Cross references:    Serotonin Receptors       Serotonin & Impulsivity Serotonin Detection    Stress          HPA Axis    Limbic System    Hypothalamus    Hippocampus   Cerebral Cortex    Pituitary Gland   Adrenal Glands        Hormones    Corticosteroids      Glucocorticoids    Glucocorticoid Receptors     Cortisol      ACTH     Melatonin           
Corticotropin-releasing hormone (CRH)
      Prefrontal Cortex    
    The serotonin story really begins with 
Melatonin .    Melatonin appeared very early in evolution as an antioxidant, and, at first, serotonin was no more than just an intermediary in   Melatonin's   biosynthesis.      

Serotonin (Wiki) 
    "Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans. It is a well-known contributor to feelings of well-being; therefore it is also known as a "happiness hormone" despite not being a hormone.  
    Approximately 80 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements.[1][2]  
    The remainder is synthesized in serotonergic neurons in the CNS where it has various functions. These include the regulation of mood, appetite, sleep, as well as muscle contraction. Serotonin also has some cognitive functions, including in memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

Serotonin is mainly metabolized to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase ( MAO ) to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys.
In addition to animals, serotonin is also found in fungi and plants.[3]


    When someone perceives a situation as disagreeable or dangerous, a general response to this  Stress is triggered in their body. Depending on the situation and the person's experience with such situations, he or she will choose a behaviour: either fight, or flight, or inhibition of action (the status quo).

The body's response from the time it perceives a danger to the time it secretes the  Hormones to prepare to deal with it involves the following structures, in the following order:

1) the Limbic System,  

2) the Hypothalamus, 3) the Pituitary Gland, and 4) the Adrenal Glands. The adrenal glands secrete Glucocorticoids (such as Cortisol, in human beings), which interact with the Serotonin Receptors in the brain.

Tool Module : Cybernetics









    When someone experiences a stressful event, the level of glucocorticoids in their blood rises. Via specific receptors in the Hippocampus, this activates the hypothalamus, which then secretes Corticotropin-releasing hormone (CRH). The CRH in turn causes the pituitary gland to release adrenocorticotropic hormone ( ACTH) into the bloodstream, from which it enters the adrenal glands and causes them to secrete cortisol.

     This process creates a negative feedback loop in which the excess cortisol activates the brain's glucocorticoid receptors and suppresses the production of CRH. In depressed patients, however, this loop no longer works, resulting in excess production of CRH and hence of cortisol.

Many seriously depressed patients have high blood levels of cortisol, caused by chronic stress.

    In rats, chronic stress and/or a high level of glucocorticoids alters certain Serotonergic Receptors (increases the 5-HT2A receptors in the Cerebral Cortex and reduces the 5-HT1A receptors in the hippocampus). These same changes have been observed in humans who have committed suicide or suffered from diseases that cause hypersecretion of glucocorticoids. The continued administration of antidepressants causes changes in the serotonergic receptors that are the opposite of the changes produced by chronic stress. It also reverses the hypersecretion of stress hormones.

     Not incidentally, in humans, many
Glucocorticoid Receptors (GRs) and mineralocorticoid receptors (MRs) (see sidebar, below) are located in the hypothalamus and the hippocampus, two structures involved in mood control and the ability to experience pleasure. These receptors are sensitive both to the levels of the various Corticosteroids in the body and to the length of time that they are active, so their activation mechanisms will have direct impacts on the behavioural response chosen to a given stimulus.

     For example, when corticosteroids circulate at low levels they facilitate, via the MR receptors,
the reactions associated with fear (momentary paralysis and turning toward the frightening stimulus). But when corticosteroids circulate at high levels (for example, when the organism is exposed to chronic stress), they instead potentiate inhibition of action, via the GR receptors .

     Prolonged chronic stress also seems to alter the response of the MR and GR receptors and to have very harmful effects on people's mental equilibrium, especially when social or family supports are absent. Under these conditions, the glucocorticoid response, which was originally highly adaptive, becomes clearly maladaptive.

    It has long been known that depressed persons display hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis (see illustration and explanation above). A prolonged state of inhibition of action is also known to encourage the emergence of a depressive state. This chronic excess stress on the HPA Axis is believed to result in structural changes in certain parts of the brain. For example, region CA3 of the hippocampus loses large numbers of neurons when subjected to prolonged stress.

