Biomedical subjects
George A Ricaurte
Publications and source records attributed to George A Ricaurte.
Positron emission tomography of striatal serotonin transporters in Parkinson disease.
BACKGROUND: Little is known about serotonin neurons in Parkinson disease (PD). OBJECTIVE: To study the serotonin system in PD with positron emission tomography, using the serotonin transporter radioligand [11C](+)McN5652. DESIGN AND PATIENTS: We measured the density of the serotonin transporter and the density of [11C]WIN35,428-labeled dopamine transporters in the striatum of 13 adults with PD and 13 age- and sex-matched controls. To assess the effects of possible differences in blood flow or brain atrophy, we also measured regional cerebral blood flow and the size of the regions of interest for the caudate nucleus and putamen. RESULTS: Patients with PD showed reductions in the specific distribution volumes of [11C](+)McN5652 in the caudate (P<.01) and putamen (P<.01), along with the expected reductions in striatal [11C]WIN35,428 binding (P<.01). There were no reductions in regional cerebral blood flow or the sizes of the regions of interest, mitigating against potential confounding effects of blood flow, brain atrophy, or partial volume effects. Reductions in serotonin transporter binding correlated with ratings of disease staging. CONCLUSIONS: These results suggest that the density of serotonin transporters, like that of dopamine transporters, is reduced in the striatum of patients with PD and that these changes are related to disease stage.
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.
MDMA- and p-chlorophenylalanine-induced reduction in 5-HT concentrations: effects on serotonin transporter densities.
Low levels of serotonin may reduce the density of the serotonin transporter (SERT) by either increasing trafficking or reducing synthesis; a "neuroadaptive response". To determine whether 3,4-methylenedioxymethamphetamine (MDMA)-induced reductions in SERT density could be related to such a mechanism, p-chlorophenylalanine or MDMA was administered to rats, and brain serotonin and SERT density were measured. As expected, both treatments led to serotonin depletion 1, 7 and 14 days later. However, only MDMA reduced SERT density. This observation suggests that MDMA-induced reductions in SERT density do not represent neuroadaptive responses to decreased levels of brain serotonin, but may occur in response to some other stimulus or to the neurotoxic effects of MDMA.
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.
Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine neurotoxicity.
The mechanism by which 3,4-methylenedioxymethamphetamine (MDMA) produces serotonin (5-HT) neurotoxicity is unknown but considerable evidence suggests that endogenous brain dopamine (DA) is involved. However, it has recently become apparent that some of the data implicating brain DA in MDMA neurotoxicity may be confounded by drug effects on thermoregulation. The purpose of the present studies was to examine the role of DA in MDMA neurotoxicity, while controlling for possible confounding effects of drug- induced changes in core temperature. Rats were treated with reserpine, alone and in combination with alpha-methyl-p -tyrosine (AMPT), to deplete vesicular and cytoplasmic stores of DA. When drug-induced hypothermia was averted (by raising ambient temperature), the 5-HT neuroprotective effects of reserpine and AMPT were no longer apparent. The lack of neuroprotection by AMPT and reserpine, alone and in combination, in studies that control for the effects of these drugs on core temperature, suggests that DA per se is not essential for the expression of MDMA-induced 5-HT neurotoxicity.
Effect of glucoprivation on serotonin neurotoxicity induced by substituted amphetamines.
The present studies were conducted to further explore the potential role of metabolic compromise in substituted amphetamine-induced serotonin (5-HT) neurotoxicity. To this end, we examined the glucoprivic effects of 2-deoxy-D-glucose (2-DG) on the 5-HT neurotoxic effects of fenfluramine (FEN) and methylenedioxymethamphetamine (MDMA). Rats were treated with either FEN or MDMA, alone and in combination, with doses of 2-DG known to produce glucoprivic effects at either 22 +/- 1 or 28 +/- 1 degrees C. At 22 +/- 1 degrees C, FEN produced hypothermia, MDMA induced hyperthermia, and both drugs produced significant long-term reductions in regional brain 5-HT neuronal markers. 2-DG did not enhance 5-HT neurotoxicity induced by either FEN or MDMA; indeed, in some instances, it afforded partial neuroprotection. Although 2-DG afforded partial protection from both FEN and MDMA-induced 5-HT neurotoxic changes, it also caused significant hypothermia, raising the possibility that protection was due to a lowered temperature. Increasing the ambient temperature to 28 +/- 1 degrees C largely eliminated drug-induced hypothermia and eliminated the neuroprotective effects of 2-DG. Thus, even without the confounding effect of temperature, 2-DG still did not potentiate FEN or MDMA-induced 5-HT neurotoxicity. These findings suggest that the role of metabolic compromise in amphetamine-induced 5-HT neurotoxicity merits further study.
