Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats.

The investigation of methamphetamine exposure during neonatal development in rats has demonstrated that long-term spatial learning deficits are induced. A previous dose-response study showed that administration of 5 mg/kg methamphetamine, four times daily from postnatal days 11 to 20 produced these deficits, although the effects were not as severe as at higher doses of 10 or 15 mg/kg. This study examined concentrations of methamphetamine at or below 5mg/kg given over the same period of time. Five different concentrations of methamphetamine (i.e., 5, 2.5, 1.25, 0.625, or 0) were administered every 2 h four times daily from postnatal days 11 to 20. Body weights, zero maze performance, and Morris water maze learning were examined. A dose-dependent decrease in body weight was observed during the period of methamphetamine administration and these lower weights continued throughout adulthood for the 5, 2.5, and 1.25 mg/kg concentrations, although the adult decreases were negligible. No differences were noted in the zero maze. In the Morris water maze during the acquisition period, dose-dependent differences in spatial orientation were seen, however non-dose related deficits were observed for other parameters. During the shifted platform phase ("reversal"), a similar dose-dependent difference in spatial orientation was observed, although no other effects were noted during this phase. Females performed worse than males regardless of treatment or the phase of learning in the Morris water maze. These data suggest that even lower doses of methamphetamine can alter learning and memory in adulthood, although with less consistent results than with doses higher than 5 mg/kg/dose. These data would caution against even casual use of methamphetamine by women during pregnancy since even low doses could alter the ability of the child to learn.

Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze.

RATIONALE: Neonatal administration of methamphetamine (MA) to rats from postnatal day (P) 11 to 20, but not from P1 to P10, produces lasting deficits in spatial learning and memory. The preweaning period of development in the rat corresponds to human third trimester hippocampal development and because of the increased use of MA in women of childbearing age, there is a greater likelihood that fetuses will be exposed to this drug. Development of the hippocampus is dependent upon many factors, including an optimal level of corticosterone (CORT). We have demonstrated that the CORT response of animals on P11 to MA is protracted relative to administration on P15 or P20. Interestingly, the P11 animals are still in the stress hyporesponsive period. OBJECTIVES: We postulated that because of the prolonged CORT response on P11, the effects of MA on spatial learning and memory may be confined to a shorter period of exposure. METHODS: Neonatal rats were administered MA (10 mg/kg) 4 times daily from either P11 to P15 or from P16 to P20, raised to adulthood and tested against animals only administered saline (SAL) from P11 to P20 for anxiety, swimming ability, and spatial learning and memory. RESULTS: Animals exposed to MA, regardless of exposure period, tended to be less anxious in the Zero maze relative to SAL animals. No differences were noted for swimming ability. Only animals exposed to MA from P11 to P15 demonstrated deficits in spatial learning and memory during acquisition as well as during a shifted platform phase where learning a new position was required. CONCLUSIONS: The results demonstrate that spatial learning and memory deficits produced by MA administration are dependent upon when the exposure of the animal occurs and appears to be during the period of development in the rat when the response to threatening environments, stressors, is greatly reduced.

Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress.

Previously, we have shown that rats administered MDMA from postnatal (P) days 11-20 had reductions in body weight during the period of treatment and as adults they had deficits in sequential and spatial learning and memory. In the present study, to control for weight reductions, we used litters with double the number of offspring to induce growth restriction comparable to that of standard size litters treated with MDMA. Litters were treated twice daily from P11 to 20 with vehicle or MDMA (20 mg/kg) or only weighed. Males, but not females, exposed to MDMA had longer latencies and more errors in the Cincinnati water maze compared to males of the other treatments. In the Morris water maze (210 cm pool, 10x10 cm platform), the MDMA animals were impaired relative to all other treatments during acquisition. Only the MDMA females showed deficits when the platform was shifted to a new location, however, both MDMA males and females were impaired when the location of the platform was again shifted and a reduced platform (5x5 cm) used. No differences were observed in the ability to swim a straight channel, locate a platform with a cue, or the endocrine response to forced swim among the treatment groups. No differences were seen between animals injected with saline and those only weighed. The data suggest that factors, such as growth retardation, multiple injections, or the composition of the litter, do not affect the development of learning and memory impairments resulting from P11 to 20 MDMA exposure. The large litter approach offers a novel method to control for undernutrition during the preweaning period in rodents.