Neurol Ther DOI 10.1007/s40120-013-0015-0 ORIGINAL RESEARCH Chronic Treatment with the 5-HT1A Receptor Partial Agonist Tandospirone Increases Hippocampal Neurogenesis Masayoshi Mori • Yusuke Murata • Asami Matsuo • Tomoyo Takemoto • Kazunori Mine To view enhanced content go to www.neurologytherapy-open.com Received: October 15, 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com ABSTRACT depression and anxiety. The present study aimed to elucidate whether or not 5-hydroxytryptamine Introduction: A large-scale clinical trial, the 1A (5-HT1A) receptor partial agonists have a Sequence Trial Alternatives to Relieve potential therapeutic effect for the treatment of Depression (STAR*D) study, concluded that depressive and anxiety disorders, from the about one-third of the studied patients with standpoint of neurogenesis. major depressive disorder remitted during the Methods: Male Sprague–Dawley rats were initial treatment with selective serotonin subcutaneously administered a vehicle or reuptake inhibitors and that approximately half tandospirone (TDS) (1 or 10 mg/kg) once daily of the remitted subjects relapsed over a 1-year for 14 days. The effects of chronic TDS treatment follow-up. The development of new therapeutic on neurogenesis were evaluated on the day after approaches with potent efficacy and good the last injection. The quantification of tolerability for the treatment of depressive hippocampal neurogenesis was estimated using disorders is of great importance. Adult immunostaining with doublecortin (DCX), a hippocampal neurogenesis has been proposed to marker protein of newborn neurons. be important for understanding and treating Results: Chronic TDS treatment resulted in a significant increase in the number of DCX- Electronic supplementary material The online version of this article (doi:10.1007/s40120-013-0015-0) positive cells per volume of dentate gyrus in a contains supplementary material, which is available to dose-dependent manner. authorized users. Conclusion: The results strongly suggest that M. Mori Á Y. Murata (&) Á A. Matsuo Á T. Takemoto 5-HT1A receptor partial agonists would be Department of Psychosomatic Medicine, Faculty of useful and beneficial in the treatment of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, depressive and anxiety disorders through Japan increased hippocampal neurogenesis. e-mail: [email protected] K. Mine Keywords: 5-HT1A receptor partial agonist; Faculty of Neurology and Psychiatry, Mito Hospital, Shime-Higashi, Shime-Machi, Kasuya-Gun, Chronic treatment; Clinical efficacy; Fukuoka, Japan Neurol Ther Depression and anxiety; Dose dependent; neurons occurs throughout the lifetime of Doublecortin; Hippocampal neurogenesis; animals, including humans [8, 9]. Novelty suppressed feeding; Tandospirone Accumulating evidence shows that adult hippocampal neurogenesis is decreased by INTRODUCTION stress and increased by chronic administration of antidepressants, such as fluoxetine [10, 11]. Depression and anxiety are common public Thus, changes in adult hippocampal health problems, affecting 5–10% of the neurogenesis may be related to the world’s population at any given time, and pathophysiology of depressive and anxiety they share a high degree of comorbidity (up to disorders and to the beneficial effects of 80–90%) [1]. Although there are a number of antidepressant treatment [7, 9, 12, 13]. medications available for the treatment of The azapirone drugs, including buspirone, depressive and anxiety disorders, a tandospirone (TDS), and gepirone which act as considerable number of patients cannot 5-hydroxytryptamine 1A (5-HT1A) receptor achieve remission [2]. The Sequenced partial agonists, have been widely used in the Treatment Alternatives to Relieve Depression treatment of anxiety disorder [14, 15]. In (STAR*D) study, a large-scale clinical trial for practice, benzodiazepines are most frequently major depressive disorder (MDD), demonstrated used in combination with standard that only about one-third of the participants antidepressants for the initial treatment and remitted during the initial treatment with maintenance therapy for depressive disorders citalopram and that approximately half of the when comorbid anxiety exists [16]. We and remitted participants relapsed over a 1-year many other researchers have shown that follow-up [3–5]. Baldwin et al. [6], in a review benzodiazepines produce drug dependence, of previous studies of pharmacotherapies for sedation, and cognitive impairment in generalized anxiety disorder (GAD), concluded humans and rodents [17–20]. In contrast, that the remission rate is less than 60% for GAD azapirone-type 5-HT1A receptor agonists have patients treated with selective serotonin the advantage of producing