Classic Clock

Rabu, 07 Agustus 2013

BELAJAR TENTANG DAMPAK BURUK DARI NEUROTOXIC MDMA

Table I: Studies of Long-term Changes after Neurotoxic MDMA Regimens in Nonhuman Animals

Species and StrainMDMA RegimenSignificant Differences in MDMA-treated animalsMeasures showing no significant differenceReference
Rhesus Monkeys10 mg/kg IM, twice a day, for 4 daysRight shift in MDMA and d-fenfluramine dose-response curve for time estimation,  learning task, and motivation tasks at post 1 mo.Baseline performance on all tasks.Frederick et al., 1998
Rhesus MonkeysEscalating doses of 0.10, 0.3, 1.0, 1.75, 3.0, 5.6, 7.5, 10.0, 15.0, and 20 mg/kg, IM, twice daily for 14 consecutive days at each dose.Right shift in MDMA dose-response curve for time estimation, short-term memory, color and position discrimination, and motivation tasks at post 21 mo.Baseline performance on all tasks.Frederick et al., 1995
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysNone, although researchers note that 2 of 8 MDMA-exposed rats failed to acquire lever pressing with 20 sec reinforcement delays during the 8 hr session.Acquisition of and behavior on a lever-press responding task at post 14 days.Byrne, Baker, & Poling 2000
Rats, Sprague-Dawley10 mg/kg SC, twice a day for 4 daysSignificant pretreatment x treatment x crossing times interaction, suggesting altered S-MDMA -induced behavioral activation at post 21 days.Drug-free locomotion at 21 days; RU24969-induced behavioral activation at 21 days.Callaway & Geyer 1992
Rats, Wistar10 mg/kg SC per day for 4 daysIncreased core temperature when placed in either 22 °C or 28 °C ambient temperature at post 4 or 14 wks.NoneDafters & Lynch 1998
Rats, Long-Evans40 mg/kg SC, twice a day for 4 daysNoneSexual behaviors at post 10 days; Spontaneous motor activity.Dornan, Katz, & Ricaurte 1991
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysDecreased electrical-stimulated 5-HT release in DRN at post 2 wks.Electrical-stimulated 5-HT release in MRN or hippocampus at post 2 wks; Number and firing pattern of classical 5-HT neurons and burst-firing neurons in DRN.Gartside, McQuade, & Sharp 1996
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysNoneDOI-induced head twitch responses, locomotion, and rearing activity.Granoff & Ashby 1998
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysIncreased conditioned place preference response to cocaine in MDMA group at 2 post wks.Horan, Gardner, & Ashby 2000
Rats, Sprague-Dawley5 mg/kg sc once per day or 20 mg/kg SC, twice a day for 4 days, followed by 5 mg/kg MDMA 2 days laterIncreased motor stimulant effects of 5.0 mg/kg SC MDMA in both MDMA-treated groups at post 11 days; Increased motor stimulant effects of 15.0 mg/kg IP cocaine in both MDMA-treated groups at post 11 days; Increased MDMA-stimulated DA release in the nucleusBasal DA in nucleus accumbens at post 2 wks.Kalivas, Duffy, White 1998
Rats, Sprague-Dawley15 mg/kg IPLoss of rate-dependence of response of nigrostriatal cells to either quipazine or apomorphine at post 1 wk.Basal activity of nigrostriatal DA neurons; Quipazine-induced inhibition of nigrostriatal DA cell firing for all cells at post 1 wk.Kelland, Freeman, & Chiodo 1989
Rats, Sprague-Dawley6 mg/kg SC, twice a daily for 4 daysLeft shift in MDMA dose-response curve on DRL task in MDMA group.NoneLi et al., 1989
Rats, Lister Hoodedascending regimen of 10, 15, and 20 mg/kg IP, each dose given twice daily for one dayDecreased performance in operant delayed match to nonsample task.Spontaneous behavior, body temperature, and skilled paw reach ("staircase task").Marston et al., 1999
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysIncreased cocaine-induced dopamine release in nucleus accumbens in MDMA group at 2 wks after neurotoxic regimen.NoneMorgan et al., 1997
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysIncreased morphine-induced antinociception (assessed by tail flick test) at post 2 wks.Baseline behavior in tail flick test.Nencini, Woolverton, & Seiden 1988
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysDecreased inhibitory effects of DA and SKF38393 on glutamate-evoked firing in nucleus accumbens cells at post 9-15 days.Inhibitory effects of GABA on glutamate-evoked firing in nucleus accumbens cells at post 9-15 days.Obradovic, Imel, & White 1998
Rats, Sprague-Dawley20 mg/kg SCIncreased 8-OH-DPAT-induced prolactin release at post 2 weeks.  Decreased 8-OH-DPAT-stimulated ACTH release at 2 weeks.Basal ACTH and prolactin concentrations and ACTH and prolactin response to saline injection.Poland 1990
Rats, Sprague-Dawley20 mg/kg SCIncreased d,l-Fenfluramine-stimulated prolactin release at post 2 and 4 months.  Decreased d,l-Fenfluramine-stimulated ACTH release at 2-8 months.d,l-Fenfluramine-stimulated ACTH at 12 months; d,l-Fenfluramine-stimulated prolactin at 8 and 12 months.Poland et al., 1997
Rats, Sprague-Dawley20 mg/kg SC, twice a day for 4 daysIncreased d,l-Fenfluramine-stimulated prolactin release at post 4 and 8 months.  Decreased d,l-Fenfluramine-stimulated ACTH release at post 4, 8, and 12 months.Saline-stimulated ACTH and prolactin release at post 2 weeks; d,l-Fenfluramine-stimulated prolactin release at post 12 months.Poland et al., 1997
Rats, Lister Hooded20 mg/kg SC, twice a day for 4 days with entire regimen repeated 2 wks laterNonePerformance in a spatial memory task using a T-maze and scopolamine-induced changes in performance on this task.Ricaurte et al., 1993
Rats, Sprague-Dawley10 mg/kg IP, twice a day for 4 daysIncreased time to find hidden platfrom in first trial of spatial navigation task at post 2 days.Spatial navigation task after 1st trial, skilled reaching task, place navigation learning-set task, foraging task, with or without atropine pretreatment.Robinson, Castaneda, & Whishaw 1993
Rats, Sprague-Dawley20 mg/kg SC twice a day for 4 daysDecreased discrimination of 1.0 mg/kg MDMA from saline at post 13-15 days.Discrimination of 0.5 or 1.5 mg/kg; Conditioned place preference from MDMA.Schechter 1991
Rats, Sprague-Dawley20 or 40 mg/kg SC twice a day for 4 daysDecreased d-fenfluramine-stimulated 5-HT release in frontal cortex at post 2 wks.NoneSeries, Cowen, & Sharp 1994
Rats, Sprague-Dawley10 mg/kg IP, every 2 h for 4 injectionsDecreased behavioral, hyperthermic, and 5-HT-releasing effects of MDMA at 1 wk after neurotoxic regimen.NoneShankaran & Gudelsky 1999
Rats, Sprague-Dawley20 or 40 mg/kg SC twice a day for 4 daysIncreased cerebral glucose utilization in molecular layer of dentate gyrus and in CA2 and CA3 fields of Ammon's horn in hippocampus at post 14 days.Cerebral glucose utilization in neocortex, raphe nuclei, and some hippocampal areas at post 14 days.Sharkey, McBean, & Kelly 1991
Rats, Sprague-Dawley5 or 10 mg/kg PO daily for 4 daysNoneAuditory startle, emergence from darkened chamber, complex maze navigation, response to hot plate, FI 90 operant behavioral task at post 2 to 4 weeks..Slikker et al., 1989
Rat Pups, Sprague-Dawley10 mg/kg SC every 12 hrs for 4 or 7 injectionsDecreased rate of ultrasonic vocalization measured up to post 11 days.Behavioral responses to the 5-HT1a agonist 8-OH-DPAT, the 5-HT1b agonist TFMPP, and the 5-HT2 agonist DOI at post 8 days.Winslow & Insel 1990

