Valproic acid improves the tolerance for the stress in learned helplessness rats
Highlights
► We produced animals with depressive-like behaviors using the learned helplessness paradigm. ► We investigated preventive effects of valproic acid on recurrence of depressive-like behaviors. ► Valproic acid significantly reduced immobility time in forced swimming test. ► Synapsin I was increased only in learned helplessness rats. ► Valproic acid may have a preventive effect on the recurrence of depressive symptoms.
Introduction
Major depressive disorder is one of the most common and serious health problems in societies worldwide. Appropriate pharmacological or psychotherapeutic treatments are becoming accessible to increasing numbers of patients. Nevertheless, it is still associated with high rates of relapse and recurrence during a patient's lifetime. Although the average rate of recurrence in patients continuing with antidepressants was found to be 10%, their discontinuation resulted in an increase in this rate to 30% (Hirschfeld, 2001). Thus, a better understanding of the biological basis of recurrence is needed to reduce this rate.
The hippocampus is important in cognitive processes such as learning and memory (Eichenbaum et al., 1996). Several magnetic resonance imaging (MRI) studies have demonstrated decreased volume of the hippocampus in patients with major depression (Mervaala et al., 2002). Preclinical studies have shown that exposure to stress causes a range of changes in neuronal elements of this structure. These include shrinkage of apical dendrites of CA3 pyramidal neurons (Magariños et al., 1996), downregulation of neurogenesis in dentate gyrus and putative glial changes (Czéh and Lucassen, 2007 for a review). Moreover, synapse-related components in the hippocampus have also been found to be affected functionally and morphologically by stress conditions (Sousa et al., 2000, Rosenbrock et al., 2005). Antidepressants were shown to reverse some of the adverse effects of stress on the synaptic/dendritic structure in this brain region (Sairanen et al., 2007). Taken together, these results indicate enormous vulnerability to stress of the synaptic structures in the hippocampus and the ability of antidepressants to reverse the disadvantageous changes.
Learned helplessness (LH) paradigm is thought to be an animal model of depression (Seligman and Beagley, 1975). It has been well documented that LH rats present behavioral and neurochemical abnormalities that appear to be associated with depression (Martin et al., 1990). Iwata et al. (2006) showed that the expression of synapsin I (presynaptic marker) was decreased and that of microtubule-associated protein-2 (MAP-2, postsynaptic marker) was increased in animals about a week after the attainment of LH. In addition, Reinés et al. (2008) reported that the LH paradigm caused a reduction in the expression of synaptophysin (presynaptic marker) and postsynaptic density 95 (PSD-95: postsynaptic marker). Furthermore, antidepressants reversed both behavioral despair and their expressions to control levels, suggesting that antidepressants could alleviate behavioral and neurochemical changes in LH animals.
Valproic acid (VPA) is broadly accepted to prevent manic or depressive recurrences in patients with bipolar disorder (Gyulai et al., 2003). In addition, the drug has preclinically been shown to reduce immobility time, a key measure of behavioral despair in animal model of depression, suggesting antidepressant effects of VPA (Fernández Teruel et al., 1988). However, it is not known whether VPA could prevent the recurrence of depressive episodes in patients with unipolar depressive disorder.
In this study, we designed two-stage experimental protocols to address the recurrence-preventive effects of VPA using animals showing behavioral remission from LH. First, we produced animals with depressive-like behaviors using the LH paradigm, and then investigated whether or not such behaviors would be reduced four weeks after LH induction. We indeed confirmed the animals’ behavioral improvement, which appeared to be closely related to remission in the clinical setting. Second, we administered either VPA or Saline for 21 days to those animals thereafter and assessed vulnerability to stress behaviorally using forced swimming test (FST) as well as the neurochemical changes in the hippocampus in terms of brain-derived neurotrophic factor (BDNF), presynaptic protein marker (synapsin I) and postsynaptic marker (MAP-2).
Section snippets
Animals and drugs
Animal-use procedures were in accordance with the Tottori University Guide for the Care and Use of Laboratory Animals and were approved by the Tottori University Animal Care and Use Committee. All experiments conformed to international guidelines on the ethical use of animals. The number of animals used and their suffering were minimized.
A total of 172 adult (12-week-old) male Sprague–Dawley rats weighing 250–300 g at the beginning of the experiments were used. They were housed under a 12 h
Confirmation of behavioral improvement in depressive-like behaviors
After the recovery period of 28 days, on day 32 of the entire experimental schedule, we evaluated the behavior of the Control and LH rats. Fig. 2A and B shows results of a two-way conditioned avoidance behavior test and FST, respectively. There was no statistically significant difference between Control and LH rats in the failure numbers during the two-way conditioned avoidance test (p = 0.31, Student's t-test) or immobility time during FST (p = 0.90 Student's t-test). These results suggest that LH
Discussion
The main findings in the present study are as follows: (1) depressive-like behaviors, which were caused by the LH paradigm and subsequently assessed using either conditional avoidance test or FST, disappeared within 28 days following its induction, indicating that LH animals then exhibited behavioral remission. (2) There were main reducing effects of repeated treatment with VPA (200 mg/kg) for 21 days on depressive-like behaviors assessed on day 54. These effects were statistically significant
Acknowledgement
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.
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