Testosterone decrease does not play a major role in the suppression of hippocampal cell proliferation following social defeat stress in rats Bauke Buwalda a, ⁎, Karin van der Borght a , Jaap M. Koolhaas a , Bruce S. McEwen b a Behavioral Physiology, University of Groningen, P.O. Box 14, 9750AA HAREN, The Netherlands b Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA abstract article info Article history: Received 30 March 2010 Received in revised form 13 August 2010 Accepted 16 August 2010 Keywords: Testosterone supplementation Proliferation Survival Resident-intruder Corticosterone Social stress Stress of social defeat in rodents is known to have a strong and long-lasting effect on brain, physiology and behavior, which bears similarities with certain human stress related psychopathologies. Previous experiments in this lab showed that social defeat stress suppresses testosterone secretion and causes a lasting desensitization of the serotonergic 5-HT 1A receptors. Testosterone supplementation in socially stressed tree shrews prevented a decrease in hippocampal 5-HT 1A receptor binding. These receptors are hypothesized to play an important role in neurogenesis in this brain structure. We designed the present experiment to test if social defeat reduces hippocampal cell proliferation and neurogenesis in rats and if testosterone supplementation can prevent this reduction. The results indicate that repeated social defeat stress on 5 successive days induces a significant drop in plasma testosterone levels in male rats and suppresses hippocampal cell proliferation 24 h and 3 weeks after the end of the stress period. Testosterone supplementation prevented the social stress induced drop in plasma testosterone levels. The hormone supplementation also reduced the negative effect of stress on hippocampal BrdU labeling at 3 weeks post- defeat. This effect was, however, rather weak and was caused by the tendency of the hormone in itself to suppress proliferation and the failure to fully recover the proliferation rate. Survival of dentate gyrus cells that either proliferated prior to the stress period or 24 h after the last defeat was not affected by the social defeats. Thus the stress-induced lowering of hippocampal cell proliferation is not likely to be caused by transient inhibition of testosterone secretion during social stress. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Stressful life events are considered to play an important role in the etiology of human mood disorders [1]. Depending on the character- istics of the stressor even short-lasting events potentially can induce structural and functional alterations in various brain regions that subsequently lead to changes in physiology and behavior for a long time after the actual stressor is gone [2]. One of the most intensively studied brain structures with regard to stress-induced neuronal plasticity is the hippocampal formation. It has been shown that stress causes reductions in hippocampal apical dendritic length and the number of branch points [3,4]. Furthermore, cell proliferation and neurogenesis in the hippocampal dentate gyrus is at least temporarily inhibited by certain types of stress [5,6]. Adrenocortical corticosterone release plays an important role in this stress-induced reduction of cell proliferation [7–9]. The majority of the newly formed cells, however, initially have no glucocorticoid or mineralocorticoid receptors [10]. It has been suggested that cortico- sterone may regulate proliferation indirectly via other local cells in the dentate gyrus [11]. One of the neurotransmitters that are known to be affected by corticosterone is serotonin [12–14]. The effects of corticosterone on hippocampal neurogenesis may be mediated in part through its effect on this neurotransmitter. Selective serotonin reuptake inhibitors (SSRIs) were shown to potently stimulate hippocampal cell proliferation [15,16] and to stimulate the matura- tion [17] of these adult-born cells. Serotonergic neurotransmitter release might play a crucial role in this since lowering serotonergic input to the hippocampus decreases cell proliferation in the hippocampus [18,19] and the serotonergic 1A (5-HT 1A ) receptor is the most likely receptor candidate for this effect [20–22]. Stress [23] and corticosterone [24] have been shown to reduce 5-HT 1A receptor binding in the dentate gyrus. We have shown before that social stress also impairs 5-HT 1A functionality [25]. Other studies indicate that also social stress inhibits hippocampal cell proliferation [26,27]. During social defeat stress, testosterone (T) levels are lastingly suppressed in defeated male rats [28]. Since corticosterone inhibits testosterone-biosynthetic activity [29] it is likely that the stress-induced increase in adrenal glucocor- ticoid release is involved in this suppression. A study in chronically stressed tree shrews showed that testosterone supplementation Physiology & Behavior 101 (2010) 719–725 ⁎ Corresponding author. Tel.: + 31 50 3632352; fax: + 31 50 3632331. E-mail address: b.buwalda@rug.nl (B. Buwalda). 0031-9384/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2010.08.010 Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/phb