receptors

Dear Qamarul Hafiz Zainol Abidin,

you probably do not pay attention to my answers . Are they not interested in you ?

Sorry, but I have to refuse to participate in the discussion.

I wish you success.

Yours sincerely,

Professor (full), PhD, MD , Honored Scientist of the Russian Federation.

Hi Professor P. F. Zabrodskii,

I am sorry if this discussion in anyway offended you. I already apprehend your points and takes yours view into consideration when deciding the next course of action.