Differential Effects of Valproic Acid on Immobility Responses and Locomotor Activity in Female and Male Rats

Margarita Franco-Colín,Linda Garcés-Ramírez,Oriana Hidalgo-Alegría,Fidel De La Cruz,Gonzalo Flores,José Luna-Muñoz,Oscar Morales-Dionisio

doi:10.4236/pp.2017.810025

Abstract

Valproic acid (VPA) is used in the treatment of epilepsy and behavioral disorders. However, the exposure to VPA during pregnancy increases the risk of having offspring with autism spectrum disorder (ASD). Reports indicate that men are more likely to suffer ASD than women who were exposed to VPA prenatally. Few studies have related the sex differences and behavioral changes in the ASD rat model. Our aim was to determinate whether male and female Wistar rats whose mothers were exposed to either VPA (600 mg/kg; animal model for ASD) or saline (0.9%) i.p. at 12.5 day of gestation, have different effects on immobility induce by clamping (IC), dorsal immobility (DI), catalepsy, locomotor activity, stereotypes, and analgesia (tail flick). For this purpose, we made four groups (n = 8). Group: A) saline male rats, B) saline female rats, C) VPA male rats and D) VPA female rats. At 35 (prepubertal age), 56 (postpubertal age) and 180 days, we tested the behaviors previously mentioned. Finding that VPA has the same effect on IC, catalepsy, and analgesia in male and female rats, the time of these tests was increased. However, VPA only has an effect on DI in males but not in female rats. On the contrary, there is hyperactivity and an increase of stereotypes in female but not in male rats. Thereby, VPA has an effect on the three immobility responses tested (IC, DI and catalepsy), locomotor activity and analgesia but in a differential way on DI, stereotypes and locomotor activity between male and female rats.

Highlights

Valproic Acid (VPA) is used as anticonvulsant drug due to its efficiency treating seizures, and it is prescribed as a mood stabilizer
According to the DSM-V 5th edition [6], the diagnostic is mainly based on: 1) persistent deficits in social interaction, 2) presence of repetitive behaviors such as stereotypical movements, 3) the symptoms that must be present in early developmental stages, though symptoms may manifest in later stages, 4) impairment in social functioning, 5) intellectual disability and social communication abilities that are lower than expected for general development level, which are not explained by intellectual disabilities
In male rats prenatally exposed to VPA (Figure 1(a)), the time of immobility response induced by clamping significantly increased on day 35 vs. control (interaction treatment X age F(2,23) = 6.624, P = 0.005; post-hoc test P < 0.001) but there was not effect at 56 and 180 days

Summary

Introduction

Valproic Acid (VPA) is used as anticonvulsant drug due to its efficiency treating seizures, and it is prescribed as a mood stabilizer. The use of VPA during the pregnancy, as well as other antiepileptic drugs, is associated with teratogenic alterations and congenital malformations [1]. Even if VPA is administered with another anticonvulsant drug, it can induce effects more pervasive than that it induces itself [2]. VPA has been proposed as an important factor in the etiology of autism. Some reports show that mothers who were administered with VPA when they were pregnant had children with similar symptoms to children with autism [3] [4] [5]. The autistic spectrum disorder (ASD) is a pervasive developmental disorder (PDD). According to the DSM-V 5th edition [6], the diagnostic is mainly based on: 1) persistent deficits in social interaction, 2) presence of repetitive behaviors such as stereotypical movements, 3) the symptoms that must be present in early developmental stages, though symptoms may manifest in later stages, 4) impairment in social functioning, 5) intellectual disability and social communication abilities that are lower than expected for general development level, which are not explained by intellectual disabilities

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