Abstract:
Fischer C, Hatzidimitriou G, Wios J, Katz J, Ricaurte G. Reorganization of Ascending 5-HT Axon Projections in Animals Previously Exposed to the Recreational Drug (+-) 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"). J of Neuroscience 15 (8):5476-5485, 1995.
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 in 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.
In my view, the message from our most recent study is that if you severely injure serotonin neurons in non-human primates, normal axonal recovery does not take place. As to possible implications for humans, we don't yet know. First, we need to know if in fact MDMA injures serotonin neurons in humans. If it does, then additional studies are needed to see if the abnormal axonal recovery of the type seen in monkeys also occurs in humans. Finally, if abnormal reenervation is noted in the human brain, possible functional consequences would still need to be investigated.
-- George Ricaurte MD, Ph.D., September 10, 1995