Age-dependent effects of neonatal methamphetamine exposure on spatial learning

Abstract

Neonatal rats exposed to (+)-methamphetamine (MA) display spatial learning and reference memory deficits in the Morris water maze. In separate experiments the emergence and permanence of these effects were determined. Twenty litters were used in each experiment, and two male/female pairs/litter received saline or MA (5 mg/kg four times a day) on postnatal days (P) 11-20. In experiment 1, one MA and one saline pair from each litter began testing on either P30 or P40, whereas in experiment 2, testing began on P180 or P360. Animals received trials in a straight swimming channel and then in the Morris maze (acquisition, reversal, and reduced platform phases). In both experiments, MA-treated groups showed impaired learning in the platform trials and impaired reference memory in the probe trials, which were largely independent of age. The P30 and P40 MA impairments were seen on acquisition and reduced platform trials but not on reversal. In the probe trials, MA effects were seen during all phases. The P180 and P360 MA-induced deficits were seen in all phases of the platform trials. In probe trials, deficits were only seen during the reversal and reduced platform phases. The results demonstrate that neonatal MA treatment induces spatial learning and reference memory deficits that emerge early and persist until at least 1 year of age, suggesting permanence.

Fig. 1

Experiment 1. (P30, P40) Morris water maze, acquisition phase, platform trials for path length: (a), path length (cm) averaged across 4 trials/day and across sexes for the P30 groups. (b) Same as in panel (a) except that data are for the P40 groups. (c) Same as in (a) except that data are the combined averages of the P30 and P40 groups. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. **P<0.01 vs. saline.

Fig. 2

Experiment 1. (P30, P40) Morris water maze, acquisition phase, platform trials. (a) Angle of first bearing to the platform site measured in the first 13 cm at the start of each trial averaged across 4 trials/day for 5 days for male and female rats. (b) Time in the periphery of the maze (outer annulus) on platform trials averaged as in (a). Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times per day on P11–20. **P<0.01.

Fig. 3

Experiment 1. (P30, P40) Morris water maze, reversal phase, platform trials for path length: (a) Path length (cm) averaged across 4 trials/day and across sexes for the P30 groups. (b) Same as in (a) except as applicable to the P40 groups. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20.

Fig. 4

Experiment 1. (P30, P40) Morris water maze, reversal phase, platform trials for first bearing: (a) First bearing (degrees) for the P30 groups averaged across 4 trials/day and across sexes. (b) Same as in (a) except as applied to the P40 groups. (c) The average across trials, days, sexes, and test ages to show the main effect of Group. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. *P<0.05 **P<0.01 vs. saline.

Fig. 5

Experiment 1. (P30, P40) Morris water maze, reversal phase, first bearing probe trial: Data are shown separately for male and female rats to reflect Group × Sex interaction. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. *P<0.05 vs. saline.

Fig. 6

Experiment 1. (P30, P40) Morris water maze, phase 3: Phase 3 was with the platform position being moved to a different quadrant from that during acquisition or reversal and with a smaller (5 × 5 cm) platform. (a) Path lengths averaged across 4 trials/day and across sexes for the P30 groups. (b) Path lengths as in (a) but for the P40 age groups. (c) First bearing averaged across trials, days, sexes, and ages to show the main effect of Group. (d) Time in the periphery (s) averaged across trials, days, sexes, and ages to show the main effect of Group. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. *P<0.05 **P<0.01 vs. saline.

Fig. 7

Experiment 1. (P30, P40) Morris water maze, phase 3, probe trial, first bearing: Data shown are for the P30 and P40 groups and for the combined averages of both test ages to show the main effect of Group. Data are averaged across sexes. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. *P<0.05 vs. saline.

Fig. 8

Experiment 2. (P180, P360) Morris water maze, acquisition phase, platform trials, path length: (a) Path length (cm) averaged across 4 trials/day and across sexes for the P180 groups. (b) Same as in (a) except as applied to the P360 groups. (c) Same as in (a) except that data are the combined averages of the P180 and P360 groups. Data are means ± SEM. Rats received 5 mg/kg methamphetamine. (MA) four times a day on P11–20. *P<0.05 vs. saline.

Fig. 9

Experiment 2. (P180, P360) Morris water maze, acquisition phase, probe trial, first bearing: First bearing, averaged across male and female rats, for the groups tested at P180, P360 or the combined average of both. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11-20. *P<0.05 vs. saline.

Fig. 10

Experiment 2. (P180, P360) Morris water maze, reversal phase, platform trials, path length: (a) Path length (cm) averaged across 4 trials/day and across sexes for the P180 groups. (b) Same as in (a) except as applied to the P360 groups. (c) Same as in (a) except that data are the combined averages of the P180 and P360 groups, which are also averaged across days, to show the main effect of Group. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. *P<0.05 vs. saline.

Fig. 11

Experiment 2. (P180, P360) Morris water maze, reversal phase, probe trial, average distance: Average distance (cm) is the mean distance from the platform site recorded every 55 ms during the probe trial. Data are shown for average distances averaged across male and female rats tested at P180 and P360 and for the combination of both ages. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. **P<0.01 vs. saline.

Fig. 12

Experiment 2. (P180, P360) Morris water maze, reduced phase (phase 3), platform trials, path length: (a) Path length (cm) averaged across 4 trials/day and across sexes for the P180 groups. (b) Same as in (a) except as applied to the P360 groups. (c) Same as in (a) except that data are the combined averages of the P180 and P360 groups, averaged across days to show the main effect of Group. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. *P<0.05 vs. saline.

Fig. 13

Experiment 2. (P180, P360) Morris water maze, reduced phase (phase 3), probe trial, average distance: Average distance (cm) is the mean distance from the platform site recorded every 55 ms. Data are shown as average distances averaged across male and female rats tested at P180 and P360 and across the combination of both ages. Data are means ± SEM. Rats received 5 mg/kg methamphetamine (MA) four times a day on P11–20. **P<0.01 vs. saline.