Elsevier

European Journal of Pharmacology

Volume 797, 15 February 2017, Pages 106-114
European Journal of Pharmacology

Full length article
Protective effects of gabapentin against the seizure susceptibility and comorbid behavioral abnormalities in the early socially isolated mice

https://doi.org/10.1016/j.ejphar.2017.01.024Get rights and content

Highlights

  • Early SIS increased seizure risk in adult socially isolated mice.

  • Seizure in SIS mice is comorbid with psychiatric difficulties.

  • Gabapentin acutely reversed the negative behavioral impacts of early SIS.

  • Chronic gabapentin prevented the shaping of seizure and behavioral abnormalities.

Abstract

Adolescence is a pivotal period of brain development during lifespan, which is sensitive to stress exposure. Early social isolation stress (SIS) is known to provoke a variety of psychiatric comorbidities as well as seizure risk. Psychiatric comorbidities present challenging dilemmas for treatment and management in people with seizure disorders. In this study, we aimed to investigate whether gabapentin (GBP) as an anti-epileptic drug is able to alleviate the seizure activity as well as comorbid behavioral abnormalities in socially isolated mice. Results showed that early SIS induced proconvulsant effects along with depressive, aggressive and anxiety-like behaviors. Whereas the administration of both acute and chronic GBP at sub-effective doses produced no alterations in the behavioral profile of socially conditioned counterparts the same treatments effectively reversed the seizure susceptibility to pentylenetetrazole and behavioral deficits in isolated mice. Results of the study indicate that 1) Early SIS could be considered as an animal model of psychosocial stress to investigate the psychiatric comorbidities in seizure disorders, 2) Chronic administration of low dose GBP prevented the shaping of behavioral abnormalities in adulthood, 3) Chronic administration of low dose GBP produced no negative behavioral effects in socially conditioned mice suggesting the safety of the drug, 4) Gabapentin at low doses may be considered as an agent for management of epilepsy in individuals with psychiatric comorbidities.

Introduction

The developing brain is susceptible to environmental influences and exposure to stressful conditions profoundly affects brain development (Lupien et al., 2009). Adolescence is a pivotal state in cortico-limbic development and is associated with maturation of behavioral and cognitive abilities (Andersen and Teicher, 2008, Paus, 2005). Ample evidence indicates that experiencing psychological stress during adolescence potently predisposes the development of psychiatric difficulties in adulthood (Fone and Porkess, 2008). Evidence is accumulating that epilepsy is associated with incidence of psychiatric disorders (Kanner et al., 2012, Thapar et al., 2009). Psychiatric comorbidities in seizure disorders are accompanied by notable burden in morbidity, management of patients, treatment and quality of life (Fazel et al., 2013, McCagh et al., 2009). Anxiety and depression are of most prevalent psychiatric comorbidities which occur which occur 4–5 more often in subjects with seizure disorders than in normal populations (Maguire and Salpekar, 2013). Surprisingly, although there is a large body of evidence indicating the importance of psychiatric comorbidity in seizure disorders, fewer studies have focused on the treatment of such comorbidities (Kanner, 2003, Swinkels et al., 2005).

Recently, we showed that early social isolation stress (SIS) provoked seizure risk along with affective behavioral dysfunctions in adult mice (Amiri et al., 2014). Early life stress is known to increase the risk of epileptogenesis and occurrence of psychiatric comorbidities (Huang, 2014, Jones et al., 2014). It has been suggested that applying animal models such as early SIS provides conditions to investigate the psychopathological similarities which are observed in humans (Nestler and Hyman, 2010).

There is a large body of evidence, which indicates that anti-epileptic drugs have positive effects on mood and behavior (Perucca and Mula, 2013, Russo et al., 2013). Gabapentin (GBP), as an anti-epileptic drug with normothymic properties, is structurally similar to γ-aminobutyric acid (GABA). Increasing lines of research suggest that GBP has therapeutic effects in mental disorders including mood and anxiety disorders (Perucca and Mula, 2013). Gabapentin is known to reduce the neural excitability in the central nervous system via binding to α2-δ subunit of voltage-gated calcium channels leading to a decrease in excitatory neurotransmission. Also, GBP has an ability to increase ambient GABA levels in the brain indicating its effects on alteration of GABA synthesis or release (Brickley and Mody, 2012, Honmou et al., 1995). However, the mechanism of action of GBP is not clear well (Sills, 2006).

In this study, as early SIS induces proconvulsant effects along with affective behaviors in mice, we aimed to investigate whether GBP is able to attenuate the proconvulsant effect of SIS along with psychiatric comorbidities in male mice. GBP was used in this study because it is a safe drug with minor side effects and has a high therapeutic index (Arif et al., 2009, Perucca and Mula, 2013).

Section snippets

Animals and housing conditions

Male NMRI mice weighing 10–12 g on postnatal day 21 (PND: 21) (Pasteur Institute, Tehran, Iran) were used. Animals were housed under standard conditions (temperature: 22±2 °C, humidity: 50±10%, 12-h light–dark cycle, and free access to food and water) for 4 weeks in two conditions: social condition (SC) and isolated condition (IC). Socially conditioned mice were housed (6 per cage) in Plexiglas cages (25 cm×25 cm ×15 cm) while IC mice were housed individually in Plexiglas cages (24 cm×17 cm ×12 cm) in

Effects of different housing conditions and GBP treatments on the seizure threshold dose of PTZ

As shown in Fig. 1A, t-test revealed that SIS significantly decreased the seizure threshold in comparison with SC mice (t=10.65 df=10, P<0.001). Acute treatment with different doses of GBP 60 min before the test significantly increased the seizure threshold in the PTZ-induced seizure in SC and IC animals (F (7, 52) =14.831, P<0.001, Fig. 1B). The Tukey's post hoc test showed that acute injection of GBP significantly increased the seizure threshold in SC mice at doses 3 and 5 mg/kg (P<0.05 and

Discussion

In this study, we showed that early SIS provoked a variety of behavioral abnormalities relevant to depression, anxiety and aggressiveness. In addition, behavioral alterations in adult IC mice correlated with increased seizure susceptibility to PTZ. Results of this study also demonstrated that administration of GBP (acute and chronic) reversed the proconvulsant effects of early SIS as well as psychiatric comorbidities. However, the same treatment with GBP produced no behavioral alteration in the

Conclusion

Taken together, in this study we found that chronic administration of GBP during adolescence not only had no adverse effect on the behavioral profile of SC mice but also reversed the seizure susceptibility and psychiatric comorbidities in IC mice. Results of this study provided preliminary evidence that GBP (at lower doses than therapeutic dose) despite having anti-epileptic properties also possesses protective effects against long-term consequences of psychological stress. In future studies,

Acknowledgment

This study was supported by a research Grant (NO: 28088) from Tehran University of Medical Sciences, Tehran, Iran. The authors would like to thank Prof. Ahmad Reza Dehpour for his collaboration on this study.

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