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Stress and Serotonin

John H. johnhkm at netsprintXXXX.net.au
Thu Jan 13 04:02:39 EST 2000

John, during the interim while his ISP has vainly tried to restore the news
server to full function, has been reading some of the following and would
appreciate some help in understanding the same.

6/01/00 13:55

Lately I've been trying to develop an delude myself into understanding the
various inter-relationships between stress, apoptosis, and cognitive
function. The HPA axis seems to be rather sensitive, the study below
suggests chronic stress may make it more suspectible to activation not only
through the reapplication of the initial stressor but the application of any
future stressors.

5-HT1A autoreceptor desensitization by chronic ultramild stress in mice

Laurence Lanfumey, CA Marie-Christine Pardon, 1 Nora Laaris, Chantal
Joubert, Naima Hanoun, Michel Hamon and Charles Cohen-Salmon 1

NeuroReport 10, (1999)


Exposure to CUMS for 8 weeks changed neither the specific binding of [ 3
H]alnespirone to 5-HT1A receptors in hippocampal, cortical and brain stem
membranes nor that of [ 3 H]WAY 100635 in cortical membranes. Data in Table
2 show that both 5-HT and 5- HIAA levels were generally decreased (up to
33%) in brain areas from mice subjected to CUMS compared to paired controls.
A significant reduction( . 18%) in the 5-HIAA/5-HT ratio was also noted in
the brain stem, hippocampus and striatum, but not in the cerebral cortex in
stressed mice (Table 2)."

Note: CUMS is a procedure to induce stress in mice.

We also saw a marked increase ( . 350%, p ,0.01) in serum corticosterone
levels in mice subjected to CUMS. If the circulating levels of
corticosterone actually reflected activation of the HPA axis, it can be
inferred that chronic exposure to different stres- sors such as those used
in the present CUMS procedure probably renders the HPA axis super- sensitive
to each consecutive unpredictable stress session. Indeed, repeated exposure
to the same stress such as immobilization does not increase basal
corticosterone levels [23], but enhances the cortico- sterone response to
another stress [24].

Previous studies in rats have shown that elevated corticosterone levels
probably play a major role in stress-induced DRN 5-HT1A autoreceptor
desensiti- zation, because this phenomenon can be prevented by adrenalectomy
and is mimicked by the direct application of the hormone onto brain stem
slices [7,8]."


The elevated corticosterone levels of ongoing stress has some rather
unfortunate implications:

Cortisol levels during human aging predict hippocampal atrophy and memory
Sonia J. Lupien, Mony de Leon, Susan de Santi, Antonio Convit, Chaim
Tarshish, N.P.V.
Nair, Mira Thakur, Bruce S. McEwen, Richard L. Hauger and Michael J. Meaney

Nature Neuroscience,  volume 1, no 1, may 1998

" We found considerable variation in plasma cortisol levels, as well as
clear evidence for three subgroup patterns: progressive increase in cortisol
levels with currently high basal cortisol levels (termed "increasing/high
cortisol"), progressive increase in cortisol lev-els with currently moderate
cortisol levels ("increasing/moder-ate cortisol"), or progressive decrease
in cortisol levels with currently moderate cortisol levels
("decreasing/moderate corti-sol"). Both acute and chronic cortisol
elevations induce cogni-tive deficits in human populations 12,13 ."

Two groups on the up, over a 6 year study. It would be interesting to know
if similiar patterns appear across all cultures and lifestyles. What it does
demonstrate though is that prolonged stress, apart from potentially making
one quite stupid, is not really tolerated that well by important bits of us.
Parts of our brain do not appear to be well adapted to chronic stressors
even if we are externally managing them. I wonder if evolution has prepared
the CNS for prolonged stress "attacks", perhaps that is why there appears to
be so much redundancy. (I still have difficulty with the idea that all this
extra grey matter is lying just in case a bit gets injured etc etc. It may
be adaptive mechanism to cope with an over-enthusiastic immune system but I
can't argue that case.)

Excerpt from Robert Sapolsky.

Junk Food Monkeys, Headline Press, 1998, p 118

"... [These people] don't appear to have all that many stressors. They claim
they're not depressed or anxious, and the psychological tests they are given
show they're right. In fact, they describe themselves as pretty happy,
successful and accomplished (and, according to personality tests conducted
by psychologist Dirk H. Hellhammer and colleagues at Trier University in
Germany, they really are all the above). Yet these people (comprising
approximately 5 percent of the population) have chronically activated stress
responses. What's their problem?

"These are the archetypal people who cross all their Ts and dot all the Is.
... keep a tight lid on their emotions ... stoic, hardworking, productive,
solid folks ... Careful study indicates that some repressors are indeed
mostly concerned about keeping up appearances."


Like that's so unique, this class of individuals is to some extent reflected
in all of us. I'm not confident there exists a clearcut threshold between
this class of people and the greater mass. Additionally, in such a class a
people I would expect some identifiable cognitive deficits (with age)
arising as a result of chronic stress, but my feeling is that with this
class that will not be the case (they are hardworking, successful, and happy
... ). Or am I seriously over-estimated the degree of corticosterone effect

Perhaps chronic HPA activation is not bad for all people. Slow steady damage
can be managed remarkably well. Perhaps the richness of the peoples' lives
in the above example offers a counter prevailing tendency by encouraging
neurogenesis and inhibiting apoptosis ("Environmental enrichment inhibits
spontaneous apoptosis, prevents seizures and is neuroprotective." Nature
Medicine, Vol 5, No. 4 , April 1999).

An unmobilised but stressed brain may be committing slow suicide, a simple
numbers game perhaps, cells may be suffering through prolonged HPA
activation but the constant stimulation (even if only via vainly searching
for a solution to the problem but anything will do, may prohibit the same,
or at least protect those regions involved in this cognitive activity). To
give up under these circumstances is to commence a slow death. Chicken and

A little stress also enhances some cognitive functions while too much does
the opposite. Chronic sleep deprivation will lower IQ and memory, is there
any relationship between sleep cycles, sleep deprivation, and stress hormone

Is this the general rule with depression in human beings: high
corticosterone and lowered 5HT activity?

Do elevated corticosterone levels increase oxidative stress? It does
encourage apoptosis, though by which mechanism I'm not sure. I don't want to
take the long way home. What must I do to save my hippocampus?

John H.
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