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BEHAVIORAL PHARMACOLOGY
Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland
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Abstract |
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; Kendler et al., 2004). Consistent historically and across cultures, depression, the leading cause of disease-related disability among women in the world, occurs twice as frequently in women as in men (Kornstein et al., 2000; Piccinelli and Wilkinson, 2000; Angst et al., 2002; Bebbington et al., 2003; Kessler, 2003). This prominent gender difference in major depression begins in adolescence, prior to which the rates of major depression are equal in girls and boys, suggesting the potential role of estrogen fluctuation in female depression vulnerability (Payne, 2003). The female preponderance of the disorder, however, has heretofore not been reflected in animal models. On the contrary, male animals show more immobility than females in the forced swimming test (Alonso et al., 1991; Contreras et al., 1995; Marvan et al., 1996; Barros and Ferigolo, 1998). The learned helplessness model of depression has also been reported to induce either more escape impairment in male animals (Steenbergen et al., 1989) or no sex-based difference (Setnik et al., 2004).
The novel open space swim test (OSST) used here consists of three daily inescapable trials that induce in rats a nonsearching immobility (Sun and Alkon, 2003, 2005). Unlike the forced swim test, the OSST provides sufficient space for rats to swim and develop and execute escape strategies. In addition, no human judgment and scoring are involved. The induced depressive behavior is sensitive to the three prototypic classes of antidepressants (prototypic monoamine reuptake inhibitors, monoamine oxidase inhibitors, and atypical antidepressants) and the second-generation antidepressants, the selective serotonin reuptake inhibitors (Sun and Alkon, 2003) but not to buspirone, an anxiolytic (Sun and Alkon, 2004), when the agents are introduced in the depression-induction phase. Chronic treatment of this induced rat immobility with antidepressants, starting after the immobility behavior is established, also requires weeks of antidepressant treatment to achieve the effectiveness (Sun and Alkon, 2004), a response pattern resembling the human disorder clinically. Thus, the OSST provides an animal model in which long-term effects of antidepressants can be followed and determined individually (Sun and Alkon, 2004), including a direct evaluation of whether a particular antidepressant treatment can actually cure the disorder (maintenance of behavioral recovery after discontinuation of the treatment). In this study, we further investigate whether rats exhibit a gender and estrous cycle-dependent differential vulnerability, and if so, whether sex and stress-related hormones and neurotrophic factor may be involved. Our results show that there is a gender- and estrous cycle stage-dependent difference in vulnerability to OSST induction of the depressive behavior in rats and that the induced depressive behavior is associated with impaired performance in the passive avoidance task. The induced depressive behavior in the males and females, however, converges on its sensitivity to glucocorticoid receptor antagonism, inhibition of protein synthesis, and antidepressant treatment.
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Materials and Methods |
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OSST. Rats were placed individually in a round pool, which had a diameter of 152 cm and height of 60 cm and was filled with 40 cm of H2O (24 ± 1°C). No escape was provided in the OSST trials. Rats were free to swim (or not) for 7, 11, or 15 min (the particular set of trial length for each group) and were then returned to their home cages after drying. The observer(s) were obscured from sight of the rats but were able to observe the animals' behaviors on-line (Video Monitor BWM9; Javelin Electronics Inc., Los Angeles, CA). The same procedure with the same set of trial length for each group was followed 24 h later for 2 more days. For instance, the OSST trials for 11-min groups consisted of three consecutive trials at a frequency of one trial per day (11 min/trial). The swimming/drifting path and distance were recorded with a video-tracking system (Poly-Track Video Tracking System; San Diego Instruments, Inc., San Diego, CA). Imipramine was administered (10 mg/kg, i.p.) 23, 3, and 1 h before the second and third OSST trials. To determine a potential involvement of sex hormones in the gender-related vulnerability to OSST, we evaluated the effects of male sex hormone in females and female sex hormone in males on their sensitivity to OSST, respectively. Estradiol or androsterone was administered at 200 µg (s.c.), starting 8 days before the first OSST trial. This was followed with two more doses administered every third day after the previous injection, with the last (the third) dose administered the day before the first OSST trial. Mifepristone and spironolactone (20 mg/kg, i.p.) were administered immediately after the first trial and 1 h before the second and third trials. Anisomycin was injected (40 mg/kg, i.p.) immediately after the first and second trials. BDNF was administered bilaterally (1 µg/µl/side i.c.v.) approximately 0.5 h after the first and second trials. For i.c.v. injections, agents were solubilized in artificial cerebrospinal fluid consisting of 125 mM NaCl, 3 mM KCl, 1.3 mM MgSO4, 2.4 mM CaCl2, 26 mM NaHCO3, 1.25 mM NaH2PO4, and 10 mM glucose. Estradiol, mifepristone, and spironolactone were solubilized in dimethyl sulfoxide and diluted/suspended with a 2-fold volume of saline. The other pharmacological agents were solubilized in saline. The control rats received appropriate vehicle injections.
