Effects of Repeated Low Doses of MDMA on EEG Activity and Fluoro‐Jade B Histochemistry

Abstract: The psychostimulant 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) is an amphetamine derivative that is widely abused. In previous studies, depending on the animal species, neurotoxicity has been demonstrated for either serotonin (5‐HT) or/and dopamine (DA) nerve endings. These studies focused on the basal ganglia circuitry; however, in humans chronic abuse of MDMA often results in neurological symptoms that last after MDMA withdrawal and are not related to the extrapyramidal system such as electroencephalographic (EEG) abnormalities and cognitive impairment. These alterations might be due to the concomitant intake of other illicit compounds, the consequence of MDMA‐induced hyperthermia, or to a primary neurotoxicity directed to extrastriatal regions. These observations call for a more in‐depth analysis on the potential involvement of brain areas outside the basal ganglia in the toxic effects induced primarily by MDMA. In the present study, we treated C57Black mice chronically (25 days) with daily injections of MDMA (2.5 mg/kg). During treatments, mice were monitored in order to detect behavioral modifications, and epidural electrodes were installed to perform EEG recording. Behavioral data showed a sensitization as measured by locomotor activity, which related to progressive and long‐lasting EEG changes and neuronal degeneration within the hippocampus.

[1]  L. Schmued.  Demonstration and localization of neuronal degeneration in the rat forebrain following a single exposure to MDMA , 2003, Brain Research.

[2]  Karen L. Anderson,et al.  Relevance of MDMA ("ecstasy")-induced neurotoxicity to long-lasting psychomotor stimulation in mice , 2003, Psychopharmacology.

[3]  U. McCann,et al.  Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy") , 2002, Science.

[4]  A. Parrott,et al.  Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity , 2002, Pharmacology Biochemistry and Behavior.

[5]  F. Carvalho,et al.  Effect of 3,4-methylenedioxymethamphetamine ("ecstasy") on body temperature and liver antioxidant status in mice: influence of ambient temperature , 2002, Archives of Toxicology.

[6]  A. Parrott.  Human psychopharmacology of Ecstasy (MDMA): a review of 15 years of empirical research , 2001, Human psychopharmacology.

[7]  J. Powell,et al.  Recreational use of 3,4-methylenedioxymethamphetamine (MDMA) or ‘ecstasy’: evidence for cognitive impairment , 2001, Psychological Medicine.

[8]  K. Zakzanis,et al.  Memory impairment in abstinent MDMA (“Ecstasy”) users: A longitudinal investigation , 2001, Neurology.

[9]  Kevin S. Chen,et al.  Biochemical effects of the monoamine neurotoxins DSP‐4 and MDMA in specific brain regions of MAO‐B‐deficient mice , 2001, Synapse.

[10]  L. Schmued,et al.  Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration , 2000, Brain Research.

[11]  M. Gill,et al.  Agony and ecstasy: a review of MDMA effects and toxicity , 2000, European Psychiatry.

[12]  E. Gouzoulis-Mayfrank,et al.  Impaired cognitive performance in drug free users of recreational ecstasy (MDMA) , 2000, Journal of neurology, neurosurgery, and psychiatry.

[13]  J. Shih,et al.  Striatal Dopamine Metabolism in Monoamine Oxidase B‐Deficient Mice : A Brain Dialysis Study , 1999, Journal of neurochemistry.

[14]  Z. Szabo,et al.  Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings , 1998, The Lancet.

[15]  A. Lees,et al.  Cognitive performance in recreational users of MDMA or 'ecstasy': evidence for memory deficits , 1998, Journal of psychopharmacology.

[16]  M. Colado,et al.  The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype , 1995, British journal of pharmacology.

[17]  E. London,et al.  Effects of methylenedioxymethamphetamine on local cerebral glucose utilization in the rat , 1989, Neuropharmacology.

[18]  B. Logan,et al.  Differences between rats and mice in MDMA (methylenedioxymethylamphetamine) neurotoxicity. , 1988, European journal of pharmacology.

[19]  G. Battaglia,et al.  Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  J. Langston,et al.  Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration , 1988, Brain Research.

[21]  B. Yamamoto,et al.  The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. , 1988, European journal of pharmacology.

[22]  G. Hanson,et al.  Differences in the central serotonergic effects of Methylenedioxymethamphetamine (MDMA) in mice and rats , 1987, Neuropharmacology.

[23]  L. Seiden,et al.  α-Methyltyrosine blocks methylamphetamine-induced degeneration in the rat somatosensory cortex , 1986, Brain Research.

[24]  H. Steinbusch,et al.  Distribution of serotonin-immunoreactivity in the central nervous system of the rat—Cell bodies and terminals , 1981, Neuroscience.

[25]  J. Sharkey,et al.  Alterations in hippocampal function following repeated exposure to the amphetamine derivative methylenedioxymethamphetamine (“Ecstasy”) , 2006, Psychopharmacology.

[26]  A. Young,et al.  A study of the effect of a single neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") on the subsequent long-term behaviour of rats in the plus maze and open field , 2002, Psychopharmacology.

[27]  J. Krystal,et al.  Psychopharmacology: The Third Generation of Progress , 1989, The Yale Journal of Biology and Medicine.

[28]  L. Seiden,et al.  alpha-Methyltyrosine blocks methylamphetamine-induced degeneration in the rat somatosensory cortex. , 1986, Brain research.