Elsevier

Neuropharmacology

Volume 55, Issue 7, December 2008, Pages 1121-1130
Neuropharmacology

(±)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: A comparison of single vs once per week treatment for 5 weeks

https://doi.org/10.1016/j.neuropharm.2008.07.006Get rights and content

Abstract

3,4-Methlylenedioxymethamphetamine (MDMA) administration (4 × 15 mg/kg) on a single day has been shown to cause path integration deficits in rats. While most animal experiments focus on single binge-type models of MDMA use, many MDMA users take the drug on a recurring basis. The purpose of this study was to compare the effects of repeated single-day treatments with MDMA (4 × 15 mg/kg) once weekly for 5 weeks to animals that only received MDMA on week 5 and saline on weeks 1–4. In animals treated with MDMA for 5 weeks, there was an increase in time spent in the open area of the elevated zero maze suggesting a decrease in anxiety or increase in impulsivity compared to the animals given MDMA for 1 week and saline treated controls. Regardless of dosing regimen, MDMA treatment produced path integration deficits as evidenced by an increase in latency to find the goal in the Cincinnati water maze. Animals treated with MDMA also showed a transient hypoactivity that was not present when the animals were re-tested at the end of cognitive testing. In addition, both MDMA-treated groups showed comparable hyperactive responses to a later methamphetamine challenge. No differences were observed in spatial learning in the Morris water maze during acquisition or reversal but MDMA-related deficits were seen on reduced platform-size trials. Taken together, the data show that a single-day regimen of MDMA induces deficits similar to that of multiple weekly treatments.

Introduction

While use of ±3,4-methylenedioxymethamphetamine (MDMA) has declined recently, prevalence data show that 20% of 25–26 year olds in the United States have tried MDMA (Johnston et al., 2007). In the European Union, MDMA use varies widely among countries with a range of 0.6–8.8% of 15–34 year olds reporting use (EMCDDA, 2004). It is known that MDMA exposure to humans, rats, and nonhuman primates leads to reductions in brain serotonin (5-HT) levels (Green et al., 2003). In adult rats, it has been shown that 5-HT is reduced in the prefrontal cortex, neostriatum, and hippocampus (structures important for learning and memory) following 4 doses of 15 mg/kg of MDMA administered over a single day (Able et al., 2006). MDMA exposure also leads to moderate decreases in neostriatal dopamine levels long after treatment (Able et al., 2006, Cohen et al., 2005, Commins et al., 1987, McGregor et al., 2003).

Cognitively, MDMA exposure in humans leads to impairment of verbal, prospective, and working memory (Kalechstein et al., 2007, Zakzanis and Campbell, 2006). Central executive and decision making skills are also altered in persistent MDMA users (Bolla et al., 1998, Klugman and Gruzelier, 2003, Parrott et al., 1998), and abstaining from MDMA does not ameliorate these effects (Zakzanis and Campbell, 2006). Similar to humans, MDMA administration in rats also leads to cognitive deficits. For example, MDMA treatment produced reference memory deficits on probe trials in the Morris water maze (MWM) (Able et al., 2006, Sprague et al., 2003). With a short retention time of 15 min, MDMA-treated animals showed deficiencies in a test of novel object recognition (Morley et al., 2001), however, with a longer retention interval of 1 h no deficits were seen (Morley et al., 2001, Able et al., 2006). Taken together, these findings imply that MDMA treatment may affect the function of the hippocampus, which is supported by the observed reduction in 5-HT levels. The Cincinnati water maze (CWM) is a multiple T-maze that requires a combination of path integration and spatial learning abilities when run under lighted conditions. A previous study showed that a single-day treatment regimen of MDMA leads to deficits in the CWM, as evidenced by increases in latency to find the escape and number of errors (Able et al., 2006). While this study was able to detect learning and memory deficits following a single day of administration, this regimen does not mimic the pattern of human abusers (i.e., weekend binges). Another substituted amphetamine, fenfluramine (FEN), also affects CWM performance (Skelton et al., 2004, Williams et al., 2002a), however, these animals do not show any deficits in the MWM (Skelton et al., 2004, Williams et al., 2002a). Taken together, these data suggest that path integration learning is an important form of cognitive deficit induced by substituted amphetamines that deserves further study.

While many studies have been conducted using an acute model of administration, few studies have examined a chronic abuse model of MDMA use. In one study 10 mg/kg MDMA was administered 2 times per day (4 h interdose interval, i.e., 2 × 10 mg/kg) every 5 days from postnatal day (P)35–60 (Piper and Meyer, 2004). In a subsequent study the dose frequency was changed from 2 to 4 doses with interdose intervals of 1 h and with a lowered dose of 5 mg/kg/dose (i.e., 4 × 5 mg/kg) (Piper et al., 2005). The 2 × 10 mg/kg MDMA regimen leads to decreases in novel object recognition with a 15 min retention interval, whereas no deficits were seen with the 4 × 5 mg/kg dose regimen (Piper et al., 2005, Piper and Meyer, 2004). The 2 × 10 mg/kg dose regimen of MDMA also led to decreases in anxiety in the elevated plus maze, while no changes in these measures were observed with the 4 × 5 mg/kg MDMA dose regimen (Piper et al., 2005, Piper and Meyer, 2004).