A short OSST version consisting of three 400-s trials at intervals of 2 h between the trials was used for an evaluation of the vulnerability of female rats to depression induction at a particular estrous cycle stage. In this test, imipramine was administered at 15 and 10 mg/kg (i.p.) 1 h before the second and third trials, respectively.
Estrous Cycle Stage Verification. In the short OSST version test, which was completed in a day, female rats were used after at least one and usually two complete and regular 4-day estrous cycles and determined daily and followed for each rat. Vaginal samples were collected between 12:00 PM and 1:00 PM by gently immersing a sterile cotton-tipped applicator in physiological saline. Animals with vaginal smears that contained predominantly leukocytes (
60%) and numerous large nucleated epithelial cells were classified as metestrus. Diestrous smears contained relatively few cells of any type (60% leukocytes and occasional nucleated epithelial cells). Smears that contained primarily nucleated epithelial cells (60%) and few leukocytes (
10%) were classified as proestrous. Smears that contained primarily cornified cells (90%) were classified as estrous.
Passive Avoidance Learning and Memory Task. An avoidance apparatus (Gemini II Avoidance System; San Diego Instruments, Inc.) was used for the multitrial passive avoidance task (Sun and Alkon, 2004). The task consisted of two trials: an acquisition trial and a retention trial. In the acquisition trial, 24 h after the last OSST trial, the rat was placed individually in the compartment on the right side (the initial compartment). The intercompartment door was opened after a 60-s acclimation period. At the same time, the house light and tone in the initial compartment were also automatically switched on. If the rat stepped into the dark compartment on the left side (the dark compartment), the door was closed automatically and an inescapable foot shock (0.3 mA/2 s) was delivered through the grid floor of the dark compartment. After receiving the foot shock, the rat was returned to the initial compartment. The same acquisition procedure was repeated until the rat stayed in the initial compartment for 120 s. The number of training trials needed for the rat to stay in the initial compartment for 120 s was used as the index of learning acquisition.
The retention trial started 24 h after the end of the acquisition trial. Each rat was placed individually in the initial compartment. The door was opened after a 60-s acclimation period, with house light and tone being switched on automatically at the same time. The step-through latency in the retention trial (with a maximum 300-s cut-off time) was used as the index of retention of the learned experience.
For evaluation of the effects of antidepressants and other agents on depression-related impact on the multitrial passive avoidance task, all agents were administered during the OSST phase (imipramine) or pre-OSST trials (estradiol and androsterone), as described above. Agents-only control groups received the same doses of agents with the same injection schedules as the test groups. These control rats were also brought to the OSST trial room (although without subjecting to the OSST trials) during the OSST trial days. No agents were administered during the multitrial passive avoidance task.
In Vivo Cannulation. Rats were anesthetized with sodium pentobarbital (60 mg/kg, i.p. with supplemental doses if necessary) and placed in a stereotactic apparatus (Kopf Instruments, Tujunga, CA). The core temperature of rats was monitored and kept constant (38.0 ± 0.5°C) with a warming light. Two stainless steel guide cannulas were placed with the tips positioned at the coordinates (anterior-posterior, 0.5 mm; lateral, 1.5 mm; horizontal, 3.2 mm) under aseptic conditions. At the end of surgery and under appropriate anesthesia, rats received (s.c.) banamine (1 mg/kg) and ketoprofen (5 mg/kg). A 7-day recovery period from surgery was allowed. For i.c.v. injection, the injection cannula was connected via PE20 tubing to a Hamilton microsyringe (Hamilton Company, Reno, NV). The injection was slow and in small volume (1 µl/2 min) using a micro-injection pump.
All procedures were conducted according to National Institutes of Health Animal Care and Use Committee guidelines and approved by the Ethical Committee of the Institute. Statistical analysis was performed using the analysis of variance followed by Newman-Keuls multiple comparisons test. P < 0.05 was considered significant.
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Results |
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).
