Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats

Abstract

Systemic administration of MK-801, an NMDA-receptor antagonist, impairs reversal learning in weanling rats [Chadman, K.K., Watson, D.J., & Stanton, M.E. (2006). NMDA-receptor antagonism impairs reversal learning in developing rats. Behavioral Neuroscience, 120(5), 1071-1083]. The brain systems responsible for this effect are not known in either adult or young animals. This study tested the hypothesis that hippocampal NMDA receptors are engaged in weanling-age rats during spatial discrimination reversal training in a T-maze. In Experiment 1, 26-day-old Long-Evans rats (P26) showed a dose-related impairment on this task following bilateral intrahippocampal administration of either 2.5 or 5.0microg MK-801 or saline vehicle during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but received intrahippocampal MK-801 (2.5microg) during acquisition, reversal, both, or neither. MK-801 failed to impair acquisition, ruling out nonspecific "performance effects" of the drug. MK-801 impaired reversal irrespective of drug treatment during acquisition. NMDA-receptor antagonism in the hippocampus is sufficient to account for the previously reported effects of systemic MK-801 on reversal of T-maze position discrimination.

Figure 1

Schematic representation of cannula placements targeted to the dHPC in Experiment 1. Coordinates represent distances posterior to Bregma (Paxinos & Watson, 2005).

Figure 2

Mean (±SE) percentage of correct responses for the three treatment groups beginning on P26 in Experiment 1 as a function of training phase (acquisition or reversal), 12-trial blocks, and dose. During the reversal phase only, the intrahippocampal treatment groups were vehicle (SALINE: open circles), or one of two drug doses (2.5 μg MK-801: closed circles; 5.0 μg MK-801: closed squares). All treatment groups received saline infusions during acquisition. Dashed line at 50 percent indicates chance performance.

Figure 3

Analysis of trials to criterion (TTC) and error types during reversal for P26 rats as a function of dose of MK-801 in Experiment 1. Mean (±SE) for TTC (A), total errors (B), perseverative errors (C), and regressive errors (D).

Figure 4

Schematic representation of cannula placements targeted to the dHPC in Experiment 2. Coordinates represent distances posterior to Bregma (Paxinos & Watson, 2005).

Figure 5

Mean (±SE) percentage of correct responses for the four MK-801 (2.5 μg) treatment groups in Experiment 2 beginning on P26 as a function of training phase (acquisition or reversal), 12-trial blocks, and treatment. The intrahippocampal treatment groups were saline-saline (SAL-SAL: open circles), saline-MK-801 (SAL-MK: closed circles), MK-801-SAL (MK-SAL: open triangles), or MK-801-MK-801 (MK-MK: closed triangles). Dashed line at 50 percent indicates chance performance.

Figure 6

Analysis of trials to criterion (TTC) and error types during reversal for P26 rats as a function of dose of MK-801 in Experiment 2. Differences were not found between a first (SAL-MK) or second (MK-MK) infusion of MK-801during reversal, thus the SAL-MK and MK-MK treatment groups were pooled into Group MK (open bars), and the saline groups (MK-SAL and SAL-SAL) were pooled into Group SAL (closed bars). Mean (±SE) for TTC (A), total errors (B), perseverative errors (C), and regressive errors (D).