First thx for reply:-), Secondly, the final sentence is key and i will quote you: The brain serotonergic activity is characterized by the 5-HIAA/S-HT ratio !!!! I am interested in what way, in molecular way, what is happening mechanistically?? Why is that ratio characterizes serotonergic activity?

During serotonergic neurotransmission, serotonin is released into the synaptic cleft. After exerting its action in the postsynaptic neuron, part of the serotonin is transported again into the presynaptic neuron by specific transporters (SERT). Once again in the presynaptic neuron, part of this serotonin is incorporated again into vesicles and part is metabolized by the monoamine oxidase (MAO) and other enzymes to form 5HIAA. In a few words, when the serotonergic activity is high, more serotonin is released in the synapses, and consequently, more serotonin is metabolized to 5HIAA. Therefore, the 5HIAA/serotonin ratio would be higher. Hope this helps!

Just to check out loud. This means that the more higher 5 HIAA levels you get, as the main end product/ser metabolite of 5 HT catabolism you have greater ser transmission?? You judge about the activity of ser transmission in respect to the levels of main metabolite?? Also a metabolism of certain body molecules means that you have both anabolism (syntheses, in this case from L-tryptophan to 5 HT) and catabolism (from 5 HT to 5 HIAA) of that molecule. Also, thinking out loud, if this is true on the basis of 5 HIAA levels we can assume only the impairments in catabolism step, from 5 HT to 5 HIAA (impairments in MAO or Aldehyde dehydrogenase function/activity) and not in the syntheses step. Is this true?

Yes, when using the ratio, you are linking the metabolite levels with serotonergic transmission. This is because, before the serotonergic transmission, the serotonin is stored in vesicles and is not available for its catabolization by the MAO. So 5HIAA is mostly formed after serotonergic discharge. Anyway, the ratio is only an estimator of the serotonergic activity that could be useful under some circumstances. The ratio give us information about the catabolic rate, that could be linked with serotonergic activity under several assumptions. One of them is that MAO activity is not impaired by any factor in our experiment. For instance, if MAO activity is being inhibited by any drug, it would make no sense to use the 5HIAA/5HT ratio as a serotonergic activity estimator.

To have a more complete view of the serotonergic metabolism it is useful to pay attention not only to the ratio, but also to 5HIAA and 5HT levels. For instance, having higher 5HIAA levels don't imply that you have a higher ratio since the 5HT levels could be also higher. A simultaneous increase in both 5HIAA and 5HT could indicate an increase in serotonergic anabolism and vice versa.

To summarize, the use of the 5HIAA/5HT ratio has important limitations and should be used with caution. A better characterization of the serotonergic activity would require the measurement of extracellular serotonin levels with more complex techniques (ventricular cannulation, etc.) than the mere evaluation of the amines in a piece of brain tissue.

Once again thank you very much for this knowledge exchange. But, what happens with 5HIAA/5HT ratio in MDD patients, what changes would you expect based on monoamine theory of depression? I am reading papers and i am finding confronting results. Did you read paper entitled: Elevated Brain Serotonin Turnover in Patients With Depression?? They find elevated ratio in MDD patients, and they are not talking about ser transmission, just turnover!!! Also, I agree with everything that you stated about metabolism, but than I think that when we are using this ratio we cant talk about serotonergic activity or transmission ! These are terns for complete ser. signaling including the sythesis, expelling ser to synaptic cleft, binding ser on postsynaptyc neuron and activating the GPCR and then you have further action, all together is serotonin transmission !!! In our case, we are determining the ser turnover that tells us about dynamic of processes from cleft to reuptake and catobolism of 5 HT to 5 HIAA in presynaptic neuron. Possible impairments could be find in the SERT, MAO or Aldehyde DH functioning!! What do you think, is this a bs what I stated or is it true? :-)

You are right, the term "serotonin transmission" is too generic and "serotonin turnover" is probably a better term for what we are talking about. Regretfully I have no familiarity with depression but, as Chinmaya said, serotonin turnover is indeed related to stress, and it is known that chronic stress may lead to depression. In different animal models it is known that stress induce an increase in serotonergic turnover, but often also in dopaminergic and noradrenergic turnover. These alterations are transient if the stress is acute (for example a persecution by a predator). If the stress becomes chronic (for exmple, cohabitation with a dominant specimen), important and long-lasting changes in the monoaminergic systems could occur. Also, chronically stressed animals usually present symptoms similar to those observed in MDD patients.

The 5HIAA/5HT ratio could be useful for different purposes. One of them is its use as an estimator of the serotonergic activity (for example, a group of acutely stressed rats is expected to have a higher 5HIAA/5HT ratio than control rats, due to their higher serotonergic turnover).

The 5HIAA/5HT could also serve to detect, as you said, impairments in the function of enzymes or transporters (Obviously, if MAO is being inhibited by a MAO inhibitor, one would expect a lower 5HIAA/5HT). However, what I want to mean is that, if the MAO (or SERT, or other key factor) is affected by any factor in your experiment, you cannot use 5HIAA/5HT ratio as an estimator of serotonin discharge. For example, you can not use the ratio to compare the serotonergic activity between a control and a MAO-inhibitor-treated rat: In this example both rats could have the same serotonergic activity, but the 5HIAA/5HT ratio would be very different, since the catabolization of the discharged serotonin would be very different..

Hi, do you have a reference to the article that says the meaning of 5-HIAA/5-HT ratio?

I'm having some trouble explaining the correlation I found in my data with de 5-HIAA/5-HT ratio, and I would like to use that reference for the dicussion.

Thank you!

Hi Karolina,

Maybe you can try this reference:

Shannon, N.J., Gunnet, J.W., and More, K.E. 1986. A comparison of biochemical indices of 5-hydroxytryptaminergic activity following electrical stimulation of dorsal raphe nucleus. J. Neurochem. 47: 958–965.

Best regards

Hi Manuel Gesto, what about drugs that inhibit SERT? Can 5-HIAA/5-HT ratio used when drugs that inhibit SERT activity used?

Figure 1 in the following article gave me a clear idea of 5HT metabolism and the answer to why the 5-HIAA/5-HT ratio is a common measure of 5-HT metabolic activity

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482548