Effects of neonatal (+)-methamphetamine on path integration and spatial learning in rats: effects of dose and rearing conditions

Abstract

Postnatal day (P)11-20 (+)-methamphetamine (MA) treatment impairs spatial learning and reference memory in the Morris water maze, but has marginal effects on learning in a labyrinthine maze. A subsequent experiment showed that MA treatment on P11-15, but not P16-20, is sufficient to induce Morris maze deficits. Here we tested the effects of P11-15 MA treatment under two different rearing conditions on Morris maze performance and path integration learning in the Cincinnati water maze in which distal cues were unavailable by using infrared illumination. Littermates were treated with 0, 10, 15, 20, or 25mg/kg MA x 4/day (2 h intervals). Half the litters were reared under standard housing conditions and half under partial enrichment by adding stainless steel enclosures. All MA groups showed impaired Cincinnati water maze performance with no significant effects of rearing condition. In the Morris maze, the MA-25 group showed impaired spatial acquisition, reversal, and small platform learning. Enrichment significantly improved Morris maze acquisition in all groups but did not interact with treatment. The male MA-25 group was also impaired on probe trial performance after acquisition and on small platform trials. A narrow window of MA treatment (P11-15) induces impaired path integration learning irrespective of dose within the range tested but impairments in spatial learning are dependent on dose. The results demonstrate that a narrower exposure window (5 days) changes the long-term effects of MA treatment compared to longer exposures (10 days).

Fig. 1

Partial enrichment. Rats were raised in one of two environments: box cages with hardwood bedding without stainless steel huts, or box cages with hardwood bedding with stainless steel huts as partial enrichment (pE). Although the photograph shows only one rat in the cage, in the experiment rats were house in same-sex pairs.

Fig. 2

Mean (± SEM) performance in the Cincinnati Water Maze (CWM). A, average daily number of errors (2 trials/d). B, average daily latency (s) to reach the escape ladder. C, average daily number of returns to the start. Since enrichment was not significant, the standard and pE (partial enrichment) groups were combined; accordingly, group sizes are Males/Females: Saline = 40/39, MA-10 = 38/40, MA-15 = 35/37, MA-20 = 38/38, and MA-25 = 31/32.

Fig. 3

Mean (± SEM) performance in the Cincinnati water maze averaged across days and shown as a function of rearing condition. ‘Standard; refers to animals reared prior to and after weaning in box cages (after weaning in same sex pairs); ‘Partial Enrich’ (pE) refers to rearing under conditions identical to standard conditions except with the addition of a stainless steel hut (see Methods for details). A, Errors; B, latency, and C, returns (2 trials/day). **P < 0.01 vs. SAL. Group sizes are as in Fig. 2.

Fig. 4

Morris water maze performance during the 3 phases of hidden platform learning shown separately by rearing conditions (standard vs. pE (partial enrichment)). Data are (mean ± SEM) for cumulative distance from the platform measured every 0.1 s and averaged across trials, days, and sexes. A: acquisition (10 × 10 cm platform; B: reversal (10 × 10 cm platform), C: shifted-reduced platform trials (5 × 5 cm platform). For each phase, there were 4 trials/d for 5 consecutive days. **P < 0.01 vs. SAL. Rearing condition was a significant main effect but did not interact with drug treatment during acquisition. With males and females combined, groups sizes are for standard/pE rearing: Saline = 39/40, MA-10 = 39/39, MA-15 = 38/34, MA-20 = 37/38, MA-25 = 32/31.

Fig. 5

Morris water maze (hidden platform) performance during acquisition shown as the mean ± SEM for each day (sexes combined) to illustrate the learning curve for cumulative distance. The MA-25 group was the only group significantly impaired (see Fig. 4). Group sizes are as in Fig. 4.

Fig. 6

Morris water maze shifted-reduced hidden platform phase. Shown are the mean (± SEM) latency to find the platform for males and females on each day. Inset: Mean (± SEM) averaged across days to show the effect of the MA-25 group vs. SAL in males. **P < 0.01 vs. SAL. Group sizes are: standard rearing, male, Saline = 20, MA-10 = 19, MA-15 = 18, MA-20 = 18, MA-25 = 15; standard rearing, female, Saline = 19, MA-10 = 20, MA-15 = 20, MA-20 = 19, MA-25= 17. For pE rearing, male, Saline = 20, MA-10 = 19, MA-15 = 17, MA-20 = 19, MA-25 = 16, and pE rearing, female Saline = 20, MA-10 = 20, MA-15 = 17, MA-20 = 19, MA-25 = 16.

Fig. 7

Morris water maze probe trial performance 24 h after the last trial of acquisition. Shown are mean (± SEM) percent time (top panel) and distance (bottom panel) spent in the target quadrant with the platform removed during the 30 s probe trial. *P < 0.05, **P < 0.01 vs. SAL. Group sizes are as in Fig. 6.

Fig. 8

Comparisons of sex differences in the CWM versus MWM. Left, mean (±SEM) errors in the CWM averaged across days, trials and treatment groups are shown for males (M) and females (F). Right, mean (±SEM) cumulative distance (cm) from the platform in the MWM averaged across days, trials, and treatment groups during the acquisition phase (similar male/females differences were seen on reversal and reduced platform trials and on all probe trials) are shown for males (M) and females (F).