Repeated electroconvulsive stimuli have long-lasting effects on hippocampal BDNF and decrease immobility time in the rat forced swim test
Introduction
Electroconvulsive therapy (ECT) is a well-known non-pharmacological antidepressant that is effective for the treatment of severe depression. Clinical study reported that onset of tricyclic antidepressants (e.g. imipramine) or selective serotonin reuptake inhibitors (SSRIs)'s action requires at least 2 weeks of therapy (Artigas et al., 1994, Blier and Bergeron, 1995, Katz et al., 2004). In addition, it is advised that continuation of antidepressant treatment should last a minimum of 3–6 months following acute response, because there is high risk of relapse in this period (Keller, 1999, Hirschfeld, 2000). In contrast to long-term treatment of pharmacological antidepressant, 5 to 10 repeated of ECT produce a fast onset of action and long-lasting attenuation of disease symptoms (Weiner, 1989). A clinical study also reported that the effect of ECT was unusually long-lasting and persisted for at least 6 months after the last treatment (Pettinati et al., 1994). Moreover, it is reported that major depression in patients treated with ECT reduced length and cost of hospital stay compared with tricyclic antidepressant or other medication (Markowitz et al., 1987).
BDNF is a member of the neurotrophin superfamily with a recognized role in development, neural regeneration, synaptic transmission, synaptic plasticity and neurogenesis, mossy fiber sprouting (Malberg et al., 2000, Pencea et al., 2001, Schinder and Poo, 2000, Thoenen, 1995, Zigova et al., 1998, Vaidya et al., 1999). Clinical, pharmacological and animal studies support the hypothesis that BDNF is involved in the pathophysiology of depression. Repeated administration of fluoxetine, desipramine, tranylcypromine and ECS treatments enhance BDNF mRNA in the rat brain (Nibuya et al., 1995, Jacobsen and Mork, 2004). ECS, tranylcypromine and lithium treatment also increases BDNF protein in the rat brain (Altar et al., 2003, Fukumoto et al., 2001, Jacobsen and Mork, 2004). In animal behavior study, it was reported that the infusion of BDNF into the intraventricular, dorsal raphe and hippocampus reduces the learned helplessness, the forced swim test and inescapable shock models, indicating an antidepressant-like effect in rats (Shirayama et al., 2002, Siuciak et al., 1997). In humans, BDNF protein immunoreactivity was elevated in postmortem tissue from antidepressant treated patients (Chen et al., 2001) and a reduced BDNF mRNA level was also reported in both the prefrontal cortex and hippocampus in the postmortem brains of suicide subjects study (Dwivedi et al., 2003). These and related findings suggest a role for BDNF protein in the etiology and treatment of depression (Altar, 1999, Duman et al., 1997).
We previously investigated that repeated ECS treatment decreased the immobility time in the rat forced swim test and increased BDNF protein in the hippocampus (Li et al., 2006). However, there is little known effect of withdrawal from ECS on immobility time in the forced swim test and BDNF protein in the hippocampus. In the present study, we investigated whether or not withdrawal from ECS has a decreasing effect of immobility time in the forced swim test in rats, and also examined the effect of ECS on BDNF protein levels.
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Animals
Male Wistar strain rats (8–10 weeks of age, 300–330 g at the time of testing) were obtained from Charles River (Yokohama, Japan). All animals were housed in an animal room maintained at 22 ± 1 °C under a 12 h/12 h light/dark cycle with lights on from 7:00. Food and water were available ad libitum. Experiments began after 1-week period of acclimatization. Animal experiments were performed in compliance with the Guidelines for Animal Experimentation and with the approval of the Committee of Animal
Effect on locomotor activity in rats
Fig. 1 shows that the locomotor activity in the open-field test. One-way ANOVA showed a significant effect of ECS treatment [F5, 36 = 4.237, p < 0.01]. Locomotor activity was significantly (p < 0.01) increased 6 h after the last ECS treatment and the increased effect persisted during 7 days of the test period.
Effect on immobility time in the forced swim test in rats
Fig. 2 shows that the effect of repeated treatment of ECS on the immobility time in the forced swim test. One-way ANOVA showed a significant effect of ECS treatment [F5, 36 = 4.680, p < 0.01].
Discussion
Previous studies have reported that acute ECS treatment failed to produce a decrease of immobility time in the rat forced swim test (Kawashima et al., 1987), and that repeated ECS treatment had the decreasing effect of immobility time 24 h after last ECS treatment in rats or mice (Kawashima et al., 1987, Suzuki and Masuda, 1999, Li et al., 2006). In the present study, we confirmed that the decreasing effect of immobility time not only decreased 24 h after, but also decreased 3 days after the
Acknowledgment
This work was supported in part by the Japanese Health Science Foundation and a Grant-in Aid for Scientific Research (No. 17590127) from the Japanese Ministry of Education, Science, Sports and Culture in Japan, and the Uehara Memorial Foundation.
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