Research report
Physical activity–antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model

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Abstract

The mechanism of antidepressant action, at the cellular level, is not clearly understood. It has been reported that chronic antidepressant treatment leads to an up-regulation of brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus, and that physical activity (voluntary running) enhances this effect. We wished to investigate whether BDNF expression brought about by these interventions may overcome deficits caused by acute stress, and might impact behavior in an animal model. In this report, we have tested the hypothesis that the combination of the antidepressant, tranylcypromine, and physical exercise could lead to decreased neurotrophin deficits and enhanced swimming time in animals that have been forced to swim in an inescapable water tank. Rats were either treated with tranylcypromine, engaged in voluntary running, or both for one week. After these treatments, the animals underwent a two-day forced swimming procedure. BDNF mRNA levels were significantly depressed in untreated animals subjected to forced swimming. Animals that either underwent prior activity or received antidepressant showed BDNF mRNA levels restored to baseline. Animals receiving the combined intervention showed an increase in hippocampal BDNF mRNA well above baseline. Swimming time during a five-minute test was significantly enhanced in animals receiving the combined intervention over untreated animals. Swimming time was not significantly enhanced over that of animals receiving antidepressant alone, however. Enhanced swimming time correlated with increased levels of BDNF mRNA in one hippocampal sub-region (CA4-hilus). These results suggest that the combination of exercise and antidepressant treatment may have significant neurochemical, and possibly behavioral, effects. In addition, these results support the possibility that the enhancement of BDNF expression may be an important element in the clinical response to antidepressant treatment. The induction of BDNF expression by activity/pharmacological treatment combinations could represent an important intervention for further study, to potentially improve depression treatment and management.

Introduction

Brain-derived neurotrophic factor (BDNF), the most abundant of the neurotrophins in the brain, enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in use-dependent plasticity mechanisms such as long-term potentiation and learning [12], [20], [21]. In recent years, evidence has been gathering that BDNF expression may be a downstream target of catecholamine-enhancing, mood-stabilizing antidepressant treatments, and could be an important agent for therapeutic recovery from depression and the protection against stress-induced neuronal damage. The direct infusion of BDNF has been shown to lead to the recovery of hallmark behavioral deficits in depression-model animals [41]. Moreover, chronic treatment with a variety of antidepressant medications has been shown to up-regulate BDNF mRNA levels in the rat hippocampus and cerebral cortex [27]. Hippocampal BDNF has also been shown to be down-regulated in response to stress [42]. Both clinical and animal studies have indicated that prolonged and severe stress may play an important role in the pathophysiology of depression and other psychiatric disorders. Neuronal atrophy and death have been observed in the hippocampi of animals exposed to chronic stress [35], [44], and animals subjected to stress also show behavioral changes associated with a depressive state [2], [31]. Humans with a history of chronic, recurrent depression or post-traumatic stress disorder have shown significant hippocampal atrophy in imaging studies [4], [38].

Physical activity has been evidenced to lead to improvements in psychiatric status in some human clinical reports [15], [18]. In recent studies, physical activity appeared to both enhance and accelerate the BDNF up-regulation brought about by antidepressant treatment in the rat [34], [37]. After 1 week, levels of two BDNF mRNA transcripts were found to be significantly higher with the combination of exercise and antidepressant than with each intervention alone [34].

In this study, it is our aim to assess whether the enhancement of BDNF expression brought about by antidepressant treatment, exercise and the combination could overcome diminishment brought about by acute stress, and whether this enhancement could be associated with behavioral change in an animal model. We have assessed the immobilization time during forced swimming in a water tank in the absence of a platform (similar to Porsolt et al. [30]), a paradigm that is known to be stressful to animals [1], [17], [22]. Animals underwent forced swimming after one week of treatment with tranylcypromine, one week of exercise, or the combination of these two interventions. A fourth group of animals underwent the forced swim procedure after no treatment, and a sedentary control group was not subjected to forced swimming. Quantitative in situ hybridization was performed to assess hippocampal BDNF mRNA levels in these groups, and to test the hypothesis that behavioral improvement (decreased immobilization under stress) may correlate with BDNF mRNA expression in this brain area.

Section snippets

Animal subjects

Male Sprague–Dawley rats of approximately 3 months of age (source: Charles River) were housed singly with food and water ad libitum and a 12:12 h (06:00–18:00 h) light/dark cycle. The rats were allowed to acclimate to the vivarium for one week prior to the start of experiments. All animal use procedures, described below, were in strict accordance with the National Research Council's guide for the Care and Use of Laboratory Animals (1996), and all efforts were made to minimize the number of

BDNF mRNA levels were significantly down-regulated after the forced swim procedure

Quantitative in situ hybridization for BDNF mRNA in untreated animals revealed depressed mRNA levels in all hippocampal cellular fields after the 2 day forced swimming procedure (see Fig. 1 for example autoradiographs). ANOVA comparing BDNF mRNA levels in the various animal groups revealed a significant difference in several hippocampal areas: CA1 [F(4,30)=5.243, P=0.0025], CA3 [F(4,30)=7.257, P=0.0003], CA4 [F(4,30)=14.343, P<0.001] and DG (dentate gyrus) [F(4,30)=6.123, P=0.001]. BDNF mRNA

Discussion

The improvement of behavioral management, and a greater understanding of the mechanisms of antidepressant treatments, is an essential goal. In recent years, much evidence has emerged that BDNF plays a significant role in the maintenance and function of neurotransmitter systems involved in the pathology and treatment of mental disorders, and may itself have therapeutic effects [7], [23], [40], [41]. It has been demonstrated that general physical activity [26] and antidepressant treatment [27]

Acknowledgements

Thanks to Kenneth Chuang for assistance with behavioral testing. This work has been supported by US Public Health Service Grant MH-59776 to ARN, AG-13880 to JPK, and a NARSAD Young Investigator Award to ARN.

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