Neurotoxic effects of MDMA (ecstasy) on the developing rodent brain.
The incidence of methamphetamine abuse is particularly high in adolescents and is a common problem among women of childbearing age, leading to an increasing number of children with prenatal exposure. MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is an amphetamine-like stimulant and is known to induce apoptotic damage to fine serotonergic fibers in the adult rat brain. Little is known about toxic effects of MDMA and potential underlying molecular mechanisms in the developing brain. Here, we investigated whether MDMA exposure during the period of rapid brain growth causes neurodegeneration in the developing rat brain. MDMA significantly enhanced neuronal death in the brains of 6-day-old rat pups at a dose of 60 mg/kg, but no significant toxicity was detected at the ages of 14 and 21 days. Brain regions mainly affected were the cortex, septum, thalamus, hypothalamus and the cornu ammonis 1 region. To explore possible molecular mechanisms involved in this neurodegenerative process, we investigated the impact of MDMA on the expression of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor. Neonatal exposure of 6-day-old rats to MDMA triggered a considerable increase in cortical BDNF and NT-3 levels. Moreover, P7 CD1/BDNF knockout mice were noticeably more sensitive to MDMA exposure as compared to their wild-type age-matched littermates. These data suggest that a single injection of MDMA causes neurodegeneration in the neonatal rat brain. The upregulation of BDNF and NT-3 expression may indicate an important compensatory mechanism leading to the survival of neuronal cells in the developing brain.
Dzietko
M
M
Department of Neonatology, Children's Hospital, Charité - Universitätsmedizin Berlin, Berlin, Germany. dzietkom @ peds.ucsf.edu
Sifringer
M
M
Klaus
J
J
Endesfelder
S
S
Brait
D
D
Hansen
H H
HH
Bendix
I
I
Felderhoff-Mueser
U
U
D000293:Adolescent; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D018490:Serotonin Agents / Q000633:toxicity*; D055815:Young Adult
D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3; D018490:Serotonin Agents; D020932:Nerve Growth Factor; D018817:N-Methyl-3,4-methylenedioxyamphetamine