Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "ecstasy")

MDMA destroys serotonin axons in the brain. After injury, these axons can regrow, but the new connections are often abnormal. In rats and squirrel monkeys studied 12–18 months after MDMA exposure, some brain regions remained denervated while others became reinnervated or even hyperinnervated. Distant targets like the dorsal neocortex stayed denervated, whereas proximal targets such as the amygdala and hypothalamus recovered. Longer or more highly arborized axons had lower recovery probability. This lasting reorganization of serotonin projections may have implications for humans who use MDMA recreationally.

Study at a glance

Abstract

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.