Attenuation by a sigma1 (sigma1) receptor agonist of the learning and memory deficits induced by a prenatal restraint stress in juvenile rats

Abstract

1. Stress during pregnancy results in complex neurochemical and behavioral alterations throughout the offspring lifetime. We here examined the impact of prenatal stress (PS) on memory functions in male and female offspring and report the efficacy of a selective sigma(1) (sigma(1)) receptor agonist, igmesine, in alleviating the observed deficits. 2. Dams received an unpredictable 90-min duration restraint stress from gestational day E17 to E20. Learning was examined in offspring between day P24 and P36 using spontaneous alternation in the Y-maze, delayed alternation in the T-maze, water-maze learning and passive avoidance. 3. Both male and female PS rats showed impairments of spontaneous and delayed alternation performances. Acquisition of a fixed platform position in the water-maze was unchanged in PS rats, but the probe test revealed a diminution of time spent in the training quadrant. Acquisition of a daily changing platform position demonstrated impaired working memory for male and female PS rats. Finally, passive avoidance deficits were observed. 4. Pretreatment with the selective sigma(1) agonist igmesine (1-10 mg x kg(-1) i.p.) reversed the PS-induced learning deficits in offspring rats for each test. The sigma(1) antagonist BD1063 failed to affect performances alone but blocked the igmesine effect, confirming the involvement of the sigma(1) receptor. 5. PS thus induces delayed memory deficits, affecting spatial and nonspatial, short- and long-term memories in juvenile male and female offspring rats. Activation of the sigma(1) neuromodulatory receptor allows a significant recovery of the memory functions in PS rats.

Figure 1

Effect of the σ₁ receptor agonist igmesine on the spontaneous alternation behavior deficits observed in prenatally stressed rats in the Y-maze test: alternation percentages (a, b) and total number of arm entries (c, d). Male (a, c) and female (b, d) rats subjected to prenatal stress (PS) were administered i.p. with vehicle solution (V), igmesine (1, 3, 10 mg kg⁻¹) and/or BD1063 (10 mg kg⁻¹) 20 min before the session. The number of animals per group is indicated within the columns in (c, d). ^*P<0.05, ^**P<0.01 vs ^**V-treated no stress group; # P<0.05, ## P<0.01 vs V-treated PS group; °°P<0.01 vs igmesine (10 mg kg⁻¹)-treated PS group in (a); Dunnett's test.

Figure 2

Effect of the σ₁ receptor agonist igmesine on the delayed alternation deficits in PS rats in the T-maze test: ratio of the time spent in the novel arm over the time spent in the previous arm (a, b) and ratio of the number of entries into the novel arm over entries into the previous arm (c, d). Male (a, c) and female (b, d) PS rats were examined separately. Animals were allowed to explore the T-maze, with one short arm closed, for 10 min. After 1 h time interval, the pattern of exploration of the whole maze was recorded during 2 min. Rats were administered i.p. with vehicle solution (V), igmesine (1, 3, 10 mg kg⁻¹) and/or BD1063 (10 mg kg⁻¹) 20 min before the second session. The number of animals per group is indicated within the columns in (c, d). ^*P<0.05, ^**P<0.01 vs V-treated no stress group; # P<0.05, ## P<0.01 vs V-treated no stress group; °P<0.05, °°P<0.01 vs igmesine (10 mg kg⁻¹)-treated PS group; Dunnett's test.

Figure 3

Acquisition profiles of nonstressed (a, c) or PS (b, d) rats for place learning in the water-maze: male (a, b) or female (c, d) rats. Animals were administered i.p. with vehicle solution (V), igmesine (1, 3, 10 mg kg⁻¹) and/or BD1063 (10 mg kg⁻¹) 20 min before the first trial and submitted during 5 days to three swims per day, with ITI of 10 min. The figures show acquisition profiles for Veh- and igmesine (10 mg kg⁻¹)-treated groups only. In (b, d), the profile of the control (no stress+Veh) group is added as a simple line. The number of animals per group was n=7–12 and 8–10 for the profiles shown in the figure. ^*P<0.05, ^**P<0.01 vs latencies shown by the vehicle-treated PS group during the same training day; Dunn's test.

Figure 4

Performances of PS rats in the probe test for place learning in the water-maze: spatial preference among quadrants for male (a) and female (b) rats and effect of the σ₁ receptor agonist igmesine on the time spent in the training quadrant for male (c) and female (d) rats. At 1 h after the last swim trial, the platform was removed and animals were submitted to a 60-s swim. The presence in each quadrant was measured. Quadrants: T, training; AL, adjacent left; O, opposite; AR, adjacent right. The number of animals per group is indicated within the columns. ^*P<0.05, ^**P<0.01 vs time spent in the T quadrant; ## P<0.01 vs no stress group; Dunnett's test in (a, b). ^**P<0.01 vs V-treated no stress group; # P<0.05 vs V-treated no stress group; Dunnett's test in (c, d).

Figure 5

Working memory deficits observed in the water-maze effect for PS rats and beneficial effect of the σ₁ receptor agonist igmesine. Swim latency profiles among the four trials for nonstressed and PS rats (a, b). Effect of the σ₁ receptor agonist igmesine on the second trial latency (c, d) for male (a, c) and female (b, d) rats. The number of animals per group is indicated within the columns in (c, d). ^**P<0.01 vs the same trial latency in no stress group; Mann–Whitney's test in (a, b). ^*P<0.05, ^**P<0.01 vs V-treated no stress group; # P<0.05, ## P<0.01 vs V-treated PS group; °P<0.05 vs igmesine (10 mg kg⁻¹)-treated PS group; Dunn's test in (c, d).

Figure 6

Effect of the σ₁ receptor agonist igmesine on the passive avoidance deficits in PS rats: step-through latencies showed by male (a) and female (b) rats, during the retention session. Rats were administered i.p. with vehicle solution (V), igmesine (1, 3, 10 mg kg⁻¹) and/or BD1063 (10 mg kg⁻¹) 20 min before the training session. After 24 h, they were placed into the white compartment and the latency was recorded up to 300 s. The number of animals per group is indicated between parantheses. ^*P<0.05 vs V-treated no stress group; # P<0.05 vs V-treated PS group; °P<0.05 vs igmesine (10 mg kg⁻¹)-treated PS group; Dunn's test.