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This induced depressive behavior also had substantially negative impact on cognitive capacity as evaluated in the multitrial passive avoidance task. This learning deficit, however, occurred only after the males were exposed to 15-min/trial (F1,15 = 20.362, p < 0.001; Fig. 2a) but not after the 11-min/trial OSST, although such impairment was observed in the females after the 11-min/trial (F1,15 = 15.568, p < 0.01; Fig. 2b) and 15-min/trial (F1,15 = 24.262, p < 0.001; Fig. 2b). There were significant effects of groups (F7,112 = 16.971, p < 0.001) and groups x sex (F7,112 = 8.522, p < 0.001). No learning and memory deficits were observed in the male and female groups after the 7-min/trial OSST (data not shown).
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The retention test of the multitrial passive avoidance task further revealed that depressed rats exhibited memory deficits (Male 15-min group: F1,15 = 5.300, female 11-min group: F1,15 = 5.216, female 15-min group: F1,15 = 5.167; all with p < 0.05, versus their controls; Fig. 2, c and d), although these rats received more training trials during the acquisition. The depression-related memory deficits were sensitive to imipramine treatment during the OSST trial phase, revealing no significant difference in the memory performance of the male 15-min trial and female 11-min and 15-min trial groups with the imipramine treatment during the OSST trial phase, as compared with their corresponding control groups (all with p > 0.05; Fig. 2, c and d). Imipramine treatment itself (without the OSST trials) did not affect the recall in the task for either sex, nor did it have a significant effect on the recall in the males after the 11-min OSST trials in which immobility was not induced.
Sensitivity of Gender-Dependent Depression Vulnerability to Sex Hormones and Imipramine Treatment. To evaluate the involvement of underlying signal cascade in the female vulnerability to depression induction, we used several additional approaches. Given this clear female vulnerability to the OSST depression model, we directly evaluated roles of sex hormones in the differential vulnerabilities to the induction of the depressive behavior. After an 8-day treatment with estradiol, an estrogen receptor agonist, male rats became more vulnerable to a subsequent OSST (Male 11-min-estradiol group: F1,15 = 5.689, p < 0.05, versus male 11-min group; Fig. 1a) and depression-related cognitive deficits (Fig. 2, a and c). This increased vulnerability was sensitive to imipramine treatment, because no significant decrease in mobility over trials was observed with imipramine treatment (male 11 min/trail, estradiol + imipramine; F2,21 = 0.414, p > 0.05; data not shown). Administration of androsterone, an androgen receptor agonist, to female rats for the same duration, on the other hand, eliminated their higher vulnerability to depression induction (Female 11-min-androsterone group: F1,15 = 4.582, p < 0.05, versus female 11-min group; Fig. 1b) and the depression-related cognitive deficits (Fig. 2, b and d), whereas the hormones themselves at the same dose and with the same administration schedule in rats that were not subject to the OSST trials did not have significant impact on the learning and memory (Fig. 2).
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Converging Effects of a Glucocorticoid Receptor Antagonist on the Depression Induction. We directly evaluated whether the OSST-induced decrease in mobility was sensitive to blocking the glucocorticoid receptors in the three one-trial/day OSST. Administration of mifepristone, a glucocorticoid receptor antagonist, eliminated the decrease in mobility in either sex (male 15-min groups: F2,63 = 3.231, p < 0.05; Fig. 4a; female 11-min groups: F2,63 = 3.166, p < 0.05; Fig. 4b), whereas spironolactone, a mineralocorticoid receptor antagonist, was ineffective in both sexes (p > 0.05; Fig. 4).
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Whereas the coadministration of anisomycin effectively blocked the antidepressant effects of imipramine in both sexes and androsterone in the females, intracerebroventricular administration of BDNF completely reversed the blockade produced by anisomycin in both sexes [anisomycin + BDNF versus anisomycin in males: (F1,15 = 18.726, p < 0.001) and in females (F1,15 = 17.118, p < 0.001; Fig. 5)]. No significant changes in mobility over trials were observed in BDNF groups of either sex (p > 0.05; Fig. 5). These results are in line with the evidence reported by others that estrous cycle stage- and stress-related hormones decrease the expression of BDNF in the hippocampus and the prefrontal cortex, that antidepressant treatment increases the production of BDNF (Russo-Neustadt et al., 2000), and that central administration of BDNF produces antidepressant-like behavioral effects (Shirayama et al., 2002).
