(+/-)3,4-Methylenedioxymethamphetamine (MDMA) dose-dependently impairs spatial learning in the morris water maze after exposure of rats to different five-day intervals from birth to postnatal day twenty

Abstract

During postnatal days (PD) 11-20, (+/-)3,4-methylenedioxymethamphetamine (MDMA) treatment impairs egocentric and allocentric learning, and reduces spontaneous locomotor activity; however, it does not have these effects during PD 1-10. How the learning impairments relate to the stress hyporesponsive period (SHRP) is unknown. To test this association, the preweaning period was subdivided into 5-day periods from PD 1-20. Separate pups within each litter were injected subcutaneously with 0, 10, 15, 20, or 25 mg/kg MDMA x4/day on PD 1-5, 6-10, 11-15, or 16-20, and tested as adults. The 3 highest MDMA dose groups showed reduced locomotor activity during the first 10 min (of 60 min), especially in the PD 1-5 and 6-10 dosing regimens. MDMA groups in all dosing regimens showed impaired allocentric learning in the Morris water maze (on acquisition and reversal, all MDMA groups were affected; on the small platform phase, the 2 high-dose groups were affected). No effects of MDMA were found on anxiety (elevated zero maze), novel object recognition, or egocentric learning (although a nonsignificant trend was observed). The Morris maze results did not support the idea that the SHRP is critical to the effects of MDMA on allocentric learning. However, since no effects on egocentric learning were found, but were apparent after PD 11-20 treatment, the results show that these 2 forms of learning have different exposure-duration sensitivities.

Fig. 1

Locomotor activity: horizontal distance (least-squares means ± SEM in centimeters ) summed over a 1-hour test session in 10-min intervals for each treatment regimen. Group sizes, summed across regimens and sexes (male/female), were: saline = 78/79, MDMA-10 = 79/76, MDMA-15 = 74/72, MDMA-20 = 69/70, and MDMA-25 = 62/59. * p < 0.05, ** p < 0.01 compared to saline controls.

Fig. 2

Locomotor Activity: horizontal distance (least-squares means ± SEM in centimeters) in the center of the arena during the first 10-min interval of the 60-min test shown separately for each regimen with males and females combined. Group sizes, summed across sexes, for each regimen are: PD 1–5: saline = 38, MDMA-10 = 36, MDMA-15 = 32, MDMA-20 = 24, MDMA-25 = 9; PD 6–10: saline = 40, MDMA-10 = 40, MDMA-15 = 39, MDMA-20 = 38, MDMA-25 = 37; PD 11–15: saline = 39, MDMA-10 = 40, MDMA-15 = 38, MDMA-20 = 37, MDMA-25 = 35; PD 16–20: saline = 40, MDMA-10 = 39, MDMA-15 = 39, MDMA-20 = 40, MDMA-25 = 40. * p < 0.05, ** p < 0.01 compared to saline controls.

Fig. 3

MWM treatment regimen effects: path length (least-squares means ± SEM in centimeters) to find the submerged platform averaged across trials, sexes and treatment groups to illustrate the main effect of treatment regimen (age). a Regimen effects during phase 1 (acquisition) of testing on day 1. b Regimen effects during phase 2 (reversal) of testing on day 2. Group sizes averaged across treatment groups and sexes for each regimen were: PD 1–5: = 139, PD 6–10 = 194; PD 11–15 = 189; PD 16–20 = 198. ** p < 0.01 between the regimens connected by brackets.

Fig. 4

MWM treatment effects: path length (LS means ± SEM in centimeters) during the 3 phases of MWM averaged across days, trials, and regimens. Group sizes averaged across days, trials, and regimens were: saline = 157, MDMA-10 = 155, MDMA-15 = 149, MDMA-20 = 138, and MDMA-25 = 121. * p < 0.05, ** p < 0.01 compared to saline controls.

Fig. 5

MWM phase 1 (acquisition) learning curves. Main panel: mean ± SEM path lengths (cm) shown for each treatment group averaged across 4 daily trials, regimens, and sexes. Inset: path length shown by trial on day 1 averaged across regimens and sexes (ordinate = cm). Significant treatment group differences are shown in figure 4. Group sizes for each group by regimen with sexes combined are (in regimen order: PD 1–5/6–10/11–15/16–20): saline = 38/40/39/40; MDMA-10 = 36/40/40/39; MDMA-15 = 33/39/38/39; MDMA-20 = 23/38/37/40; MDMA-25 = 9/37/35/40.