Effects of MDMA on Complex Brain Function in Laboratory Animals

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Abstract

FREDERICK, D.L. AND M.G. PAULE. Effects of MDMA on complex brain function in laboratory animals. NEUROSCI BIOBEHAV REV 21(1) 67–78, 1997.—This review surveys experiments that have examined the effects of acute and chronic MDMA exposure on schedule-controlled operant behaviors thought to engender responses that reflect the expression of complex brain functions. Such functions include time estimation, short-term memory, learning, motivation, and color and position discrimination. Recent experiments conducted in the Behavioral Toxicology Laboratory at the National Center for Toxicological Research concerning MDMA's acute and long-term effects on rhesus monkey performance in an operant test battery are compared to previous studies involving the effects of MDMA on operant behaviors. Results of these experiments suggest that when given acutely, MDMA disrupts complex brain functions associated with learning and time estimation more than those associated with short-term memory and visual discrimination, and that behavioral tasks requiring relatively high rates of responding are particularly sensitive to the disruptive effects of MDMA. Repeated exposure to doses of MDMA sufficient to produce long-lasting changes in brain neurotransmitter systems results in residual effects (e.g. tolerance, sensitivity) on behavioral task performance when subjects are subsequently challenged with acute MDMA, whereas baseline (non-challenged) performance of these tasks after such exposure generally remains unchanged. Although the experiments described herein were conducted on a relatively small number of non-human subjects, they raise the possibility that long-term effects on cognitive processes may also occur in humans exposed to repeated or acute high doses of MDMA. Published by Elsevier Science Ltd.

Section snippets

INTRODUCTION

3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA or “Ecstasy”) is a phenylisopropylamine amphetamine analog possessing both stimulant-like (dopaminergic) and hallucinogen-like (serotonergic) properties 42, 50, 68, presumably as a result of its serotonin (5-HT) and dopamine (DA) releasing effects, and/or its ability to inhibit 5-HT and/or DA reuptake or monoamine oxidase 7, 25, 33, 42. In laboratory animals, the acute behavioral effects of MDMA appear to be qualitatively more like stimulants than

ACUTE EFFECTS OF MDMA ON COMPLEX BRAIN FUNCTION

In our laboratory at the National Center for Toxicological Research (NCTR), the acute effects of MDMA were assessed in three adult male rhesus monkeys using performance in the NCTR Operant Test Battery (OTB) [15]. The specific tasks contained in the OTB have been described in detail elsewhere [61], and a diagram of the OTB behavioral panel is presented in Fig. 1. The OTB currently consists of five tasks thought to engender or elicit behaviors that are believed to model aspects of time

CHRONIC EFFECTS OF MDMA ON COMPLEX BRAIN FUNCTIONS

As mentioned previously, short course, high dose MDMA administration has been shown to cause long-lasting changes in 5-HT systems (i.e. decreased brain 5-HT and 5-HIAA concentrations, and suspected 5-HT axon terminal degeneration) in laboratory animals. However, from the relatively few studies that have compared post-treatment behavior to pre-exposure behavior or to the behavior of non-treated controls, few significant differences have been reported. The majority of these experiments have not

SUMMARY

In MDMA-naïve animals, operant schedules in which correct performance is thought to depend upon the learning and time estimation capabilities of subjects appear to be more sensitive to the acute effects of MDMA than tasks thought to depend upon short-term memory and visual discriminations. Schedule-controlled operant behaviors thought to assess aspects of motivation to work for food also seem to be particularly sensitive to the acute effects of MDMA, possibly reflecting the anorectic properties

Acknowledgements

D. L. Frederick was supported through an appointment to the Oak Ridge Associated Universities Postgraduate Research Program. The authors thank Jeannette Coleman for her assistance in the preparation of this manuscript, and the animal care personnel at the NCTR (Crystal Brown, Larry Dawson, James Henderson, Teresa Howard, Pamela Morgan, Randy Thompson, Arnold Tripp, Josephine Watson, O. T. Watson and Betty White) for their excellent care and handling of the monkeys.

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      The blunted responsiveness to MDMA shown here agrees with previous reports of tolerance to diverse effects of MDMA in rats, including anorexia (Zacny et al., 1990), discriminative stimulus properties (Schechter, 1991; Virden and Baker, 1999), hyperthermia (Shankaran and Gudelsky, 1999; Piper et al., 2006) and locomotor activity (Callaway and Geyer, 1992; Brennan and Schenk, 2006). Tolerance to behavioral actions of MDMA is also well documented in non-human primates (Frederick et al., 1995; Frederick and Paule, 1997; Fantegrossi et al., 2004; Fantegrossi, 2007). On the other hand, a number of studies in rodents provide evidence for sensitized responsiveness after repeated MDMA exposure (Poland et al., 1997; Kalivas et al., 1998; Giorgi et al., 2005), suggesting tolerance development is not a universal outcome.

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