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Archives of Toxicology
https://doi.org/10.1007/s00204-018-2226-8
ORGAN TOXICITY AND MECHANISMS
Aged rats are more vulnerable than adolescents to “ecstasy”-induced
toxicity
R. Feio‑Azevedo
1
· V. M. Costa
1
· D. J. Barbosa
1
· A. Teixeira‑Gomes
1
· I. Pita
2
· S. Gomes
2
· F. C. Pereira
2
·
M. Duarte‑Araújo
3
· J. A. Duarte
4
· F. Marques
5
· E. Fernandes
6
· M. L. Bastos
1
· F. Carvalho
1
· J. P. Capela
1,7
Received: 30 January 2018 / Accepted: 17 May 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a widespread drug of abuse with known neurotoxic proper-
ties. The present study aimed to evaluate the differential toxic effects of MDMA in adolescent and aged Wistar rats, using
doses pharmacologically comparable to humans. Adolescent (post-natal day 40) (3 × 5 mg/kg, 2 h apart) and aged (mean 20
months old) (2 × 5 mg/kg, 2 h apart) rats received MDMA intraperitoneally. Animals were killed 7 days later, and the frontal
cortex, hippocampus, striatum and cerebellum brain areas were dissected, and heart, liver and kidneys were collected. MDMA
caused hyperthermia in both treated groups, but aged rats had a more dramatic temperature elevation. MDMA promoted
serotonergic neurotoxicity only in the hippocampus of aged, but not in the adolescents’ brain, and did not change the levels
of dopamine or serotonin metabolite in the striatum of both groups. Differential responses according to age were also seen
regarding brain p-Tau levels, a hallmark of a degenerative brain, since only aged animals had significant increases. MDMA
evoked brain oxidative stress in the hippocampus and striatum of aged, and in the hippocampus, frontal cortex, and striatum
brain areas of adolescents according to protein carbonylation, but only decreased GSH levels in the hippocampus of aged
animals. The brain maturational stage seems crucial for MDMA-evoked serotonergic neurotoxicity. Aged animals were
more susceptible to MDMA-induced tissue damage in the heart and kidneys, and both ages had an increase in liver fibrotic
tissue content. In conclusion, age is a determinant factor for the toxic events promoted by “ecstasy”. This work demonstrated
special susceptibility of aged hippocampus to MDMA neurotoxicity, as well as impressive damage to the heart and kidney
tissue following “ecstasy”.
Keywords “Ecstasy” · Neurotoxicity · Aged rats · Tau · Cardiotoxicity · Nephrotoxicity
Abbreviations
5-HIAA 5-Hydroxyindoleacetic acid
5-HT Serotonin
* R. Feio-Azevedo
* J. P. Capela
joaoc@ufp.edu.pt
1
UCIBIO, REQUIMTE (Rede de Química e Tecnologia),
Laboratório de Toxicologia, Departamento de Ciências
Biológicas, Faculdade de Farmácia, Universidade do Porto,
Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto,
Portugal
2
Instituto de Farmacologia e Terapêutica Experimental,
Coimbra Institute for Clinical and Biomedical Research
(iCBR), Faculty of Medicine, Universidade de Coimbra,
Coimbra, Portugal
3
Departamento de Imunofisiologia e Farmacologia, Instituto
de Ciências Biomédicas de Abel Salazar (ICBAS),
Universidade do Porto, Porto, Portugal
4
CIAFEL, Faculdade de Desporto, Universidade do Porto,
Porto, Portugal
5
UCIBIO, REQUIMTE, Laboratório de Bioquímica,
Departamento de Ciências Biológicas, Faculdade de
Farmácia, Universidade do Porto, Porto, Portugal
6
LAQV, REQUIMTE, Laboratório de Química Aplicada,
Departamento de Química, Faculdade de Farmácia,
Universidade do Porto, Porto, Portugal
7
FP-ENAS (Unidade de Investigação UFP em Energia,
Ambiente e Saúde), CEBIMED (Centro de Estudos em
Biomedicina), Faculdade de Ciências da Saúde, Universidade
Fernando Pessoa, Porto, Portugal
@Phil_Robichaud
@deepthiw
@JoseServera