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SSRI's and diurnal Serotonin cycle ?

David Longley David at longley.demon.co.uk
Mon Jun 5 13:18:10 EST 1995

In article <3qrq9i$d2a at nntpd.lkg.dec.com>
           jenkinsj at ozy.dec.com "Jon Jenkins" writes:

> Does anyone know the exact mechanism by which this
> class of drugs work ?

Unfortunately, the simple answer is going to be no. 

5-Hydroxytryptamine (serotonin) is one of the monoamine (an indoleamine) 
transmitters which has its cell bodies in various nuclei in the brain stem, 
and its terminals just about *everywhere* rostral to there. 

The groups of cell bodies (the raphe nuclei) which give rise to these widely 
innervating terminals have been the focus of an enormous amount of research 
since the late 1960s. As is the case with the anatomically similar 
catecholamines (dopamine and particularly noradrenaline, they seem to go 
almost everywhere. 

As the SSRIs block the re-uptake mechanism of the neurone, more transmitter 
is available at the synapse as a consequence. However, it is difficult to 
make sense of the drugs this way, because whilst one might speak of effects 
at the re-uptake sites as an *immediate pharmacologically definitive* effect, 
the *clinical* effect on the individual (which with other, tricyclic anti-
depressants may take 3 weeks), may or may not be related to this immediate
re-uptake mechanism effect. 

There are so many factors to consider, that in the absence of a good working 
model of what the monoamines are doing (generally, or specifically) it is 
almost impossible to say what the 'exact' mechanisms are.

I made myself very unpopular in sci.med.psychobiology recently by saying that
I thought it counter productive to speculate, as I could see such speculation 
leading people to tinker with their medication. In the end, I just apologised 
for saying anything at all <g>.

So, apart from the cautions I'll just say that you now know from first hand
experience why so much research has been addressed to trying to find out what 
the monoamines do in the brain - most if not all of the mood altering drugs
seem to be mediated by the monoamines, so a lot of the early research was on
the role such systems may play in reward and punishment - but as more and more
work was done throughout the 70s and 80s, such a simple view began to look
less credible.

Today, I am eager to hear if anyone has a coherent/empirically supported model
of what the monoamines are doing as you are. However, one word of caution, 
how a drug works on the neurone, and how it works on behaviour requires a good 
understanding of how particular neuronal systems are involved in the control
of particular behaviours. To the best of my knowledge, and having tried to do
a PhD on 'the interactions of brain monoamines and neuropeptides in the control
of operant behaviour' 15 years ago (as a thesis topic, the title was given to 
me at NIMR - and at the beginnning it seemed a reasonable topic - honest!)...
...nobody knows...but a Nobel prize might well be waiting!.

David Longley

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