Table II: Reported Neurofunctional Differences Between Ecstasy Users and Nonusers
MeasureSelective for Serotonergic Differences?Relevant Animal Literature?Correlated with MDMA Exposure?Evidence for Recovery?References
Putative Serotonergic Measures
Decreased CSF 5-HIAA in 3 of 4 studiesYesDecreased up to 2 weeks after MDMA in squirrel monkeys (Ricaurte et al., 1988) and 14 weeks after MDMA in rhesus monkeys (Insel et al., 1989).NoNoDecreased in McCann et al.,1999, 1994; Ricaurte et al.,1990.  Unchanged in Peroutka et al., 1989
Decreased then Increased 5-HT2a receptor density in 1 of 1 studiesYesDecreased at 24 hr,normal at 21 d after MDMA in rats (Scheffel et al., 1992).YesNot reportedIncreased in Reneman et al., 2000a; Decreased then increased in Reneman et al., 2000b
Decreasedneuroendocrine response to serotonergic drugs, in 3 of 5 studiesYesIncreased at 2 months, normal at 12 months in rats (Poland et al., 1991)Yes in Gerra et al.,  2000NoDecreased in Gerra et al., 2000, 1998; McCann et al., 1999a.  Unchanged in Price et al., 1989; McCann et al., 1994.
Decreased SERT density, estimated with PET, in 2 of 2 studiesDisputed - ligand kinetics  may be  altered by other changes (Kuikka & Ahonen 1998).PET measures apparently decreased in one baboon up to 14 weeks after MDMA (Scheffel et al., 1998).Yes, though McCann included controls.Mixed  (Yes in Semple; No in McCann)Semple et al., 1999; McCann et al., 1998.
Increased stimulus dependence for ERP EEG N1/P2 amplitudes in 1 of 1 studiesDisputed – 5HT depletion did not change measure in one study (Dierks et al., 1999).UnknownNoNot reportedTuchtenhagen et al., 2000
Nonspecific Neurofunctional Measures
Increased brain myo-inositol measured as by 1H MRS in 1 of 1 studies-UnknownYesNot reportedChang et al., 1999
Decreased total sleep time (non-REM and stage 2 sleep) in 1 of 1 study-UnknownNoNot reportedAllen et al., 1993
Altered cerebral blood flow or volume in 2 of 4 studies-Increased blood flow 6-9 wks after MDA in rats (McBean et al., 1990)YesYesAltered in Reneman et al., 2000b and in Chang et al., 2000 (prospective study).  Unchanged in Chang et al., 2000 (user-nonuser study) and Gamma et al., in press.
Decreased cerebral glucose utilization in 1 of 1 studies-Increased in some hipppocampal areas 2 wks (Sharkey et al., 1991) after MDMA and 6-9 wks after MDA (McBean et al., 1990) in ratsNoNoObrocki et al., 1999
Increased alpha and beta EEG power in 2 of 2 studies-UnknownYesNot reportedDafters et al., 1999; Gamma et al., 2000

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