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MDMA (ecstasy) use is associated with reduced BOLD signal change during semantic recognition in abstinent human polydrug users: a preliminary fMRI study.
Raj V, Liang HC, Woodward ND, Bauernfeind AL, Lee J, Dietrich MS, Park S, Cowan RL
(2010) J Psychopharmacol 24: 187-201
MeSH Terms: Adult, Brain, Cocaine-Related Disorders, Female, Hallucinogens, Humans, Magnetic Resonance Imaging, Male, Marijuana Abuse, Memory, N-Methyl-3,4-methylenedioxyamphetamine, Oxygen, Substance-Related Disorders, Verbal Learning, Young Adult
Show Abstract · Added February 15, 2016
3,4-methylenedioxymethamphetamine (MDMA) users have impaired verbal memory, and voxel-based morphometry has shown decreased grey matter in Brodmann area (BA) 18, 21 and 45. Because these regions play a role in verbal memory, we hypothesized that MDMA users would show altered brain activation in these areas during performance of a functional magnetic resonance imaging (fMRI) task that probed semantic verbal memory. Polysubstance users enriched for MDMA exposure participated in a semantic memory encoding and recognition fMRI task that activated left BA 9, 18, 21/22 and 45. Primary outcomes were percent blood oxygen level-dependent signal change in left BA 9, 18, 21/22 and 45, accuracy and response time. During semantic recognition, lifetime MDMA use was associated with decreased activation in left BA 9, 18 and 21/22 but not 45. This was partly influenced by contributions from cannabis and cocaine use. MDMA exposure was not associated with accuracy or response time during the semantic recognition task. During semantic recognition, MDMA exposure was associated with reduced regional brain activation in regions mediating verbal memory. These findings partially overlap with previous structural evidence for reduced grey matter in MDMA users and may, in part, explain the consistent verbal memory impairments observed in other studies of MDMA users.
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15 MeSH Terms
Prior MDMA (Ecstasy) use is associated with increased basal ganglia-thalamocortical circuit activation during motor task performance in humans: an fMRI study.
Karageorgiou J, Dietrich MS, Charboneau EJ, Woodward ND, Blackford JU, Salomon RM, Cowan RL
(2009) Neuroimage 46: 817-26
MeSH Terms: Adolescent, Adult, Basal Ganglia, Cerebral Cortex, Dose-Response Relationship, Drug, Female, Humans, Magnetic Resonance Imaging, Male, Movement, N-Methyl-3,4-methylenedioxyamphetamine, Task Performance and Analysis, Thalamus, Young Adult
Show Abstract · Added February 15, 2016
MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) is a popular recreational drug that produces long-lasting serotonin (5-HT) neurotoxicity consisting of reductions in markers for 5-HT axons. 5-HT innervates cortical and subcortical brain regions mediating motor function, predicting that MDMA users will have altered motor system neurophysiology. We used functional magnetic resonance imaging (fMRI) to assay motor task performance-associated brain activation changes in MDMA and non-MDMA users. 24 subjects (14 MDMA users and 10 controls) performed an event-related motor tapping task (1, 2 or 4 taps) during fMRI at 3 T. Motor regions of interest were used to measure percent signal change (PSC) and percent activated voxels (PAV) in bilateral motor cortex, sensory cortex, supplementary motor area (SMA), caudate, putamen, pallidum and thalamus. We used SPM5 to measure brain activation via three methods: T-maps, PSC and PAV. There was no statistically significant difference in reaction time between the two groups. For the Tap 4 condition, MDMA users had more activation than controls in the right SMA for T-score (p=0.02), PSC (p=0.04) and PAV (p=0.03). Lifetime episodes of MDMA use were positively correlated with PSC for the Tap 4 condition on the right for putamen and pallidum; with PAV in the right motor and sensory cortex and bilateral thalamus. In conclusion, we found a group difference in the right SMA and positive dose-response association between lifetime exposure to MDMA and signal magnitude and extent in several brain regions. This evidence is consistent with MDMA-induced alterations in basal ganglia-thalamocortical circuit neurophysiology and is potentially secondary to neurotoxic effects on 5-HT signaling. Further studies examining behavioral correlates and the specific neurophysiological basis of the observed findings are warranted.
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14 MeSH Terms
Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants.
Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, Zou MF, Newman AH, Blakely RD
(2006) J Biol Chem 281: 2012-23
MeSH Terms: Adrenergic Uptake Inhibitors, Amino Acid Sequence, Animals, Antidepressive Agents, Binding Sites, Binding, Competitive, Blotting, Western, Cadmium, Cell Line, Cell Membrane, Citalopram, Clomipramine, Cocaine, Cysteine, Dopamine Uptake Inhibitors, Fluoxetine, HeLa Cells, Humans, Immunoprecipitation, Isoleucine, Kinetics, LLC-PK1 Cells, Mazindol, Methionine, Mice, Models, Chemical, Molecular Sequence Data, Mutation, N-Methyl-3,4-methylenedioxyamphetamine, Nomifensine, Protein Binding, Protein Structure, Tertiary, Protein Transport, Radiopharmaceuticals, Receptors, Serotonin, Serotonin, Serotonin Uptake Inhibitors, Species Specificity, Stereoisomerism, Substrate Specificity, Tyrosine
Show Abstract · Added July 10, 2013
In previous studies examining the structural determinants of antidepressant and substrate recognition by serotonin transporters (SERTs), we identified Tyr-95 in transmembrane segment 1 (TM1) of human SERT as a major determinant of binding for several antagonists, including racemic citalopram ((RS)-CIT). Here we described a separate site in hSERT TM3 (Ile-172) that impacts (RS)-CIT recognition when switched to the corresponding Drosophila SERT residue (I172M). The hSERT I172M mutant displays a marked loss of inhibitor potency for multiple inhibitors such as (RS)-CIT, clomipramine, RTI-55, fluoxetine, cocaine, nisoxetine, mazindol, and nomifensine, whereas recognition of substrates, including serotonin and 3,4-methylenedioxymethamphetamine, is unaffected. Selectivity for antagonist interactions is evident with this substitution because the potencies of the antidepressants tianeptine and paroxetine are unchanged. Reduced cocaine analog recognition was verified in photoaffinity labeling studies using [(125)I]MFZ 2-24. In contrast to the I172M substitution, other substitutions at this position significantly affected substrate recognition and/or transport activity. Additionally, the mouse mutation (mSERT I172M) exhibits similar selective changes in inhibitor potency. Unlike hSERT or mSERT, analogous substitutions in mouse dopamine transporter (V152M) or human norepinephrine transporter (V148M) result in transporters that bind substrate but are deficient in the subsequent translocation of the substrate. A double mutant hSERT Y95F/I172M had a synergistic impact on (RS)-CIT recognition ( approximately 10,000-fold decrease in (RS)-CIT potency) in the context of normal serotonin recognition. The less active enantiomer (R)-CIT responded to the I172M substitution like (S)-CIT but was relatively insensitive to the Y95F substitution and did not display a synergistic loss at Y95F/I172M. An hSERT mutant with single cysteine substitutions in TM1 and TM3 resulted in formation of a high affinity cadmium metal coordination site, suggesting proximity of these domains in the tertiary structure of SERT. These studies provided evidence for distinct binding sites coordinating SERT antagonists and revealed a close interaction between TM1 and TM3 differentially targeted by stereoisomers of CIT.
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41 MeSH Terms
The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics.
Meredith EJ, Holder MJ, Chamba A, Challa A, Drake-Lee A, Bunce CM, Drayson MT, Pilkington G, Blakely RD, Dyer MJ, Barnes NM, Gordon J
(2005) FASEB J 19: 1187-9
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Antineoplastic Agents, Apoptosis, Burkitt Lymphoma, Cell Line, Tumor, Clomipramine, Fenfluramine, Fluoxetine, Humans, Lymphoma, B-Cell, N-Methyl-3,4-methylenedioxyamphetamine, Proto-Oncogene Proteins c-bcl-2, Psychotropic Drugs, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added July 10, 2013
Following our previous description of the serotonin transporter (SERT) acting as a conduit to 5-hydroxytryptamine (5-HT)-mediated apoptosis, specifically in Burkitt's lymphoma, we now detail its expression among a broad spectrum of B cell malignancy, while exploring additional SERT substrates for potential therapeutic activity. SERT was readily detected in derived B cell lines with origins as diverse as B cell precursor acute lymphoblastic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and multiple myeloma. Concentration and timecourse kinetics for the antiproliferative and proapoptotic activities of the amphetamine derivatives fenfluramine (an appetite suppressant) and 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") revealed them as being similar to the endogenous indoleamine. A tricyclic antidepressant, clomipramine, instead mirrored the behavior of the selective serotonin reuptake inhibitor fluoxetine, both being effective in the low micromolar range. A majority of neoplastic clones were sensitive to one or more of the serotonergic compounds. Dysregulated bcl-2 expression, either by t(14;18)(q32;q21) translocation or its introduction as a constitutively active transgene, provided protection from proapoptotic but not antiproliferative outcomes. These data indicate a potential for SERT as a novel anti-tumor target for amphetamine analogs, while evidence is presented that the seemingly more promising antidepressants are likely impacting malignant B cells independently of the transporter itself.
1 Communities
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14 MeSH Terms
Methamphetamine increases dopamine transporter higher molecular weight complex formation via a dopamine- and hyperthermia-associated mechanism.
