Long-term effects of neonatal methamphetamine exposure in rats on spatial learning in the Barnes maze and on cliff avoidance, corticosterone release, and neurotoxicity in adulthood.

摘要

Methamphetamine (MA) is a commonly abused stimulant and because of its addictive properties, abusers may not cease use during pregnancy, thereby exposing the fetus to the drug. The consequences of such exposure remain largely unknown however data from animal models show that long-term deficits in spatial learning and memory in the Morris water maze (MWM) occur. In this study we explored the spatial learning ability of rats treated four times daily with MA (5 mg/kg/dose) during the sensitive period for induction of MWM deficits, postnatal days (P) 11-20, using a different maze. In adulthood the animals were tested in a non-swimming spatial task, the Barnes maze, using either aversive (bright light) or appetitive (food reward) motivation. Approximately 30 days after behavioral testing, the pituitary and adrenal response to forced swim was assessed and susceptibility to MA-induced neurotoxicity measured. MA-treated animals tested in the aversive, but not the appetitive, version of the Barnes maze demonstrated spatial learning deficits. An attenuated corticosterone response in MA-treated animals was observed following forced swimming, however no differences in ACTH were found. Following acute MA administration in adulthood to all animals, the neonatally MA-treated animals displayed longer latencies to fall from a cliff than neonatally saline-treated rats given the same acute MA dose. This effect supports previous data showing hypoactivity in neonatally MA-treated animals. Acute MA treatment caused comparable striatal monoamine depletions in all groups, although females treated with MA as neonates displayed increased basal levels of corticosterone three days after the acute dose. These data demonstrate that MA administration during the neonatal period impairs spatial learning in an aversive non-swimming task and alters the adrenal response to a forced swim stressor, suggesting that the adrenal output during learning may contribute to the spatial learning deficits.