The purpose of the present study was to extend Able et al.'s (2006) previous findings using an exposure regimen that better mimics the adult chronic MDMA abuser. This was accomplished by administering MDMA (15 mg/kg × 4 doses/day) or SAL once a week for 5 consecutive weeks. In order to directly compare the effects of a repeated dosing model with the more commonly used acute model, one group was dosed with SAL for 4 weeks and MDMA on the fifth week and the other group with MDMA each week for all 5 weeks (along with saline controls that received SAL all 5 weeks). Behavioral tests were conducted in the same order and time after last treatment as in Able et al. (2006).

Section snippets

Subjects

Male Sprague–Dawley, CD IGS rats (225–250 g) were obtained from Charles River Laboratories (Raleigh, NC). The rats were allowed to acclimatize to the colony room for 1 week prior to the day of MDMA administration. The colony room was maintained at a temperature of 21 ± 1 °C (50 ± 10% humidity) with food and water available freely, except during MDMA treatment. The animals were initially housed in pairs in cages measuring 46 × 24 × 20 cm prior to drug treatment, then singly housed during and following drug

Body weight

There were effects of treatment (F(1,65) = 5.26, p < 0.05), week (F(3,187) = 419.18, p < 0.001), and treatment × week (F(3,187) = 8.87, p < 0.001) on body weight prior to each day of treatment during the dosing period (Table 1). Since the MDMA × 1 group received saline during weeks 1–4, their data were merged with those of the SAL group after determining that they were not significantly different nor did they approach being different. On week 5 a significant effect of treatment was observed (F(1,63) = 15.63, p < 

Discussion

It was previously shown that acute MDMA treatment on a single day leads to deficits in path integration or egocentric learning in the CWM (Able et al., 2006). Accordingly, the first purpose of the present experiment was to determine if a repeated exposure model would lead to similar or more severe path integration effects. The second purpose was to determine the short-term effects of an acute MDMA treatment regimen on other behaviors; therefore behavioral testing began 5 days after the last

Acknowledgment

Supported by NIH grants DA006733 (CVV), DA007427 (GAG), and DA014269 (MTW) and training grant ES007051 (CEG, MRS, TLS).

References (61)

  • A.B. Scholey et al.

    Increased intensity of Ecstasy and polydrug usage in the more experienced recreational Ecstasy/MDMA users: a WWW study

    Addict. Behav.

    (2004)
  • P.E. Sharp et al.

    The anatomical and computational basis of the rat head-direction cell signal

    Trends Neurosci.

    (2001)
  • J.E. Sprague et al.

    Hippocampal serotonergic damage induced by MDMA (ecstasy): effects on spatial learning

    Physiol. Behav.

    (2003)
  • R. de la Torre et al.

    Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans

    Trends Pharmacol. Sci.

    (2004)
  • D. Viggiano et al.

    Dopamine phenotype and behaviour in animal models: in relation to attention deficit hyperactivity disorder

    Neurosci. Biobehav. Rev.

    (2003)
  • C.V. Vorhees

    Maze learning in rats: a comparison of performance in two water mazes in progeny prenatally exposed to different doses of phenytoin

    Neurotoxicol. Teratol.

    (1987)
  • M.T. Williams et al.

    Absorption and clearance of +/-3,4-methylenedioxymethamphetamine from the plasma of neonatal rats

    Neurotoxicol. Teratol.

    (2004)
  • M.T. Williams et al.

    Administration of d,l-fenfluramine to rats produces learning deficits in the Cincinnati water maze but not the Morris water maze: relationship to adrenal cortical output

    Neurotoxicol. Teratol.

    (2002)
  • M.T. Williams et al.

    Methamphetamine exposure from postnatal day 11 to 20 causes impairments in both behavioral strategies and spatial learning in adult rats

    Brain Res.

    (2002)
  • J.P. Balcombe et al.

    Laboratory routines cause animal stress

    Contemp. Top. Lab. Anim. Sci.

    (2004)
  • M.H. Baumann et al.

    Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges

    Neuroscience

    (2008)
  • M.H. Baumann et al.

    3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings

    Psychopharmacology (Berl)

    (2007)
  • H.T. Blair et al.

    Visual and vestibular influences on head-direction cells in the anterior thalamus of the rat

    Behav. Neurosci.

    (1996)
  • K.I. Bolla et al.

    Memory impairment in abstinent MDMA (“Ecstasy”) users

    Neurology

    (1998)
  • D.P. Cain

    Prior non-spatial pretraining eliminates sensorimotor disturbances and impairments in water maze learning caused by diazepam

    Psychopharmacology (Berl)

    (1997)
  • A.K. Cho

    Ice: a new dosage form of an old drug

    Science

    (1990)
  • A.K. Cho et al.

    Relevance of pharmacokinetic parameters in animal models of methamphetamine abuse

    Synapse

    (2001)
  • R.E. Clark et al.

    Impaired recognition memory in rats after damage to the hippocampus

    J. Neurosci.

    (2000)
  • M.A. Cohen et al.

    Learning and memory after neonatal exposure to 3,4-methylenedioxymethamphetamine (ecstasy) in rats: interaction with exposure in adulthood

    Synapse

    (2005)
  • D.L. Commins et al.

    Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain

    J. Pharmacol. Exp. Ther.

    (1987)
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