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Journal of Neuroscience, Vol 15, 5476-5485, Copyright © 1995 by Society for Neuroscience
Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy")
C Fischer, G Hatzidimitriou, J Wlos, J Katz and G Ricaurte
Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21224, USA.
The recreational drug (+/)3,4-methylenedioxymethamphetamine (MDMA,
"ecstasy") is a methamphetamine derivative that selectively destroys
central 5-HT axons and axon terminals in animals and, possibly, humans. The
fate of 5-HT neurons following MDMA injury is uncertain. In particular,
while it is known that central 5-HT axons can undergo regenerative
sprouting after MDMA injury, it has not been determined whether they
reestablish the original innervation pattern. To address this question, the
present studies examined 5-HT innervation patterns in animals lesioned with
MDMA 12-18 months previously. Both rodents (rats) and nonhuman primates
(squirrel monkeys) were examined, since there is indication that
serotonergic recovery after MDMA injury may be species dependent. 5-HT axon
projections were studied neurochemically, autoradiographically and
immunocytochemically. In both rodents and nonhuman primates previously
lesioned with MDMA, substantial serotonergic axonal sprouting was observed.
However, in a few rats and in most squirrel monkeys, the reinnervation
pattern was highly abnormal: distant targets (e.g., dorsal neocortex)
remained denervated, while some proximal targets (e.g., amygdala,
hypothalamus) were reinnervated or hyperinnervated. Although the specific
determinants of axonal recovery after MDMA injury remain to be identified,
it appears that axons which initially sustain more severe damage, are
longer, or are more highly arborized have low probability of recovering.
The observation that some brain regions remain denervated, while others are
reinnervated or hyperinnervated suggests that, under some circumstances,
MDMA injury can lead to a lasting reorganization of ascending 5-HT axon
projections. Such lasting changes in brain innervation, documented here in
MDMA-treated animals, may have implications for humans using MDMA
recreationally.
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