Fenfluramine a Neurotoxin?

Wilfred Pinto wpinto at orion.it.luc.edu
Tue Mar 11 16:51:11 EST 1997


Fenfluramine is currently deemed a serotonin releaser; several lines of
evidence suggest that it is taken up into the terminal by serotonin
transporters where it can produce extensive release of serotonin at the
synapse, and subsequent depletion of the terminals. Whether this process
is directly involved in its appetite suppresant effect is still unclear. 
There is a paper that indicates that the neurotoxic effects can be
separated from the hypophagic effects. 

The racemic d,l-fenfluramine has been studied extensively and it is clear
that at higher doses it produces neurotoxicity. The standard protocols
involve a 4 day drug treatment, and neurotoxicity evaluation atleast 2
weeks later when any acute depletion should be reversed and no residual
drug remains in the animal. When compared to animals simultaneously
treated with either PCPA or reserpine (both of which deplete serotonin but
do not produce neurotoxicity) fenfluramine treated animals have sustained,
long-lasting deficits in serotonin content and in serotonin uptake sites.
Most of these alterations happen in the serotonin projection areas leaving
cell bodies relatively intact. The depletion in serotonin content seems to
reverse slowly over a period of months, but the transporter density was
not shown to reach normal levels as long as a year after a 4 day
fenfluramine treatment.  There are some very elegant
immunocytochemical studies (also 2 weeks post treatment) where the density
of serotonin containing terminals was severely reduced and there were
morphological alterations in the remaining terminals. 

The recent hype about the stereoisomer dexfenfluramine (atleast in the US)
has propelled several different labs to study this drug's effects on the
5-HT system. New tools including immunocytochemistry for the serotonin
transporter, as well as PET studies are being employed and most of the
results confirm that dexfenfluramine (which is also the more potent
stereoisomer at releasing serotonin) is more potent at producing these
longlasting alterations in brain serotonin pathways. However, the doses
used in these studies are between 4 to 10 times the doses used in humans
for appetite suppressant effects. 

Bet, that was more than you wanted to know about fenfluramine as a
neurotoxin.

Wilfred Pinto   




David Longley (David at longley.demon.co.uk) wrote:
......

: It's 15 years since I did work on monoamines, 6-OHDA, DSP-4, 5-7-
: DHT  etc  and  the monoamines, but back  then,  fenfluramine  was 
: regarded   as  a  5-HT  analogue  of  the  catecholamine   active 
: amphetamines. 

: Things  may have radically changed, but is it not the  case  that 
: the  observed  "depletions" may be just that?  depleted  neurones 
: because of enhanced turnover in the treated animals?




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