Full length articleProtective effects of gabapentin against the seizure susceptibility and comorbid behavioral abnormalities in the early socially isolated mice
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.
References (56)
- et al.
Morphine modulates the effects of histamine H 1 and H 3 receptors on seizure susceptibility in pentylenetetrazole-induced seizure model of mice
Eur. J. Pharmacol.
(2015) - et al.
Experiencing neonatal maternal separation increased the seizure threshold in adult male mice: involvement of the opioid system
Epilepsy Behav.
(2015) - et al.
Involvement of the nitrergic system in the proconvulsant effect of social isolation stress in male mice
Epilepsy Behav.
(2014) - et al.
Co-occurrence of anxiety and depressive-like behaviors following adolescent social isolation in male mice; possible role of nitrergic system
Physiol. Behav.
(2015) - et al.
NMDA receptor antagonists attenuate the proconvulsant effect of juvenile social isolation in male mice
Brain Res. Bull.
(2016) - et al.
Stress, sensitive periods and maturational events in adolescent depression
Trends Neurosci.
(2008) - et al.
Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs
Epilepsy Behav.
(2009) - et al.
Extrasynaptic GABA A receptors: their function in the CNS and implications for disease
Neuron
(2012) - et al.
Anticonvulsant action and long-term effects of gabapentin in the immature brain
Neuropharmacology
(2001) - et al.
Effect of gabapentin (neurotonin®) on mood and well-being in patients with epilepsy
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(1996)
Behaviour in the elevated plus-maze predicts coping after subchronic mild stress in mice
Physiol. Behav.
Correlations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: evidence from inbred strains of mice
Behav. Brain Res.
Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study
Lancet
Behavioural and neurochemical effects of post-weaning social isolation in rodents—relevance to developmental neuropsychiatric disorders
Neurosci. Biobehav. Rev.
Epilepsy and anxiety
Epilepsy Behav.
Lithium attenuated the depressant and anxiogenic effect of juvenile social stress through mitigating the negative impact of interlukin-1β and nitric oxide on hypothalamic–pituitary–adrenal axis function
Neuroscience
The anticonvulsant gabapentin enhances promoted release of GABA in hippocampus: a field potential analysis
Brain Res.
Interaction between sex and early-life stress: influence on epileptogenesis and epilepsy comorbidities
Neurobiol. Dis.
Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment
Biol. Psychiatry
Depression and epilepsy: epidemiologic and neurobiologic perspectives that may explain their high comorbid occurrence
Epilepsy Behav.
Assessment of mouse anxiety-like behavior in the light–dark box and open-field arena: role of equipment and procedure
Physiol. Behav.
Stress, seizures, and hypothalamic–pituitary–adrenal axis targets for the treatment of epilepsy
Epilepsy Behav.
Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems
Pharmacol. Biochem. Behav.
Epilepsy, psychosocial and cognitive functioning
Epilepsy Res.
Mapping brain maturation and cognitive development during adolescence
Trends Cogn. Sci.
Antiepileptic drug effects on mood and behavior: molecular targets
Epilepsy Behav.
Lamotrigine positively affects the development of psychiatric comorbidity in epileptic animals, while psychiatric comorbidity aggravates seizures
Epilepsy Behav.
Neuropeptide S reduces mouse aggressiveness in the resident/intruder test through selective activation of the neuropeptide S receptor
Neuropharmacology
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