Effects of MDMA and MDA on Brain Serotonin Neurons: Evidence from Neurochemical and Autoradiographic Studies

Methylenedioxy-substituted amphetamine derivatives, including MDMA, cause widespread and long-lasting degeneration of serotonin neurons in the brain after administration in animals, without consistently affecting dopamine or other catecholamine neurons. The severity of damage depends on dose and frequency, occurs across species including primates, and can be prevented by a serotonin uptake blocker, implicating active uptake of MDMA, a toxic metabolite, or an endogenous neurotoxin. Neuronal recovery may take up to a year, while functional recovery may be permanently impaired. Neurochemical and autoradiographic data show predominant reductions in serotonin uptake sites in terminal regions, with relative sparing of axons of passage and cell bodies.

Study at a glance

Abstract

The data presented in this chapter provide strong evidence, from both neurochemical and neuroanatomical studies, demonstrating that, following in vivo administration of a number of methylenedioxy-substituted amphetamine derivatives, there is widespread and long-lasting degeneration of serotonin neurons in brain, without any major or consistent effects on catecholamine neurons. A detailed examination of the parameters involved in the neurotoxic and neurodegenerative effects of MDMA on brain serotonin neurons indicates that: (1) the severity of the lesion by MDMA is dependent on both the dose and frequency of drug administration; (2) the neurodegenerative effects of MDMA can be elicited in a number of animal species including primates; (3) the neurodegenerative effects on brain serotonin neurons can be prevented by the serotonin uptake blocker, suggesting a role for the active uptake of MDMA, a neurotoxic metabolite of MDMA, or an unidentified endogenous neurotoxin; and (4) the neurodegenerative effects of the drug are long-lasting (up to 1 year) with respect to neuronal recovery, while functional recovery may be permanently impaired. In addition, the neurochemical and autoradiographic data suggest that there is some neuroanatomical and morphological specificity to the neurodegenerative effects of MDMA and MDA, as evidenced by predominant reductions in serotonin uptake sites in brain regions containing primarily serotonin terminals, while regions containing serotonin axons of passage and cell bodies are relatively unaffected.