The effects of early exposure to MK-801 during environmental enrichment on spatial memory, methamphetamine self-administration and cue-induced renewal in rats

Objective Accumulating evidence indicates an association between improved cognition and the early introduction of environmental enrichment (EE). The beneficial effect of EE has also been examined in the field of methamphetamine (METH) dependence. The present study was designed to examine whether early cognitive alterations by dizocilpine (MK-801) in adolescence can impact the effect of EE on spatial memory, METH self-administration (SA), and cue-induced renewal in adulthood. Methods In Experiments 1 and 2, Morris Water Maze (MWM) performance, c-Fos expression and N-methyl d -aspartate receptor subtype 2B (NMDAR2B) levels were determined in various brain regions following a change in rearing condition from EE to an isolation environment (IE) at different points (PD 41–60 or PD 51–70). In Experiments 3 and 4, MWM performance and METH SA behaviors in adulthood were tested following adolescent administration of MK-801 during different periods of adolescence (PD 41–60 or PD 51–70) under EE rearing conditions. Results The early introduction of the IE at PD 41–60 significantly decreased the beneficial effect of EE on MWM performance in adulthood as compared to IE exposure at PD 51–70. Different rearing conditions also altered c-Fos expression and NMDA2B receptor activity in a regionally specific pattern. EE induced structural and systemic changes in the hippocampus that were associated with improvements in spatial memory. Early administration of MK-801 at PD 41–60 and PD 51–70 produced distinctive effects on the behavioral outcomes of METH SA and cue-induced renewal. Conclusion Early cognitive alterations have a profound impact on spatial memory and METH dependence.