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Publications (3)19.96 Total impact

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    ABSTRACT: Repeated treatment with (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces lasting depletions in serotonin (5-HT) markers in the brains of New and Old World monkeys. We have previously shown that macaques treated with MDMA (4 days, 10 mg/kg im, b.i.d.), exhibit an immediate, approximately 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and 76-93% reductions in neocortical 5-HT content postmortem, but no lasting behavioral deficits under unchallenged conditions. Those monkeys were, however, more behaviorally sensitive to challenge with the 5-HT(2C) agonist 1-(3-chlorophenyl)piperazine (mCPP ) 1 year after the MDMA regimen. A rapid tryptophan-depletion protocol was employed to determine further if these MDMA-exposed monkeys are more behaviorally and electrophysiologically sensitive to perturbation of 5-HT neurotransmission. Acute intragastric administration of a tryptophan-deficient (TRYP(-)) mixture of amino acids resulted in significant reductions in CSF 5-HIAA in both MDMA-exposed and control monkeys. The TRYP(-) mixture also reduced the brainstem auditory-evoked potential (BSAEP) P4 latency in MDMA-exposed monkeys, similar to an effect observed for 13 weeks post-MDMA. Spatial working memory performance was improved by the TRYP(-) mixture in the control group, but not the MDMA-exposed monkeys. Other behavioral capabilities [visual recognition memory, reaction time (RT), reinforcer efficacy and fine motor control] were not significantly affected by the TRYP(-) mixture in either group of monkeys. Thus, underlying alterations in brain function resulting from prior exposure to MDMA, that were not observed under normal conditions, may be revealed following perturbation of 5-HT signaling. The BSAEP response and spatial working memory appear particularly sensitive to lasting functional differences associated with MDMA exposure.
    Pharmacology Biochemistry and Behavior 09/2003; 76(1):141-52. · 2.61 Impact Factor
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    ABSTRACT: 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.
    Neuropsychopharmacology 01/2003; 27(6):993-1005. · 8.68 Impact Factor
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    ABSTRACT: Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by approximately 50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.
    Neuropsychopharmacology 04/2001; 24(3):230-9. · 8.68 Impact Factor