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Discussion |
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). Furthermore, our results show that the higher female vulnerability fluctuates across estrous cycle stages and is, at least partially, mediated by the sex hormones. Agents that specifically target the molecular/synaptic signal pathways underlying the gender-specific mood deregulation may have therapeutic values as effective antidepressants for the treatment of depression associated with large estrogen fluctuations. On the other hand, the induced depressive behavior and effects of antidepressants in both sexes seem to share some common regulatory pathways and pathology. First, the induced depressive behavior in either sex is sensitive to imipramine, a prototypical tricyclic antidepressant, and a blockade of the glucocorticoid receptors. The higher vulnerability to depressogenic events in the females thus does not possess antidepressant-resistant profiles and may also involve the same hypothalamic-pituitary-adrenal (HPA) responses. Second, the adverse impact on learning and memory depends on the induced behavioral changes, in that impaired learning and memory occur only when immobility is induced, although the behavioral change was induced at different intensity of the depressogenic events in the females and the males. Third, the induced depressive behavior in either sex shows an apparently identical underlying phenomenon: its induction is independent of novel protein synthesis, whereas the antidepressant effects depend on novel protein synthesis. Nevertheless, these observations are consistent with the view that a unified basis for the development of the mood disorders must exist (Hattori et al., 2005), because they occur in both men and women.
It is rather interesting that the OSST induced a gender-related differential vulnerability to the induction of the depressive behavior, whereas such difference has not been observed with the forced swim test. One possible explanation for the difference between the OSST and the forced swim test may stem from searching activity in which rats can engage. The OSST setup is the same as that used for water maze spatial learning and memory (but without the escape), an environment in which rats are known for their expertise in developing spatial and procedural escape strategies. In the large pool, rats plan and execute (probably many) escape strategies, judging from their searching activity and active swimming. However, their strategies are bound to fail because no escape is provided. Defeat or despair-like responses (immobility), with hopeless expectancies, gradually predominate, consistent with the observation that a certain length of trials was required for the rats to develop the immobility. Three 7-min trials over 3 days (one-trial/day), for instance, were below the threshold in either sex to develop the behavior. The mood change is thus consistent with the learned hopelessness type of response in humans, a characteristic symptom of depression (Abela, 2001). Although the same type of behavior (immobility) was induced in the OSST, the underlying mechanisms and molecular cascades may differ from those induced with the forced swim test. For instance, one noted difference is that the depressive behavior induced with OSST is more sensitive to antidepressants (Sun and Alkon, 2003).
It had not been clearly established previously whether female sex hormones may play any role in depression vulnerability and what might be the underlying mechanism if such a role does exist. The gender and estrous differences could result from higher estradiol levels and associated stress-related HPA axis activity in females, most dramatic at proestrous and estrous stages (Miller et al., 2004; Rhodes et al., 2004). The difference in HPA activity has been tracked to circulating estrogen (Burgess and Handa, 1992). Fluctuating activities of estrogen and HPA activities are accompanied by changed activity of neurotrophins, particularly BDNF, which may play a central role in the efficacy of antidepressants (Nestler et al., 2002; Castrén, 2004), synaptic remodeling, and associated neuronal survival/neurogenesis (Santarelli et al., 2003; Sairanen et al., 2005). BDNF mRNA levels in rat hippocampus and prefrontal cortex fluctuate significantly across the estrous cycle stages, reaching their lowest levels during the proestrous stage (Gibbs, 1998) or the estrous stage (Cavus and Duman, 2003) when estrogen levels are the highest. Consistent with these findings, glucocorticoids (e.g., cortisol, corticosterone) suppress BDNF expression. Furthermore, in males, testosterone inhibits the HPA axis by activating central androgen receptors (Handa et al., 1994; Viau, 2002), and BDNF functions as the neuronal survival mediator of testosterone (Rasika et al., 1999).
