Glutamatergic N-methyl-D-aspartate (NMDA) receptors play critical roles in early brain development. It is well establised that animals neonatally treated with NMDA receptor antagonist show deficits in many types of learning and memory tasks in adulthood. However, it is uncertain whether these animals can acquire the association between reward and specific stimulus. To investigate the ability of associative learning in rats that received neonatal NMDA receptor blockade, we tested methamphetamine (MAP)-induced conditioned place preference in neonatally MK-801- or vehicle-treated rats.
Male Wistar rat pups received injection of 0.4 mg/kg of MK-801 or saline (SAL) subcutaneously twice per day on postnatal day 7 through 20. To assess the effect of chronic MK-801 treatment in adulthood, 10-week old male Wistar rats received drug injection in a similar manner to neonatal treatment. Behavioral testing started when rats were 14-16 weeks old. For the testing, a three-compartment place preference chamber was used. Prior to the conditioning, baseline test was conducted and preference to each compartment (black or white) of rats was assessed. Conditioning sessions started from the next day. Place preference conditioning was conducted for 4 days using unbiased procedure. Rats received a pairing of either drug with specific compartment once a day, and pairing of MAP and pairing of SAL were alternately carried out 2 times each. Rats were injected 1.0 mg/kg MAP or SAL intraperitoneally, and immediately after the drug injection, they were confined to the compartment predetermined for 30 min. On the following day of last conditioning session, preference test was conducted.
In preference test, rats neonatally treated with MK-801 did not show preference to MAP-paird compartment, while those nanatally treated with SAL showed preference to MAP-paired compartment. On the other hand, rats treated chronically with MK-801 in adulthood showed significant preference to MAP-paired compartment. These results suggest that chronic neonatal NMDA receptor blockade causes deficit in associative learning between reward and specific stimulus in later life.