The Experts below are selected from a list of 858 Experts worldwide ranked by ideXlab platform
Kathryn A Cunningham - One of the best experts on this subject based on the ideXlab platform.
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role of the serotonin 5 ht2a receptor in the hyperlocomotive and hyperthermic effects of 3 4 methylenedioxymethAmphetamine
Psychopharmacology, 2005Co-Authors: David V Herin, Kenner C Rice, Thomas Ullrich, Kathryn A CunninghamAbstract:Rationale Contradictory evidence exists regarding the role of the 5-HT2A receptor (5-HT2AR) in hyperactivity and hyperthermia elicited by the Substituted Amphetamine (+)-3,4-methylenedioxymethAmphetamine.
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Role of the serotonin 5-HT2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethAmphetamine.
Psychopharmacology, 2004Co-Authors: David V Herin, Kenner C Rice, Thomas Ullrich, Shijing Liu, Kathryn A CunninghamAbstract:Rationale Contradictory evidence exists regarding the role of the 5-HT2A receptor (5-HT2AR) in hyperactivity and hyperthermia elicited by the Substituted Amphetamine (+)-3,4-methylenedioxymethAmphetamine.
George A. Ricaurte - One of the best experts on this subject based on the ideXlab platform.
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PSYCHEDELIC DRUGS
2015Co-Authors: Henry David Abraham, Una D. Mccann, George A. RicaurteAbstract:As defined in this chapter, the term psychedelic drugs includes both classic hallucinogens [i.e., indolalkylamines and phe-nylalkylamines, such as lysergic acid diethylamide (LSD) and mescaline, respectively], ‘‘dissociative’ ’ drugs [i.e., arylcyclo-hexamines, such as phencyclidine (PCP) and ketamine], and Substituted Amphetamine analogues [i.e., phenylpropano-lamines, such as 3,4-methylenedioxymethAmphetamine (MDMA, ‘‘ecstasy’’)]. The use of psychedelic drugs dates from the dawn of recorded history and continues today. Indeed, in Western culture, their use appears to be on the rise. Despite the longstanding popularity of psychedelic drugs, controlled research evaluating their effects in humans has been surprisingly scant, and data from preclinical studies have been largely limited to the last several decades. This chapter reviews preclinical and clinical research involving indolalkylamines, arylcyclohexamines, and Substituted am-phetamines, for which LSD, PCP, and MDMA are used as the prototypes, respectively. Significant recent advances are highlighted, and promising areas toward which future re-search should be directed are identified
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Identifying the serotonin transporter signal in Western blot studies of the neurotoxic potential of MDMA and related drugs
Synapse (New York N.Y.), 2011Co-Authors: Michael W. Mclane, Una D. Mccann, George A. RicaurteAbstract:A number of published studies have questioned the serotonin neurotoxic potential of 3,4-methylenedioxymethAmphetamine (MDMA, “ecstasy”) and related drugs (fenfluramine, p-chloroAmphetamine) based upon results from Western blot studies using a custom synthesized serotonin transporter (SERT) antibody that found no reduction in the abundance of a 50kDa protein after Substituted Amphetamine treatment. The purpose of this study was to collect Western blot data using the same SERT antibody used in those studies, but with positive and negative controls to identify the SERT protein signal. A 63–68 kDa band that had the regional distribution expected of rat brain SERT, was decreased by 5,7-DHT, and was absent in SERT KO animals was identified as the SERT protein. Significant, lasting decreases in the abundance of the 63–68 kDa band were evident in the rat brain after treatment with MDMA and related drugs (FEN, PCA). Thus, when the band corresponding to the SERT protein is identified in Western blots through the use of positive and negative controls, reduced abundance of the SERT protein can be readily demonstrated after Substituted Amphetamine treatment. These data provide further evidence of lasting loss of the SERT protein after exposure to MDMA and other Substituted Amphetamines. Synapse, 2011. © 2011 Wiley-Liss, Inc.
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Effect of Glucoprivation on Serotonin Neurotoxicity Induced by Substituted Amphetamines
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Jie Yuan, Una D. Mccann, Branden J. Cord, Brian T. Callahan, George A. RicaurteAbstract: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°C. At 22 ± 1°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°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.
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Altered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethAmphetamine (MDMA) or fenfluramine.
Synapse (New York N.Y.), 2002Co-Authors: George Hatzidimitriou, Una D. Mccann, Elizabeth H. Tsai, George A. RicaurteAbstract: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 3½ 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. Synapse 44:51–57, 2002. © 2002 Wiley-Liss, Inc.
