Differential Effects of Novel Dopamine Reuptake Inhibitors on Interference With Long-Term Social Memory in Mice

Abstract

In the laboratory, long-term social recognition memory (SRM) in mice is highly susceptible to proactive and retroactive interference. Here, we investigate the ability of novel designed dopamine (DA) re-uptake inhibitors (rac-CE-123 and S-CE-123) to block retroactive and proactive interference, respectively. Our data show that administration of rac-CE-123 30 min before learning blocks retroactive interference that has been experimentally induced at 3 h, but not at 6 h, post-learning. In contrast, S-CE-123 treatment 30 min before learning blocked the induction of retroactive interference at 6 h, but not 3 h, post-learning. Administration of S-CE-123 failed to interfere with proactive interference at both 3 h and 6 h. Analysis of additional behavioral parameters collected during the memory task implies that the effects of the new DA re-uptake inhibitors on retroactive and proactive interference cannot easily be explained by non-specific effects on the animals' general social behavior. Furthermore, we assessed the mechanisms of action of drugs using intracerebral in vivo-microdialysis technique. The results revealed that administration of rac-CE-123 and S-CE-123 dose-dependently increased DA release within the nucleus accumbens of freely behaving mice. Thus, the data from the present study suggests that the DA re-uptake inhibitors tested protect the consolidation of long-term social memory against interference for defined durations after learning. In addition, the data implies that DA signaling in distinct brain areas including the nucleus accumbens is involved in the consolidation of SRM in laboratory mice.

Keywords: aggression social interaction; cognitive enhancement; dopamine transport inhibitor; long-term memory; retroactive interference; social recognition memory.

Figure 1

Experimental protocol for testing the effects of the defined substances on interference in social recognition memory (SRM). (A) Subcutaneous (sc) injection was performed 30 min before the 1st sampling to measure the impact of administered substances on retroactive interference during choice. (B) Subcutaneous injection was performed 30 min before the 2nd sampling to measure the effect of administered compounds on proactive interference. The two samplings were separated by a defined sampling interval (S_i). Choice took place either 24 h after the 1st sampling, when testing retroactive interference (A), or 24 h after the 2nd sampling when testing proactive interference (B).

Figure 2

Effect of subcutaneous injection of vehicle or rac-CE-123 on retroactive interference at S_i = 3 h (A) and 6 h (B) on social investigation. Recognition memory was tested during choice by exposing the stimulus animal presented during the 1st sampling (1st S) together with a novel stimulus animal mouse 24 h after the 1st sampling. *p < 0.05 and ***p < 0.01 paired Student’s t-test.

Figure 3

Effect of subcutaneous injection of vehicle or S-CE-123 on retroactive interference at S_i 3 = h (A) and 6 h (B) on social investigation. Recognition memory was tested during choice by exposing the stimulus animal presented during the 1st sampling (1st S) together with a novel stimulus animal 24 h after the 1st sampling. *p < 0.05 paired Student’s t-test.

Figure 4

Effect of S-CE-123 on proactive interference at a S_i 3 h. Recognition memory of the experimental subjects treated with S-CE-123 was tested during choice by exposing the stimulus animal presented during the 2nd sampling (2nd S) together with a novel stimulus animal.

Figure 5

Microdialysis experiments. Coronal section diagrams modified from Franklin and Paxinos (2007) and a representative photomicrograph illustrating the reconstructed tip of the probe placement and the track left by the microdialysis probe in the brain tissue, respectively in the nucleus accumbens (A). Effect of subcutaneous injection of vehicle or a low dose (10 mg/kg, B) and high dose (100 mg/kg, C) of rac-CE-123 or S-CE-123 on DA levels in dialysates from the nucleus accumbens of mice. Dopamine values in microdialysates are shown as changes in basal DA values, calculated as the mean of three consecutive samples immediately preceding the drug or vehicle injection. Data are expressed as mean ± SEM. n = 6 per group; **p < 0.01 vs. respective value in the vehicle-treated controls (two-way ANOVA followed by Fisher’s post hoc test).