3,4-Methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory

Abstract

Background: +/-3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that causes cognitive deficits in humans. A rat model for learning and memory deficits has not been established, although some cognitive deficits have been reported.

Methods: Male Sprague-Dawley rats were treated with MDMA (15 mg/kg x 4 doses) or saline (SAL) (n = 20/treatment group) and tested in different learning paradigms: 1) path integration in the Cincinnati water maze (CWM), 2) spatial learning in the Morris water maze (MWM), and 3) novel object recognition (NOR). One week after drug administration, testing began in the CWM, then four phases of MWM, and finally NOR. Following behavioral testing, monoamine levels were assessed.

Results: +/-3,4-Methylenedioxymethamphetamine-treated rats committed more CWM errors than did SAL-treated rats. +/-3,4-Methylenedioxymethamphetamine-treated animals were further from the former platform position during each 30-second MWM probe trial but showed no differences during learning trials with the platform present. There were no group differences in NOR. +/-3,4-Methylenedioxymethamphetamine depleted serotonin in all brain regions and dopamine in the striatum.

Conclusions: +/-3,4-Methylenedioxymethamphetamine produced MWM reference memory deficits even after complex learning in the CWM, where deficits in path integration learning occurred. Assessment of path integration may provide a sensitive index of MDMA-induced learning deficits.

Figure 1

A diagram of the CWM with the “correct” path noted by the line from B to A. Any perseverative swimming within the short arms of the T’s was counted as an error. Latency to swim from B to A was also measured. CWM, Cincinnati water maze.

Figure 2

Body temperature measurement during MDMA administration. MDMA increased body temperatures starting at the 2-hour time point (p < .02) and the temperatures remained elevated throughout the dosing period (p < .003). Arrows indicate MDMA administration. *p < .01. MDMA, ±3,4-methylenedioxymethamphetamine.

Figure 3

Cincinnati water maze errors. MDMA-treated animals made significantly more errors on days 4 and 5 with a trend toward significance on day 6. Latency data (not shown), while similar, only showed a trend toward significance between groups. *p < .05, †p < .1. MDMA, ±3,4-methylenedioxymethamphetamine.

Figure 4

Morris water maze testing in the acquisition phase. (A) Latencies in the acquisition phase of MWM testing approached significance (p < .1). The probe trial data for first bearing (B) and average distance (C) are represented. *p < .02, †p < .1. MWM, Morris water maze.

Figure 5

Morris water maze testing in the reversal phase. (A) Latency during the reversal phase of MWM testing. In the probe trial, first bearing (B) and average distance from the target (C) are shown. Average distance was significant in the probe phase as indicated. *p < .04. MWM, Morris water maze.

Figure 6

Neurotransmitter assessment. (A) In the hippocampus, the MDMA-treated group had depletions in 5-HT and 5-HIAA. *p < .0001. (B) In prefrontal cortex, the MDMA-treated animals had depleted 5-HT and 5-HIAA. *p < .0001, †p < .1. (C) Striatal 5-HT and 5-HIAA were depleted in the MDMA group. However, DA was also significantly depleted. *p < .03, **p < .003. Correlations were calculated to determine the relationship between neurotransmitter depletion and behavioral deficits in the MDMA-treated animals, and none were found. MDMA, ±3,4-methylenedioxymethamphetamine; 5-HT, serotonin; 5-HIAA, 5-hydroxyindoleacetic acid.