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Experimental studies on 3,4-methylenedioxymethAmphetamine (MDMA, “ECSTASY”) and its potential to damage brain serotonin neurons
Neurotoxicity research, 2001Co-Authors: George A. Ricaurte, Una D. MccannAbstract:A number of drugs that fall into the broad category of “ring-Substituted Amphetamines” have been found to be neurotoxic toward brain monoamine neurons in animals. Several of these drugs, including (3,4-methylenedioxymethAmphetamine (MDMA, “Ecstasy”) and methAmphetamine (“speed”) and fenfluramine (“Pondimin”) have been used or abused by humans. A growing body of evidence indicates that humans, like animals, are susceptible to Substituted Amphetamine-induced neurotoxic injury, and that consequences of this injury can be subtle. This article will review the effects of ring-Substituted Amphetamine analogs on brain monoamine neurons, using MDMA as the prototype. Studies documenting MDMA neurotoxic potential toward brain serotonin (5-HT) neurons in animals are summarized first. Human MDMA studies are then discussed, beginning with a consideration of methodological challenges in evaluating the status of 5-HT neurons in the living human brain. Recent findings indicating possible functional alterations in brain serotonergic systems in humans with a history of extensive MDMA exposure are then presented, including some new findings on sleep and personality in abstinent MDMA users.
David V Herin - One of the best experts on this subject based on the ideXlab platform.
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role of the serotonin 5 ht2a receptor in the hyperlocomotive and hyperthermic effects of 3 4 methylenedioxymethAmphetamine
Psychopharmacology, 2005Co-Authors: David V Herin, Kenner C Rice, Thomas Ullrich, Kathryn A CunninghamAbstract:Rationale Contradictory evidence exists regarding the role of the 5-HT2A receptor (5-HT2AR) in hyperactivity and hyperthermia elicited by the Substituted Amphetamine (+)-3,4-methylenedioxymethAmphetamine.
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Role of the serotonin 5-HT2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethAmphetamine.
Psychopharmacology, 2004Co-Authors: David V Herin, Kenner C Rice, Thomas Ullrich, Shijing Liu, Kathryn A CunninghamAbstract:Rationale Contradictory evidence exists regarding the role of the 5-HT2A receptor (5-HT2AR) in hyperactivity and hyperthermia elicited by the Substituted Amphetamine (+)-3,4-methylenedioxymethAmphetamine.
Diane B. Miller - One of the best experts on this subject based on the ideXlab platform.
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Age as a susceptibility factor in the striatal dopaminergic neurotoxicity observed in the mouse following Substituted Amphetamine exposure.
Annals of the New York Academy of Sciences, 2000Co-Authors: Diane B. Miller, James P. O'callaghan, Syed F. AliAbstract:A number of Substituted Amphetamines, including methAmphetamine (METH) are considered dopaminergic neurotoxicants. METH causes long-term depletions of striatal dopamine (DA) and its metabolites (DOPAC and HVA) that are accompanied by other changes indicative of nerve terminal degeneration. These include argyrophilia as detected by silver degeneration stains and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels. The susceptibility to the dopaminergic neurotoxicity of METH and the other Amphetamines can be affected by a number of factors including age, gender, stress, and environment. Many of these susceptibility factors have been extensively investigated in the rat but less so in the mouse. As the availability of genetically altered mice continues to expand, this species is increasingly selected for study. Thus, in previous work we determined that stress, gender, and the environment can significantly impact the neurotoxicity of the Amphetamines. Here we determined how age affects the striatal DA depletion and GFAP elevation induced by d-METH in C57BL/6 mice. Age was a significant determinant of the ability of a known neurotoxic regimen of d-METH (10 mg/kg × 4) to produce striatal DA depletion with one-month-old C57BL/6 mice displaying minimal and nonpersistent depletion of DA or its metabolites while mice 12 months of age displayed large and persistent depletions of DA (87%), DOPAC (71%), and HVA (94%). Large elevations in striatal GFAP were induced in mice 2-23 months of age by d-METH, with lower dosages of d-METH being effective in the older mice. In contrast, the usual neurotoxic regimen of d-METH was minimally effective in inducing GFAP elevations (49% over control) in one-month-old mice, despite elevations in body temperature equivalent to those observed in older mice. Although increasing the dosage of d-METH (20 to 80 mg/kg) did increase the GFAP response (100% over control), it was still well below that usually exhibited at the usual neurotoxic dosage (300-400% over control) in fully mature mice. These data suggest maturity of striatal dopamine systems may be an essential element in the striatal damage induced by the neurotoxic Amphetamines.