The induced depressive behavior is accompanied by impaired learning and memory in the multitrial passive avoidance task in both sexes, responses that are sensitive to the imipramine treatment during the OSST trial phase. Its potential long-term impact on the learning and sensitivity to chronic antidepressant treatment remain to be studied. The observation differs from the forced swim test in that the most immobile induced with the forced swim test seem to be the "smartest" (West, 1990). The multitrial passive avoidance task involves an entirely different context (pool versus compartments) and environment (in a different room) from those of the OSST so that the results are unlikely be affected by contextual/environmental similarity (if examined with water maze spatial learning and memory task). Likewise, the effects of the OSST trials and antidepressant treatment on learning and memory cannot be attributed to nonspecific changes in sensory and motor ability of the rats. First, if the OSST trials impaired the sensory and motor ability of the rats, the results would have been the opposite. A direct evaluation of the sensory and motor ability of the rats with a visible platform test after the OSST trials reveals no obvious difference between the OSST rats with or without imipramine treatment and control rats (Sun and Alkon, 2004). The imipramine was administered at the well established doses at which it does not induce changes in nonspecific locomotor activity in rats (Bai et al., 2001; Kroczka et al., 2001; Takamori et al., 2001; Kitamura et al., 2002). The learning and memory changes observed in the study are thus unlikely to be caused by a nonspecific effect of the OSST and/or drug treatment on sensory and motor ability of the animals. The impact of the male sex hormone at the administered doses on the learning ability of female is relatively big (more than 30% on average after the 11-min OSST). The group difference in passive avoidance learning induced with estradiol and 11-min OSST in the males, however, seems relatively small (less than 20% on average). It is not clear whether this is due to insufficient doses of estradiol administered in our study to overcome the impact of male hormone present in the males.
Surprisingly, the induction of depressive behavior is not affected by anisomycin. Anisomycin is a potent inhibitor of mRNA translation via interference with transpeptidation and has been used successfully at the identical dose in a number of behavioral paradigms to determine whether novel protein synthesis is involved (Lattal and Abel, 2001; Pang et al., 2004; Inda et al., 2005). Our results suggest that the development of the depressive behavior does not involve novel protein-dependent synaptic/structural remodeling, although stress is known to cause neuroadaptations in the brain (McEwen and Sapolsky, 1995). Maintenance of a healthy mood and expression of antidepressant action, on the contrary, seem to require novel protein synthesis. Antidepressants depend on novel protein synthesis and may depend on BDNF-mediated synaptic/structural remodeling and/or an active maintenance of such components. These results suggest a potential key role for BDNF, whose levels fluctuate across the estrous cycle and differ in gender-related HPA responses, in the gender and estrous cycle-correlated higher vulnerability to induction of immobility behavior. Our results suggest that BDNF is effective in all stages of the estrous cycle of the females, because its antidepressant effects were observed in the rats with mixed stages of the estrous cycle and with trial sessions across almost the entire estrous cycle. At its doses administered in the present study, BDNF is equally effective in the males and females. However, it remains to be determined whether a baseline difference between the males and the females can be revealed, probably by using smaller BDNF doses. Because of its close parallels with human female vulnerability to depression, this OSST model of depressive behavior may provide a useful procedure to search for new classes of antidepressants and also open possibilities to distinguish experimentally the molecular nature of sex differences in depression vulnerability. The effectiveness of BDNF after the administration of anisomycin in producing the antidepressant effect further raises the possibility that agents that enhance specifically the neurotrophic activity in the brain structures that control mood may be developed in the future as powerful antidepressants in both sexes.
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Footnotes |
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ABBREVIATIONS: OSST, open space swim test; BDNF, brain-derived neurotrophic factor; HPA, hypothalamic-pituitary-adrenal.
Address correspondence to: Dr. Miao-Kun Sun, Blanchette Rockefeller Neuroscience Institute, 9601 Medical Center Dr., Academic and Research Bldg., Room 319, Rockville, MD 20850. E-mail: mksun{at}brni-jhu.org
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 Y. Lin, G. J. Ter Horst, R. Wichmann, P. Bakker, A. Liu, X. Li, and C. Westenbroek Sex Differences in the Effects of Acute and Chronic Stress and Recovery after Long-Term Stress on Stress-Related Brain Regions of Rats Cereb Cortex, September 1, 2009; 19(9): 1978 - 1989. [Abstract] [Full Text] [PDF]
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A. Walf, C. Koonce, and C. Frye Adult female wildtype, but not oestrogen receptor {beta} knockout, mice have decreased depression-like behaviour during pro-oestrus and following administration of oestradiol or diarylpropionitrile J Psychopharmacol, June 1, 2009; 23(4): 442 - 450. [Abstract] [PDF]
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Y. Lin, C. Westenbroek, P. Bakker, J. Termeer, A. Liu, X. Li, and G. J. Ter Horst Effects of Long-Term Stress and Recovery on the Prefrontal Cortex and Dentate Gyrus in Male and Female Rats Cereb Cortex, December 1, 2008; 18(12): 2762 - 2774. [Abstract] [Full Text] [PDF]
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