Neuropharmacology and Neurotoxicity of 3,4-Methylenedioxymethamphetamine - Drugs of Abuse: Neurological Reviews and Protocols - page 55

in most brain regions containing 5-HT terminals (32) . There is only a partial
recovery, at best, to control concentrations of 5-HT after depletion produced
by MDMA. In fact, 5-HT concentrations remain depleted in most brain regions
up to 1 yr following MDMA administration (32 , 33) . The fact that 5-HT cell
bodies are spared by MDMA may allow for the regeneration of “pruned” 5-HT
axons. Indeed, the regeneration of 5-HT axon terminals has been reported
following a “neurotoxic” regimen of MDMA, although the pattern of rein-
nervation is abnormal (34) .
On the basis of the persistence of MDMA effects on 5-HT terminals
and the accompanying functional changes ( see Subheading 7. ), there is a
general concensus that MDMA induces selective 5-HT neurotoxicity, that is,
degeneration of 5-HT axon terminals. Nevertheless, there is a lack of consistent
histopathological or cytochemical changes that usually accompany neurotoxic-
ity in MDMA-treated rats. Specifi cally, MDMA induces little increase in silver
staining for degenerating neurons (35 , 36) , and there is little induction of glial
fi brillary acidic protein (37) . However, consistent with the view that MDMA
produces neurotoxicity, presumably within 5-HT axon terminals, is the fi nding
that MDMA treatment results in a reduction of anterograde axonal transport
of labeled material to forebrain regions containing 5-HT innervation (38) .
In addition, MDMA promotes the cleavage of the cytoskeletal protein tau in
the hippocampus (39) . These fi ndings support the conclusion that MDMA
produces structural brain damage in the rodent brain that accompanies the
long-term depletion of brain 5-HT.
3. Role of Dopamine in MDMA-Induced Neurotoxicity
The excessive release of dopamine elicited by MDMA is proposed to
contribute, in part, to the 5-HT neurotoxicity produced by this drug. A correla-
tion exists between the extent of dopamine release and extent of long-term
5-HT depletion induced by MDMA and structurally related compounds (8) .
Moreover, attenuation of the MDMA-induced release of dopamine by the
lesioning of neurons (40 , 41) , treatment with dopamine uptake inhibitors
(42 , 43) , or inhibition of dopamine synthesis (26) affords protection against
MDMA-induced 5-HT neurotoxicity. Furthermore, elimination of dopamine
transporters in the striatum with the use of antisense oligonucleotides also
prevents the MDMA-induced depletion of striatal 5-HT (44) . Conversely,
facilitation of dopamine release with 3,4-dihydroxy- L -phenylalanine ( L -DOPA)
or 5-HT 2 agonists results in an augmentation of the long-term depletion of
5-HT induced by MDMA (12 , 45) . The ontogeny of MDMA-induced 5-HT
neurotoxicity also appears to be dependent on the ability of MDMA to release
dopamine (41) .