significantly fewer reuptake inhibitors (SSRIs). Therefore, the adverse effects than benzodiazepines and result development of effective new therapeutic in little dependence [21–23]. Recently, two approaches with good tolerability for the animal studies revealed that co-administering treatment of depressive and anxiety disorders benzodiazepines with antidepressants prevents is of great importance. an SSRI-induced increase in hippocampal Adult hippocampal neurogenesis has been neurogenesis, which suggests that the use of proposed as important for understanding and benzodiazepines delays the therapeutic onset treating depression and anxiety [7]. The and reduces the clinical efficacy of SSRIs [24, hippocampus is not only involved in cognitive 25]. In contrast to above reports concerning functions, but also is a key structure for benzodiazepines, 5-HT1A receptor agonists are regulating affective and anxiety states. The considered to have an augmenting effect on subgranular zone (SGZ) in the dentate gyrus clinical efficacy for depressive disorders when (DG) of the hippocampus is one of only a few administered in combination with an SSRI. brain regions where the production of new Recently, several authors have reported that Neurol Ther augmentation therapy consisting of a effect of 5-HT1A receptor agonists on combination of antidepressants with 5-HT1A neurogenesis, Banasr et al. [30] and Soumier receptor agonist treatment is a better et al. [31] showed increased granule cell genesis therapeutic strategy for MDD than in the DG during treatment with 8-hydroxy-2- antidepressant monotherapy [3, 26, 27]. dipropylaminotetralin hydrobromide (8-OH- In our previous pilot study, we showed that DPAT), a 5-HT1A receptor full agonist. TDS, the only azapirone drug available in Japan, However, 8-OH-DPAT is a chemical reagent has excellent clinical efficacy for the treatment that is not available for clinical use. Of of GAD and mixed anxiety–depression and that interest, Radley and Jacobs [32] reported that it has no significant adverse effects [28]. We also the acute administration of 5-HT1A receptor showed that TDS had a remarkable anxiolytic full antagonist WAY100635 decreased effect in an animal model of anxiety and that neurogenesis in the DG. the potency of the pharmacological effect was Based on previous reports by many authors increased dose dependently, without a sedative and our studies described above, we effect [23]. hypothesize that hippocampal neurogenesis In addition, we conducted a preliminary plays an important role in the clinical efficacy clinical study about the efficacy of of 5-HT1A receptor partial agonists. augmentation therapy consisting of a This study aimed to elucidate the potential combination of paroxetine and TDS therapeutic effect of 5-HT1A receptor partial (Sakamoto et al., unpublished data). In that agonists in the treatment of depressive and study, among a consecutive series of 37 anxiety disorders, from the standpoint of patients with MDD who were treated with neurogenesis. the combination of paroxetine and TDS, 29 subjects (78.4%) achieved remission at 12 weeks after the start of treatment. METHODS Furthermore, our 4-year follow-up study found recurrence in only 5 (17.9%) of 28 Animals patients who had remitted. Thus, 5-HT1A receptor partial agonists, Male Sprague–Dawley rats (Kyudo Co., LTD., clinically available and safe drugs, may have Tosu, Japan) weighing 150–200 g upon arrival great usefulness in the treatment of psychiatric were studied. They were housed individually in illness, such as depression and anxiety. a temperature (23 ± 2 °C), humidity It is well known that 5-HT1A receptors play (60 ± 10%), and light-controlled room (reverse an important role in the regulation of mood, 12-h light/dark cycle, lights off at 7:00 a.m.). anxiety, and cognition [15]. 5-HT1A receptors Food and water were available ad libitum. All also have been shown to regulate hippocampal animal care and use procedures were performed neurogenesis in the SGZ of the DG. Santarelli in compliance with the regulations established et al. [29] showed that 5-HT1A receptor- by the Experimental Animal Care and Use deficient mice did not respond to chronic Committee of Fukuoka University, which are fluoxetine treatment, as measured by the in accordance with the universal principles of change in neurogenesis. Reporting on the laboratory animal care. Neurol Ther Drugs saline (PBS; pH 7.4). The brain was removed from the skull and post-fixed overnight in the Tandospirone citrate was supplied by same fixative at 4 °C, then placed into graded Dainippon Sumitomo Pharma Co., Ltd. concentrations of sucrose in PBS at 4 °C. (Osaka, Japan). The drug was dissolved in Coronal sections of the brain were cut (30 lm saline