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environment drug and stress induced alterations in body temperature affect the neurotoxicity of Substituted Amphetamines in the c57bl 6j mouse
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Diane B. Miller, James P OcallaghanAbstract:In the companion paper we demonstrated that d-methAmphetamine (d-METH), d-methylenedioxyAmphetamine (d-MDA) and d-methylenedioxymethamephetamine (d-MDMA), but not d-fenfluramine (d-FEN), appear to damage dopaminergic projections to the striatum of the mouse. An elevation in core temperature also was associated with exposure to d-METH, d-MDA and d-MDMA, whereas exposure to d-FEN lowered core temperature. Given these findings, we examined the effects of temperature on Substituted Amphetamine (AMP)-induced neurotoxicity in the C57BL/6J mouse. Levels of striatal dopamine (DA) and glial fibrillary acidic protein (GFAP) were taken as indicators of neurotoxicity. Alterations in ambient temperature, pretreatment with drugs reported to cause hypothermia in the mouse and hypothermia induced by restraint stress were used to affect AMP-induced neurotoxicity. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg) or d-MDMA (20 mg/kg) every 2 hr for a total of four s.c. injections. All three AMPs increased core temperature and caused large (> 75%) decreases in striatal dopamine and large (> 300%) increases in striatal glial fibrillary acidic protein 72 hr after the last injection. Lowering ambient temperature from 22 degrees C to 15 degrees C blocked (d-MDA and d-MDMA) or severely attenuated (d-METH) these effects. Pretreatment with MK-801 lowered core temperature and blocked AMP-induced neurotoxicity; elevation of ambient temperature during this regimen elevated core temperature and markedly attenuated the neuroprotective effects of MK-801. Pretreatment with MK-801 also lowered core temperature in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice but did not block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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neurotoxicity profiles of Substituted Amphetamines in the c57bl 6j mouse
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: James P Ocallaghan, Diane B. MillerAbstract:Dopaminergic (DA) and serotonergic (5-HT) projections to striatum and cortex have been implicated as the primary targets of Substituted Amphetamine (AMP)-induced neurotoxicity, largely on the basis of the propensity of these compounds to cause protracted decrements in DA and 5-HT rather than on the basis of AMP-induced alterations of indices linked to neural damage. Moreover, most studies of AMP-induced neurotoxicity, regardless of the endpoints assessed, have been conducted using a rat model; relatively little attention has been focused on the effects of these compounds in the mouse. Here, we evaluated the potential neurotoxic effects of d-methAmphetamine (d-METH), d-methylenedioxyAmphetamine (d-MDA), d-methylene-dioxymethAmphetamine (d-MDMA) and d-fenfluramine (d-FEN) in the C57BL6/J mouse. Astrogliosis, assessed by quantification of glial fibrillary acidic protein (GFAP), was taken as the main index of AMP-induced neural damage. A silver degeneration stain also was used to obtain direct evidence of AMP-induced neuronal damage. Assays of tyrosine hydroxylase (TH), DA and 5-HT were used to assess effects on DA and 5-HT systems. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg), d-MDMA (20 mg/kg) or d-FEN (25 mg/kg) every 2 hr for a total of four s.c. injections. d-METH, d-MDA and d-MDMA caused a large (300%) increase in striatal GFAP that resolved by 3 weeks and a 50 to 75% decrease in TH and DA that did not resolve. d-METH, d-MDA and d-MDMA also caused fiber and terminal degeneration in striatum as revealed by silver staining. d-FEN did not affect any parameters in striatum. d-METH, d-MDA and d-MDMA also increased GFAP in cortex, effects that were associated with small (10-25%) and transient decrements in cortical 5-HT. d-FEN caused prolonged (weeks) decrements (20%) in cortical 5-HT but did not affect cortical GFAP. The effects of d-METH, d-MDA and d-MDMA were stereoselective and were blocked by pretreatment with MK-801. Core temperature was slightly elevated by d-METH, d-MDA and d-MDMA but was dramatically lowered by d-FEN. The data suggest that d-METH, d-MDA and d-MDMA, but not d-FEN, produce damage to neural elements of mouse striatum and cortex.
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Environment-, drug- and stress-induced alterations in body temperature affect the neurotoxicity of Substituted Amphetamines in the C57BL/6J mouse.