Baucum AJ, Rau KS, Riddle EL, Hanson GR, Fleckenstein AE
(2004) J Neurosci 24: 3436-43
MeSH Terms: Adrenergic Uptake Inhibitors, Amphetamine-Related Disorders, Animals, Blotting, Western, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Dose-Response Relationship, Drug, Drug Administration Schedule, Fever, Macromolecular Substances, Male, Membrane Glycoproteins, Membrane Transport Proteins, Methamphetamine, Molecular Weight, N-Methyl-3,4-methylenedioxyamphetamine, Nerve Tissue Proteins, Rats, Rats, Sprague-Dawley, Time
Show Abstract · Added December 7, 2012
Multiple high-dose administrations of methamphetamine (METH) both rapidly (within hours) decrease plasmalemmal dopamine (DA) uptake and cause long-term deficits in DA transporter (DAT) levels and other dopaminergic parameters persisting weeks to months in rat striatum. In contrast, either a single administration of METH or multiple administrations of methylenedioxymethamphetamine (MDMA) cause less of an acute reduction in DA uptake and little or no persistent dopaminergic deficits. The long-term dopaminergic deficits caused by METH have been suggested, in part, to involve the DAT. Hence, this study assessed the impact of METH and MDMA administration on the DAT protein per se. Results revealed that multiple administrations of METH promoted formation of higher molecular weight (>170 kDa) DAT-associated protein complexes 24-48 hr after treatment. This increase was attenuated by either preventing hyperthermia or pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine; notably, each of these manipulations has also been demonstrated previously to prevent the persistent deficits in dopaminergic function caused by METH treatment. In contrast, either a single injection of METH or multiple injections of MDMA caused little or no formation of these DAT complexes. The addition of the reducing agent beta-mercaptoethanol to samples prepared from METH-treated rats diminished the intensity of these complexes. Taken together, these data are the first to demonstrate higher molecular weight DAT complex formation in vivo and that such formation can be altered by both pharmacological and physiological manipulations. The implications of this phenomenon with regard to the neurotoxic potential of these stimulants are discussed.
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21 MeSH Terms
Effects of (+-)3,4-methylenedioxymethamphetamine (MDMA) on brain dopaminergic activity in rats.
Matthews RT, Champney TH, Frye GD
(1989) Pharmacol Biochem Behav 33: 741-7
MeSH Terms: 3,4-Dihydroxyphenylacetic Acid, 3,4-Methylenedioxyamphetamine, Amphetamines, Animals, Behavior, Animal, Brain, Brain Chemistry, Dopamine, Dose-Response Relationship, Drug, Drug Interactions, Drug Tolerance, Haloperidol, Male, Motor Activity, N-Methyl-3,4-methylenedioxyamphetamine, Rats, Rats, Inbred Strains, Stereotyped Behavior, Time Factors
Show Abstract · Added January 20, 2015
Acute treatment with (+-)3,4-methylenedioxymethamphetamine (MDMA) at high doses (10 and 30 mg/kg, IP), but not lower doses increased locomotor activity in male rats. MDMA did not consistently produce any other stereotyped behaviors at any dose. Dopamine (DA) turnover rate as estimated by the ratio of brain tissue levels of 3,4-dihydroxyphenylacetic acid (DOPAC) over DA was decreased in the striatum for up to two hours after acute treatment with 10 mg/kg of MDMA. DA turnover rate was inconsistently decreased in the olfactory tubercle and medial basal hypothalamus, and was unchanged in the medial prefrontal cortex and the substantia nigra/ventral tegmental area. Two hours after a 30 mg/kg injection of MDMA, DA turnover rate was decreased in all brain areas tested. MDMA and d-amphetamine partially reversed a haloperidol-induced elevation of striatal DOPAC levels. In contrast, the nonamphetamine stimulant, amfonelic acid, enhanced haloperidol's effect. In chloral hydrate-anesthesized rats, MDMA injected IV partially inhibited spontaneous firing rate of DA neurons in the substantia nigra (34% decrease at 4 mg/kg of MDMA). Seventeen days after subchronic MDMA treatment (10 or 20 mg/kg, IP, twice per day for four days), DA and DOPAC levels were unchanged in all brain areas tested as compared to levels in control rats. It is concluded that acute treatment with high but not low doses of MDMA has a weak amphetamine-like effect on nigrostriatal as well as mesolimbic/mesocortical and tuberoinfundibular DA neurons in rats. Repeated treatment with MDMA does not appear to be toxic to mesotelencephalic or tuberoinfundibular DA neurons.
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19 MeSH Terms
Pineal serotonin is resistant to depletion by serotonergic neurotoxins in rats.
Champney TH, Matthews RT
(1991) J Pineal Res 11: 163-7
MeSH Terms: 3,4-Methylenedioxyamphetamine, Animals, Brain, Designer Drugs, Hydroxyindoleacetic Acid, Male, N-Methyl-3,4-methylenedioxyamphetamine, Pineal Gland, Rats, Serotonin, p-Chloroamphetamine
Show Abstract · Added January 20, 2015
Administration of 3,4-methylenedioxymethamphetamine (MDMA) or para-chloroamphetamine (pCA) to adult rats is neurotoxic to serotonin (5HT) nerve terminals and cell bodies. MDMA (10 mg/kg) reduces 5HT levels in the frontal cortex, medial basal hypothalamus, and striatum acutely and 17 days after a series of multiple injections. The acute reductions occur within 1-2 hr after injection of doses greater than 3 mg/kg. A single injection of pCA reduces 5HT levels in the above mentioned brain regions as well as in the brain stem. However, none of these treatments are able to alter 5HT levels in the pineal gland. It appears that the pineal does not contain the 5HT reuptake system that is thought to be necessary for the neurotoxicity of MDMA and pCA.
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11 MeSH Terms