Prenatal exposure of diclofenac sodium alters the behavioral development of young Wistar rats

Abstract

Diclofenac sodium (DS), a potent inhibitor of cyclooxygenase, reduces the release of arachidonic acid and formation of prostaglandins. Being a nonsteroid drug that shows antiinflammatory action, the possible side effects of fetal DS administration gain importance in public and medical applications. Herein, the effects of DS administration (1 mg/kg) during gestational days 5-20 were investigated on the performance of Wistar rat pups in a variety of behavioral tasks. Four-week-old pups were subjected to sensory motor tests, a plus maze, an open field, the Morris water maze, and a radial arm maze. Fetal DS disrupted some sensory motor performances, such as visual placing and climbing in both females and males. In the open field, DS females had a higher level of anxiety and male DS pups habituated to the environment slowly compared to controls. The DS pups showed slower rates of learning, whereas no substantial between-group differences were found in the performance of spatial memory compared to both controls. Furthermore, working memory was negatively affected by fetal DS. In conclusion, it was indicated that DS administration during pregnancy had slight behavioral impacts with a delay in learning and a defect in the short-term memory in juvenile rats.

Keywords: Diclofenac sodium; anxiety; learning and memory; rat; sensory motor tests.

Figure 1

Comparison of sensory motor parameters such as (A) visual placing, (B) walking initiation, (C) turning on an inclined screen, (D) wire hanging, (E) climbing, and (F) swimming skills in fetal diclofenac-treated female (DF) and male (DM) rat pups in comparison with male (CM and PCM) and female (CF and PCF) sham and pure control rat pups. Error bars denote SEM. Asterisks indicate significant difference at P ≤ 0.05.

Figure 2

(A) Representative picture of video tracking system showing trajectory of a rat during 5 min. (B) Comparison of the animal’s behavior in the elevated plus maze test as a function of sex (male vs. female) and treatment (D, C, and PC). The bars represent mean percentage of time spent in open and closed arms of the plus maze. Error bars denote SEM.

Figure 3

Comparison of the animal’s behavior in the open field test as (A) the mean time spent in the middle zone of the open field, (B) the mean distance moved in the outer and the inner zone of the open field to measure the locomotor activity, and (C) rearing, (D) sniffing, (E) grooming, and (F) defecation scores of animals in the open field during the total 10-min testing period for all groups. Error bars denote SEM. Asterisks indicate significant difference at P ≤ 0.05.

Figure 4

(A) Representative picture of video tracking system showing trajectory of a rat during the training and probe trial. Mean swim latency calculated for the first 4 days of MWM training with allothetic cues (B) and six consecutive days of MWM training without distal visuospatial cues in the idiothetic paradigm (C). Mean percentage of time spent in the platform quadrant on the probe trial under allothetic cues (D) and idiothetic cues (E). Error bars denote SEM. Asterisks indicate significant difference at P ≤ 0.05.

Figure 5

Comparison of the percentage of working and reference memory errors among groups at each of three training stages. Error bars denote ±SEM. Asterisks indicate significant difference at P ≤ 0.05.