Comparison of (+)-(11)C-McN5652 and (11)C-DASB as serotonin transporter radioligands under various experimental conditions.
UNLABELLED: There has been considerable interest in the development of a PET radioligand selective for the serotonin (5-hydroxytryptamine [5-HT]) transporter (SERT) that can be used to image 5-HT neurons in the living human brain. The most widely used SERT radiotracer to date, trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-(11)C-McN5652), has been successful in this regard but may have some limitations. Recently, another promising SERT radiotracer, 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ((11)C-DASB), has been described. The purpose of this study was to compare and contrast (+)-(11)C-McN5652 and (11)C-DASB under various experimental conditions. METHODS: Radioligand comparisons were performed in a control baboon, a baboon with reduced SERT density ((+/-)-3,4-methylenedioxymethamphetamine [MDMA] lesion), and a baboon with reduced SERT availability (paroxetine pretreatment). Under each of these experimental conditions, repeated (triplicate) PET studies were performed with each ligand. RESULTS: Both radiotracers bound preferentially in brain regions known to contain high SERT density. For both ligands, there was a high correlation between the amount of regional brain ligand binding and the known regional brain concentration of SERT. Binding of both ligands was decreased after MDMA neurotoxicity (reduced SERT density), and (+)-(11)C-McN5652 and (11)C-DASB were comparably effective in detecting reduced SERT density after MDMA-induced 5-HT neurotoxicity. Pretreatment with paroxetine dramatically altered the metabolism and kinetics of both tracers and appeared to displace both ligands primarily from regions with high SERT density. Compared with (+)-(11)C-McN5652, (11)C-DASB had higher brain activity and a faster washout rate and provided greater contrast between subcortical and cortical brain regions. CONCLUSION: (11)C-DASB and (+)-(11)C-McN5652 are suitable as PET ligands of the SERT and for detecting MDMA-induced 5-HT neurotoxicity. (11)C-DASB may offer some advantages. Additional studies are needed to further characterize the properties and capabilities of both ligands in health and disease.
Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic MDMA administration.
RATIONALE: Establishing functional deficits as a result of neurotoxic dosing regimens of MDMA has been difficult. However, moderate success has been achieved when sensitive animal models and drug challenge have been used together. OBJECTIVE: The present study used a repeated-acquisition technique and dose-effect determinations before, during and after neurotoxic MDMA exposure to characterize the effects of serotonergic drugs on learning, and to determine if MDMA-induced serotonin (5-HT) neurotoxicity is associated with learning deficits as measured by changes in response rate or the percentage of errors. METHOD: The effects of various serotonergic drugs were characterized in six squirrel monkeys responding under a repeated-acquisition procedure before and after neurotoxic dose regimens of MDMA. Specifically, cumulative dose-effect curves for m-CPP (0.032-1 mg/kg), fenfluramine (0.1-3.2 mg/kg) and triazolam (0.0032-0.1 mg/kg) were obtained prior to MDMA administration, with the latter drug serving as a non-5-HT control. RESULTS: In general, all of the drugs tested decreased overall response rate as the cumulative dose increased, whereas only triazolam markedly increased the percentage of errors. MDMA treatment produced significant (80-99%) decreases in brain 5-HT and 5-HIAA axonal markers, but did not lead to changes in either dependent measure of responding or shifts in the dose-effect curves obtained during pharmacological challenges with m-CPP, fenfluramine or triazolam. CONCLUSIONS: Taken together, these results demonstrate that serotonergic drugs can disrupt learning in monkeys, but indicate that MDMA-induced 5-HT neurotoxicity does not lead to disruptions in this particular type of serial learning task.