The Journal of pharmacology and experimental therapeutics, 1994Co-Authors: Diane B. Miller, James P. O'callaghanAbstract:In the companion paper we demonstrated that d-methAmphetamine (d-METH), d-methylenedioxyAmphetamine (d-MDA) and d-methylenedioxymethamephetamine (d-MDMA), but not d-fenfluramine (d-FEN), appear to damage dopaminergic projections to the striatum of the mouse. An elevation in core temperature also was associated with exposure to d-METH, d-MDA and d-MDMA, whereas exposure to d-FEN lowered core temperature. Given these findings, we examined the effects of temperature on Substituted Amphetamine (AMP)-induced neurotoxicity in the C57BL/6J mouse. Levels of striatal dopamine (DA) and glial fibrillary acidic protein (GFAP) were taken as indicators of neurotoxicity. Alterations in ambient temperature, pretreatment with drugs reported to cause hypothermia in the mouse and hypothermia induced by restraint stress were used to affect AMP-induced neurotoxicity. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg) or d-MDMA (20 mg/kg) every 2 hr for a total of four s.c. injections. All three AMPs increased core temperature and caused large (> 75%) decreases in striatal dopamine and large (> 300%) increases in striatal glial fibrillary acidic protein 72 hr after the last injection. Lowering ambient temperature from 22 degrees C to 15 degrees C blocked (d-MDA and d-MDMA) or severely attenuated (d-METH) these effects. Pretreatment with MK-801 lowered core temperature and blocked AMP-induced neurotoxicity; elevation of ambient temperature during this regimen elevated core temperature and markedly attenuated the neuroprotective effects of MK-801. Pretreatment with MK-801 also lowered core temperature in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice but did not block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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Neurotoxicity profiles of Substituted Amphetamines in the C57BL/6J mouse.
The Journal of pharmacology and experimental therapeutics, 1994Co-Authors: James P. O'callaghan, Diane B. MillerAbstract:Dopaminergic (DA) and serotonergic (5-HT) projections to striatum and cortex have been implicated as the primary targets of Substituted Amphetamine (AMP)-induced neurotoxicity, largely on the basis of the propensity of these compounds to cause protracted decrements in DA and 5-HT rather than on the basis of AMP-induced alterations of indices linked to neural damage. Moreover, most studies of AMP-induced neurotoxicity, regardless of the endpoints assessed, have been conducted using a rat model; relatively little attention has been focused on the effects of these compounds in the mouse. Here, we evaluated the potential neurotoxic effects of d-methAmphetamine (d-METH), d-methylenedioxyAmphetamine (d-MDA), d-methylene-dioxymethAmphetamine (d-MDMA) and d-fenfluramine (d-FEN) in the C57BL6/J mouse. Astrogliosis, assessed by quantification of glial fibrillary acidic protein (GFAP), was taken as the main index of AMP-induced neural damage. A silver degeneration stain also was used to obtain direct evidence of AMP-induced neuronal damage. Assays of tyrosine hydroxylase (TH), DA and 5-HT were used to assess effects on DA and 5-HT systems. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg), d-MDMA (20 mg/kg) or d-FEN (25 mg/kg) every 2 hr for a total of four s.c. injections. d-METH, d-MDA and d-MDMA caused a large (300%) increase in striatal GFAP that resolved by 3 weeks and a 50 to 75% decrease in TH and DA that did not resolve. d-METH, d-MDA and d-MDMA also caused fiber and terminal degeneration in striatum as revealed by silver staining. d-FEN did not affect any parameters in striatum. d-METH, d-MDA and d-MDMA also increased GFAP in cortex, effects that were associated with small (10-25%) and transient decrements in cortical 5-HT. d-FEN caused prolonged (weeks) decrements (20%) in cortical 5-HT but did not affect cortical GFAP. The effects of d-METH, d-MDA and d-MDMA were stereoselective and were blocked by pretreatment with MK-801. Core temperature was slightly elevated by d-METH, d-MDA and d-MDMA but was dramatically lowered by d-FEN. The data suggest that d-METH, d-MDA and d-MDMA, but not d-FEN, produce damage to neural elements of mouse striatum and cortex.
Una D. Mccann - One of the best experts on this subject based on the ideXlab platform.
