Functional Consequences of Repeated (±)3,4-Methylenedioxymethamphetamine (MDMA) Treatment in Rhesus Monkeys

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 ( Ϯ )3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.) Recreational use of the psychoactive drug ( Ϯ )3,4,-methylenedioxymethamphetamine (MDMA) has become increasingly popular over the past two decades (Peroutka 1987;Schuster et al. 1998). Although early studies focused on adverse physiological (e.g., hypertension, hyperthermia, hyponatraemia) or psychiatric (mood disorder, aggression) symptoms associated with acute and/or chronic MDMA exposure, recent evidence suggests that chronic MDMA use may also result in lasting disruption of cognitive function. A number of studies have shown that experienced, abstinent MDMA users are impaired on various tests of memory function (Bolla et al. 1998;Curran and Travill 1997;Krystal et al. 1992;Morgan 1999;, even when compared with users of other recreational drugs. The lasting functional effects of MDMA use may be relatively specific to mnemonic processing, since a number of studies have reported that MDMA users who are impaired on memory tasks exhibit normal performance on tests of reaction time, vigilance or selective attention (Krystal et al. 1992;Vollenweider et al. 1998). Additional evidence suggests that the degree of memory impairment in the MDMA user is positively correlated with the number of cumulative exposures to MDMA (Bolla et al. 1998;Parrott and Lasky 1998). Finally, recent studies have demonstrated that electroencephalographic and metabolic (PET) measures of brain function are altered in MDMA users (Dafters et al. 1999;

Cognitive Performance of MDMA-Treated Rhesus Monkeys, Sensitivity to Serotonergic Challenge

“…sufficient to produce ‫ف‬ 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid do not exhibit performance deficits in a range of cognitive domains (Taffe et al 2001). Those results were consistent with a similar investigations employing different behavioral assays in both rhesus (Frederick et al 1998) and squirrel monkeys (Winsauer et al 2002).…”

“…Three of the monkeys were exposed to a repeated, highdose regimen of ( Ϯ )3,4-methylenedioxymethamphetamine HCl (MDMA) (4 days, 10 mg/kg i.m., b.i.d., expressed as the salt) 13 months prior to beginning of the present study as has been previously described (Taffe et al 2001). The remaining three animals were treated with vehicle injections on the same schedule and serve as control subjects.…”

“…Samples were collected as described previously (Taffe et al 2001) and, for the present study, at timepoints 9, 13 and 16 months after the MDMA regimen. Samples were centrifuged to remove cellular contamination and stored at Ϫ 70 Њ C. CSF concentrations of 5-HIAA were measured by high-performance liquid chromatography with electrochemical detection (HPLC-EC) as previously described (Taffe et al 2001).…”

Prepulse Inhibition and Habituation of Acoustic Startle Response in Male MDMA (‘Ecstasy’) Users, Cannabis Users, and Healthy Controls

“…In addition, no influence of cannabis use on several conditions of ASR was observed. Previous animal data have shown that application of MDMA causes a selective and sustained reduction of 5-HT levels in the brain (Stone et al, 1986;Commins et al, 1987;Schmidt, 1987;Battaglia et al, 1988;Insel et al, 1989;Wilson et al, 1989;Ali et al, 1993;Scheffel et al, 1998;Hatzidimitriou et al, 1999;Taffe et al, 2001), and there is also some evidence for selectively lowered serotonergic neurotransmission in chronic MDMA users (McCann et al, 1994. Acute 5-HT depletion decreased PPI in animals and humans consistently (Phillips et al, 2000; Fletcher et al, Figure 2 Habituation curve diagrammed as mean amplitude of 116-dBpulse-alone trials in six blocks and a single initial 116-dB-pulse-alone trial (means7SEM).…”

“…In animals, administration of MDMA produces a rapid and marked release of serotonin (5-HT) via inhibition and reversal of the 5-HT transporter (Rudnick and Wall, 1992). There is convincing evidence that MDMA produces a substantial and sustained long-term neurotoxic loss of 5-HT nerve terminals with an associated depletion of 5-HT in several brain regions of rats, guinea pigs, and several species of nonhuman primates (Stone et al, 1986;Commins et al, 1987;Schmidt, 1987;Battaglia et al, 1988;Insel et al, 1989;Wilson et al, 1989;Ali et al, 1993;Scheffel et al, 1998;Hatzidimitriou et al, 1999;Taffe et al, 2001). Studies of MDMA use in humans have also shown selective decrements in cerebrospinal fluid (CSF) concentrations of 5-hydroxy indoleacetic acid (5-HIAA) as a marker for central serotonergic depletion, with no alterations in CSF homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolites of dopamine and norepinephrine, respectively (McCann et al, 1994.…”