     Other studies have also reported a reduced number of glucocorticoid receptors in the hippocampus and 
Prefrontal Cortex of suicide victims. Though it is hard to tell whether these structural changes are of genetic origin or the result of chronic activation of the HPA Axis, they would be consistent with hyperactivity in this axis when the natural braking effect of these receptors was reduced.

     Here's another example: people with Cushing's syndrome, a disease in which the body produces excess cortisol, display a high incidence of depression, and their depression lifts when they are given treatments that bring their cortisol levels back to normal.

     Thus, all indications are that the end products of the HPA axis—glucocorticoids— play a role in depression by influencing several
Neurotransmitter systems, including those for serotonin, Norepinephrine, and Dopamine, all three of which are involved in depression.   


    "Corticosteroids (also known as corticoids) are hormones secreted by the outer portions of the adrenal glands. They can be divided into three groups, for each of which there are separate receptors:

    Androgens, which are involved in the development of sexual traits;  

    mineralocorticoids (aldosterone, corticosterone, desoxycortisone), which regulate the body's osmotic balance; and  

    Glucocorticoids (cortisone, hydrocortisone, prednisone), which, in addition to their anti-inflammatory and immunosuppressive effects, stimulate the synthesis of glucose and increase the mobilization of fatty acids and proteins to meet the higher metabolic demands generated by stress.

     Glucocorticoids play an extremely important role in fear and anxiety reactions and in depressive states. These hormones often affect behaviour by increasing or decreasing the efficiency of certain neural pathways.

My comments
    Very important quotes from above: 
    1.  "
The adrenal glands secrete Glucocorticoids (such as Cortisol , in human beings), which interact with the Serotonin receptors in the brain."      This suggests that the  Direct Cortisol Pathway   influences the Direct Serotonin Pathway     . 
    2.  "
When someone experiences a stressful event, the level of Glucocorticoids in their blood rises. Via specific receptors in the Hippocampus , this activates the Hypothalamus , which then secretes Corticotropin-releasing hormone (CRH) . The CRH in turn causes the Pituitary Gland to release adrenocorticotropic hormone ( ACTH ) into the bloodstream, from which it enters the Adrenal Cortices and causes them to secrete Cortisol . "  
     This would seem to indicate a positive feed-back loop in the 
Direct Cortisol Pathway , which seems unlikely.   
    3.  "
In rats, chronic stress and/or a high level of Glucocorticoids alters certain Serotonin Receptors  (increases the 5-HT2A receptors in the cerebral cortex and reduces the 5-HT1A receptors in the Hippocampus). "    


Reconciling the role of central serotonin neurones in human and animal behavior (Goog) - 1986   
Only abstract available online.  I got the 46 page PDF through the library.
from the abstract    
Decreases in serotonin transmission seem to be associated with the increased performance of behaviors that are usually suppressed, though not necessarily because of the alleviation of anxiety, which might contribute to the suppression.
my impression of the PDF from memory
    This is a very long review of more-or-less everything that was known about serotonin 25 years ago.   It hypothesizes that in the strong correlation between elevated circulating
Cortisol and elevated  serotonin  activity, it is the elevated serotonin that is the cause and the elevated cortisol that is the effect.  However, it does not offer an explanation of how elevated  serotonin causes elevated cortisol.   
    An alternative hypothesis is that the elevated cortisol is the cause and the elevated serotonin is the effect.  Cortisol suppresses the sensitivity of
Luteinizing Hormone receptors on the testes, thereby reducing the production of Testosterone.  Since testosterone inhibits serotonergic receptors, the elevated circulating cortisol causes elevated serotonin activity by reducing the inhibitory effect of testosterone.   
    Full disclosure:  their position is supported by a reference that claims that "Treatment with 8-hydroxy-2(di-n- propylamino)tetralin, a specific 5-HT1A receptor Agonist, elevates plasma cortisol concentrations in catheterized rainbow trout in a dosedependent manner (34)."   
    NOTE:  The 'full disclosure', above, doesn't seem to be from the paper.  The paper doesn't use reference numbers like '(34).