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PSYCHEDELIC DRUGS
2015Co-Authors: Henry David Abraham, Una D. Mccann, George A. RicaurteAbstract:As defined in this chapter, the term psychedelic drugs includes both classic hallucinogens [i.e., indolalkylamines and phe-nylalkylamines, such as lysergic acid diethylamide (LSD) and mescaline, respectively], ‘‘dissociative’ ’ drugs [i.e., arylcyclo-hexamines, such as phencyclidine (PCP) and ketamine], and Substituted Amphetamine analogues [i.e., phenylpropano-lamines, such as 3,4-methylenedioxymethAmphetamine (MDMA, ‘‘ecstasy’’)]. The use of psychedelic drugs dates from the dawn of recorded history and continues today. Indeed, in Western culture, their use appears to be on the rise. Despite the longstanding popularity of psychedelic drugs, controlled research evaluating their effects in humans has been surprisingly scant, and data from preclinical studies have been largely limited to the last several decades. This chapter reviews preclinical and clinical research involving indolalkylamines, arylcyclohexamines, and Substituted am-phetamines, for which LSD, PCP, and MDMA are used as the prototypes, respectively. Significant recent advances are highlighted, and promising areas toward which future re-search should be directed are identified
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Identifying the serotonin transporter signal in Western blot studies of the neurotoxic potential of MDMA and related drugs
Synapse (New York N.Y.), 2011Co-Authors: Michael W. Mclane, Una D. Mccann, George A. RicaurteAbstract:A number of published studies have questioned the serotonin neurotoxic potential of 3,4-methylenedioxymethAmphetamine (MDMA, “ecstasy”) and related drugs (fenfluramine, p-chloroAmphetamine) based upon results from Western blot studies using a custom synthesized serotonin transporter (SERT) antibody that found no reduction in the abundance of a 50kDa protein after Substituted Amphetamine treatment. The purpose of this study was to collect Western blot data using the same SERT antibody used in those studies, but with positive and negative controls to identify the SERT protein signal. A 63–68 kDa band that had the regional distribution expected of rat brain SERT, was decreased by 5,7-DHT, and was absent in SERT KO animals was identified as the SERT protein. Significant, lasting decreases in the abundance of the 63–68 kDa band were evident in the rat brain after treatment with MDMA and related drugs (FEN, PCA). Thus, when the band corresponding to the SERT protein is identified in Western blots through the use of positive and negative controls, reduced abundance of the SERT protein can be readily demonstrated after Substituted Amphetamine treatment. These data provide further evidence of lasting loss of the SERT protein after exposure to MDMA and other Substituted Amphetamines. Synapse, 2011. © 2011 Wiley-Liss, Inc.
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Effect of Glucoprivation on Serotonin Neurotoxicity Induced by Substituted Amphetamines
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Jie Yuan, Una D. Mccann, Branden J. Cord, Brian T. Callahan, George A. RicaurteAbstract: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°C. At 22 ± 1°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°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.
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Altered prolactin response to M-chlorophenylpiperazine in monkeys previously treated with 3,4-methylenedioxymethAmphetamine (MDMA) or fenfluramine.
Synapse (New York N.Y.), 2002Co-Authors: George Hatzidimitriou, Una D. Mccann, Elizabeth H. Tsai, George A. RicaurteAbstract: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 3½ 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. Synapse 44:51–57, 2002. © 2002 Wiley-Liss, Inc.
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Experimental studies on 3,4-methylenedioxymethAmphetamine (MDMA, “ECSTASY”) and its potential to damage brain serotonin neurons
Neurotoxicity research, 2001Co-Authors: George A. Ricaurte, Una D. MccannAbstract:A number of drugs that fall into the broad category of “ring-Substituted Amphetamines” have been found to be neurotoxic toward brain monoamine neurons in animals. Several of these drugs, including (3,4-methylenedioxymethAmphetamine (MDMA, “Ecstasy”) and methAmphetamine (“speed”) and fenfluramine (“Pondimin”) have been used or abused by humans. A growing body of evidence indicates that humans, like animals, are susceptible to Substituted Amphetamine-induced neurotoxic injury, and that consequences of this injury can be subtle. This article will review the effects of ring-Substituted Amphetamine analogs on brain monoamine neurons, using MDMA as the prototype. Studies documenting MDMA neurotoxic potential toward brain serotonin (5-HT) neurons in animals are summarized first. Human MDMA studies are then discussed, beginning with a consideration of methodological challenges in evaluating the status of 5-HT neurons in the living human brain. Recent findings indicating possible functional alterations in brain serotonergic systems in humans with a history of extensive MDMA exposure are then presented, including some new findings on sleep and personality in abstinent MDMA users.
