Distinct periods of developmental sensitivity to the effects of 3,4-(±)-methylenedioxymethamphetamine (MDMA) on behaviour and monoamines in rats

Abstract

Previous findings showed allocentric and egocentric learning deficits in rats after MDMA treatment from postnatal days (PD) 11-20 but not after treatment from PD 1-10. Shorter treatment periods (PD 1-5, 6-10, 11-15, or 16-20) resulted in allocentric learning deficits averaged across intervals but not for any interval individually and no egocentric learning deficits individually or collectively. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. In the present experiment rat litters were treated on PD 1-10, 6-15, or 11-20 with 0, 10, or 15 mg/kg MDMA q.i.d. at 2-h intervals. Two male/female pairs/litter received each treatment. One pair/litter received acoustic startle with prepulse inhibition, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent inhibition paradigm. The other pair/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity retest with MK-801 challenge. MDMA impaired CWM learning following PD 6-15 or 11-20 exposure. In MWM acquisition, all MDMA-treated groups showed impairment. During reversal and shift, the PD 6-15 and PD 11-20 MDMA-treated groups were significantly impaired. Reductions in locomotor activity were most evident after PD 6-15 treatment while increases in acoustic startle were most evident after PD 1-10 treatment. After MK-801 challenge, MDMA-treated offspring showed less locomotion compared to controls. Region-specific changes in brain monoamines were also observed but were not significantly correlated with behavioural changes. The results show that PD 11-20 exposure to MDMA caused the largest long-term cognitive deficits followed by PD 6-15 exposure with PD 1-10 exposure least affected. Other effects, such as those upon MK-801-stimulated locomotion showed greatest effects after PD 1-10 MDMA exposure. Hence, each effect has a different window of developmental susceptibility.

Fig. 1

Developmental MDMA exposure leads to hypoactivity. Locomotor activity was assessed for 1 h in a novel environment. Regardless of dosing regimen, MDMA-treated animals had lower activity levels than Sal-treated animals. Data are presented as least squares mean±s.e.m. (n=16–20/group).

Fig. 2

MDMA induced spatial learning deficits in the Morris water maze (MWM). Rats were tested in the MWM for 6 d (four trials/day) for each phase: acquisition, reversal, and shift. Rats treated with MDMA from either PD 6–15 or PD 11–20 showed increased path lengths in each phase [(a) acquisition, (b) reversal and (c) shift] of the test compared to Sal animals. PD 1–10 MDMA treatment caused increased path lengths only for the acquisition phase compared to Sal treatment. Data are presented as least squares mean±s.e.m. * p<0.05, ** p<0.01, *** p<0.001 (n=16–20/group).

Fig. 3

MDMA induced memory deficits in the Morris water maze (MWM). Probe trials were conducted following each phase of MWM testing. MDMA-treated animals from the PD 11–20 dosing regimen had increased average distance from the platform site compared to Sal. No deficits were observed in the PD 1–10 or PD 6–15 dosing regimens. Data are presented as least squares mean±s.e.m. *p<0.05, **p<0.01, ***p<0.001 (n=16–20/group).

Fig. 4

Morris water maze learning curves. While all animals learned during the (a) acquisition, (b) reversal and (c) shift trials, MDMA-treated animals showed increased path length to the platform compared to Sal-treated animals. Data are presented as least squares mean±s.e.m. *p<0.05, **p<0.01, *** p<0.001 (n=16–20/group).

Fig. 5

MDMA-induced route-based learning deficits in the Cincinnati water maze (CWM). Rats were tested in the CWM for 18 d. MDMA-treated animals from the PD 6–15 and PD 11–20 dosing regimens showed increases in latency and errors compared to Sal-treated animals. Data are presented as least squares mean±s.e.m. of data averaged across days. * p<0.05, ** p<0.01, *** p<0.001 (n=17–20/group).

Fig. 6

Cincinnati water maze learning curves for errors committed. Errors committed by all animals decreased as testing progressed; however, MDMA-treated animals commit more errors than Sal-treated animals throughout testing. Data are presented as least squares mean±s.e.m. * p<0.05, **p<0.01, *** p<0.001 (n=17–20/group).

Fig. 7

Blunted MK-801-induce locomotor activation in MDMA-treated rats. Rats were habituated to the locomotor chamber for 30 min followed by a 0.1 mg/kg MK-801 challenge and tested for 180 min thereafter. MDMA-treated rats from the (a) PD 1–10 and (b) PD 6–15 dosing regimens show a blunted hyperactivity after MK-801 treatment compared to Sal-treated animals. (c) The PD 11–20 dosing regimen did not show an altered response to MK-801. Data are presented as least squares mean±s.e.m. * p<0.05, ** p<0.01, *** p<0.001 (n=17–20/group).