An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine.
Administration of the street drug 3,4-methylenedioxymethamphetamine (MDMA) to various experimental animals has been shown in several laboratories to induce selective damage to serotonergic axons and axon terminals. This review examines the current available evidence supporting the development of serotonin (5-HT) neurotoxicity in animals and humans. There are a plethora of hypotheses that attempt to explain the mechanisms involved in the development of this serotonergic neurotoxicity. An integrated hypothesis incorporating most of the speculated neurotransmitters theorized to be involved in the process is proposed. This hypothesis states that MDMA induces the following sequence of events resulting in the serotonergic neurotoxicity: 1. MDMA induces an acute release of 5-HT and dopamine (DA). 2. This acute release is followed by depletion of intraneuronal 5-HT stores. 3. The initially released 5-HT activates post-synaptic 5-HT2A/2C receptors located on GABA interneurons resulting in a decrease in GABAegic transmission and increased DA release and synthesis. 4. The excessive DA released then may be transported into the depleted 5-HT terminal. 5. The DA is then deaminated by monoamine oxidase B (MAO-B) located within the 5-HT terminal. This results in free-radical formation and the selective degeneration of the serotonergic axons and axon terminals. While there is no clear evidence that human users of the drug are suffering a similar neurotoxicity, data are presented suggesting that there remains cause for concern.
Sprague
J E
JE
Department of Pharmaceutical and Biomedical Sciences, Ohio Northern University, Ada 45810, USA.
Everman
S L
SL
Nichols
D E
DE
D000818:Animals; D001369:Axons / Q000187:drug effects*; D006801:Humans; D013287:Illicit Drugs / Q000633:toxicity*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000378:metabolism; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D013287:Illicit Drugs; D009498:Neurotoxins; D018377:Neurotransmitter Agents; D018490:Serotonin Agents; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine