Biomedical subjects
George Hatzidimitriou
Publications and source records attributed to George Hatzidimitriou.
Response to O'Shea and Colado: the MDMA neurotoxicity profile might provide clues to mechanisms.
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Validity of [123I]beta-CIT SPECT in detecting MDMA-induced serotonergic neurotoxicity.
Recent [123I]beta-CIT single-photon emission computed tomography (SPECT) studies revealed decreased serotonin transporters (SERT) density in the brain of humans with a history of MDMA ("Ecstasy") use. However, [123I]beta-CIT SPECT has until now not been validated as a method for detecting such serotonergic lesions. Therefore, the present study was undertaken. Following baseline [123I]beta-CIT SPECT scans, a rhesus monkey was treated with MDMA (5 mg/kg, s.c. twice daily for 4 consecutive days). SPECT studies 4, 10, and 31 days after MDMA treatment revealed decreases in [123I]beta-CIT binding ratios in the SERT-rich brain region studied (hypothalamic/midbrain region), with SERT density reduced by 39% in this brain region 31 days after treatment. Data obtained with SPECT studies correlated well with SERT density determined with autoradiography after sacrifice of the animal (-34%). In addition, ex vivo [123I]beta-CIT binding studies in rats 1 week after treatment with neurotoxic doses of MDMA (20 mg/kg s.c. twice daily for 4 consecutive days) revealed significant reductions in [123I]beta-CIT binding in SERT-rich regions (including the hypothalamus) when compared to saline-treated rats. The combined results of these studies indicate that SPECT imaging of SERT with [123I]beta-CIT can detect changes in SERT density secondary to MDMA-induced neurotoxicity in the hypothalamic/midbrain region, and possibly other brain regions.
RETRACTED: Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA ("ecstasy").
The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy") is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.
Changes in gene expression linked to methamphetamine-induced dopaminergic neurotoxicity.
The purpose of these studies was to examine the role of gene expression in methamphetamine (METH)-induced dopamine (DA) neurotoxicity. First, the effects of the mRNA synthesis inhibitor, actinomycin-D, and the protein synthesis inhibitor, cycloheximide, were examined. Both agents afforded complete protection against METH-induced DA neurotoxicity and did so independently of effects on core temperature, DA transporter function, or METH brain levels, suggesting that gene transcription and mRNA translation play a role in METH neurotoxicity. Next, microarray technology, in combination with an experimental approach designed to facilitate recognition of relevant gene expression patterns, was used to identify gene products linked to METH-induced DA neurotoxicity. This led to the identification of several genes in the ventral midbrain associated with the neurotoxic process, including genes for energy metabolism [cytochrome c oxidase subunit 1 (COX1), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase chain 2, and phosphoglycerate mutase B], ion regulation (members of sodium/hydrogen exchanger and sodium/bile acid cotransporter family), signal transduction (adenylyl cyclase III), and cell differentiation and degeneration (N-myc downstream-regulated gene 3 and tau protein). Of these differentially expressed genes, we elected to further examine the increase in COX1 expression, because of data implicating energy utilization in METH neurotoxicity and the known role of COX1 in energy metabolism. On the basis of time course studies, Northern blot analyses, in situ hybridization results, and temperature studies, we now report that increased COX1 expression in the ventral midbrain is linked to METH-induced DA neuronal injury. The precise role of COX1 and other genes in METH neurotoxicity remains to be elucidated.
Altered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethamphetamine (MDMA) or fenfluramine.
3,4-Methylenedioxymethamphetamine ("Ecstasy," MDMA) and fenfluramine, widely used by humans, are potent brain serotonin (5-HT) neurotoxins in animals. Thus, there is concern that humans previously exposed to these amphetamine derivatives may have incurred brain 5-HT neurotoxicity. However, assessing the status of brain 5-HT neurons in the living organism is challenging. To determine whether MDMA- and/or fenfluramine-induced 5-HT neurotoxicity can be detected during life using neuroendocrine methods, groups of monkeys previously treated with neurotoxic regimens of MDMA or fenfluramine, along with saline-treated controls, underwent neuroendocrine challenge with the direct 5-HT agonist and 5-HT-releasing drug, m-chlorophenylpiperazine (m-CPP). Animals treated 2 weeks previously with MDMA exhibited a nonsignificant reduction in the prolactin response to m-CPP. In contrast, monkeys treated 3 1/2 years previously with MDMA or 2 years previously with fenfluramine exhibited significantly increased prolactin responses to m-CPP. No significant differences in cortisol concentrations were noted between groups at any time point. These data indicate that neuroendocrine challenge with m-CPP is capable of detecting substituted amphetamine-induced 5-HT neurotoxicity in living primates, but that the recency of drug exposure is an important consideration. Changes in the neuroendocrine response to m-CPP over time in animals with substituted amphetamine-induced neurotoxicity may be related to aberrant 5-HT reinnervation of the basal forebrain that occurs over time in monkeys previously treated with neurotoxic doses of MDMA or fenfluramine.
Cognitive performance of MDMA-treated rhesus monkeys: sensitivity to serotonergic challenge.
Recreational users of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") exhibit poor performance on a number of neurocognitive measures, with tests of memory and attention most commonly affected. Cognitive impairments can be persistent or possibly permanent, since users who have been abstinent from MDMA for many months are also impaired. Repeated treatment of rats or nonhuman primates with MDMA has consistently been demonstrated to produce specific, lasting depletions of brain serotonin (5-HT) markers, a potential source of such cognitive symptoms. We have shown, however, that monkeys treated with a regimen of MDMA (4 days, 10 mg/kg i.m., b.i.d.), sufficient to produce a 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid in cerebrospinal fluid, do not exhibit lasting deficits in a range of cognitive domains. Acute drug challenges are often effective at unmasking consequences of amphetamine toxicity. Here, the performance of MDMA-treated and control monkeys on tests of spatial working memory (self-ordered spatial search), vigilance and reaction time (5-choice reaction time), reinforcer efficacy and sustained attention (progressive ratio responding) and fine motor control (bimanual motor skill task) was challenged with ketanserin (0.1-1.7 mg/kg, i.m.), 1-(3-Chlorophenyl)piperazine dihydrochloride (mCPP, 0.03-0.5 mg/kg, i.m.) and (+/-)8-hydroxy-DPAT hydrobromide (8-OH-DPAT, 0.032-0.1 mg/kg, i.m.). MDMA-exposed animals exhibited increased sensitivity to challenge with mCPP on the reaction time and progressive ratio tasks but otherwise were equivalently sensitive to drug challenge. Post-mortem analysis demonstrated that 76-93% reductions of 5-HT in neocortex persist 17-20 months post-MDMA. These observations suggest that large depletions of brain 5-HT produced by MDMA can persistently alter behavioral sensitivity to the disrupting effects of serotonergic agents.