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Jul 6, 2012 - Effects of Chronic Administration of Buspirone to Female Mice in Conditions of Prolonged Psychoemotional Stress. D. F. Avgustinovich and ...
Neuroscience and Behavioral Physiology, Vol. 42, No. 6, July, 2012

Effects of Chronic Administration of Buspirone to Female Mice in Conditions of Prolonged Psychoemotional Stress D. F. Avgustinovich and G. B. Vishnivetskaya

Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 97, No. 2, pp. 189–202, February, 2011. Original article submitted July 19, 2010. The effects of chronic administration (30 days) of the partial 5-HT1A receptor agonist buspirone (0.05, 1, and 10 mg/kg i.p.) on the behavior of female C57BL/6J mice in conditions of prolonged psychoemotional stress were studied. Stress was produced by keeping females in a cage with an aggressive male on the other side of a perforated partition, along with the daily occurrence of 10-min intermale confrontations between the aggressor and another male placed with it. Chronic administration of buspirone at all the doses tested had no effect on the behavior of the females assessed in the partition and open field tests at the end of the treatment period. The elevated plus maze test showed that buspirone had anxiolytic effects, but only at a dose of 1 mg/kg. In the Porsolt test, buspirone (1 mg/kg) produced a minor increase in the duration of immobility, pointing to some antidepressant effect. Thus, chronic administration of buspirone to females in conditions of prolonged psychoemotional stress had different effects on their behavior depending on the dose and test conditions. Keywords: C57BL/6J mice, females, prolonged psychoemotional stress, buspirone, behavior.

It is well known that women suffer from depression 2–3 times more frequently than men, which is evidenced by extensive epidemiological studies in various countries [20, 21, 35, 40, 46]. The creation of good models of depression in female animals for investigations of the pharmacological properties of known and medically widely used drugs, as well as newly synthesized drugs, is therefore of current interest. Our previous studies identified signs of anxiousdepressive states in conditions of chronic psychoemotional stress in female C57BL/6J mice [1, 3, 4]. Prolonged keeping of a female with an aggressive male on the other side of a perforated transparent partition in a cage with daily witnessing of confrontations between the aggressor and intruders placed with it for 10 min produced impairments in behavior in females which were apparent in a variety of tests, especially those for anxiety and depression. It has been suggested [30] that a model of the anxious-depressive state should satisfy four criteria of similarity with pathology in humans,

including the criterion of similar sensitivity of “ill” animals with people with signs of anxious-depressive disorders to the actions of anxiolytics and antidepressant used in clinical practice. Buspirone is an example of such an anxiolytic, with anxiolytic activity as high as that of benzodiazepines but, unlike benzodiazepines, lacking the marked negative adverse effects and dependence seen in humans [34]. Buspirone has been established in clinical trials as effective in the treatment of generalized anxiety and depression [10, 16, 40, 41, 43], which also applies to the most severe cases of illness, when anxiety is comorbid with depression [5, 8] – which is particularly common in women [20, 40]. Experimental studies of the anxiolytic profile of buspirone can differ depending on the model of anxiety used [18, 19, 22, 27]. Our studies on male C57BL/6J mice showed that chronic administration of buspirone had positive influences on behavior even on the background of ongoing social stress [6]. Buspirone prevented the development of anxiety and impairments to communicativeness in mice and improved the behavior of mice in tests evaluating depressivity [6]. This naturally led to interest in studies of the effects of buspirone given to females of the same strain in conditions of prolonged

Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, 10 Lavrentiev Prospekt, 630090 Novosibirsk, Russia; e-mail: [email protected].

634 0097-0549/12/4206-0634 ©2012 Springer Science+Business Media, Inc.

Effects of Chronic Administration of Buspirone to Female Mice psychoemotional stress which, like males, developed an anxious-depressive state [1, 3, 4, 25]. This interest is also due to that fact that signs of generalized anxiety in humans show greater sensitivity to prolonged treatment with buspirone in women than in men [34]. Thus, the aim of the present work was to study the effects of chronic administration of buspirone on the behavior of female C57BL/6J mice in conditions of prolonged psychoemotional stress leading to the development of signs of anxiety and depression [1, 3, 4].

METHODS Animals were kept and reared in standard animalhouse conditions at the Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, with a 12:12 (light:dark) light regime. Standard granulated feed (NPO Agricultural Technologies, Moscow) and water were provided ad libitum. After separation from mothers at age one month, mice from different litters were separated by gender and kept in groups of 8–10 individuals in cages of size 36 × 23 × 12 cm until complete maturity. Experiments were performed on female C57BL/6J mice aged three months. Prolonged psychoemotional stress. Each experimental female was placed in a cage of size 28 × 14 × 10 cm, where an aggressive male was constantly present on the other side of a perforated partition. Intermale confrontations took place every day before the female’s eyes, when another (non-aggressive) male was placed with the aggressive male for 10 min. After confrontations, the non-aggressive male was returned to its own cage and the aggressive male was replaced on the other side of the partition from the experimental female. Females remained on their own territories throughout the experiment. Drug administration. The experimental females were divided into four groups; after daily intermale confrontations, three groups of females received i.p. buspirone (Sigma Chemical Co., USA) at doses of 0.05, 1, or 10 mg/kg, while the other group received physiological saline (controls). Thus, chronic administration of agents was performed on the background of psychoemotional stress starting from the first day. The behavior of the animals was studied one day after 30 days of psychoemotional stress and drug administration using the following tests (one test per day) in the following sequence: the partition test, the elevated plus maze test, the open field test, and the Porsolt test. Psychoemotional stress on females and drug administration continued after each test. Body weight was recorded every five days (for 30 days) to a total of seven measurements. The partition test [24] provides a quantitative assessment of communicativeness in mice in terms of behavioral activity along a transparent partition in response to a partner in the neighboring sector. Numbers of approaches/social

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interactions (henceforth approaches) of females to the partition with an aggressive male on the other side were measured in each test, along with the duration of time spent at the partition and the time per approach, over a 5-min period. The familiar aggressive male was then replaced with another, unfamiliar, one (taken from the male group cage) and the female’s behavior was again tested for 5 min. Increases in the responses of mice to a new social stimulus on substitution of a familiar partner by an unfamiliar one, reflected in an increase in the duration of time spent by the partition, are also believed to reflect communicativeness [24]. As the partition test allows the animal’s behavior to be assessed in non-aversive home cage conditions, it can be used several times with the same animal in a single experiment. Thus, the behavior of the animals of the four groups in the partition test was investigated twice: 30 min after the first dose of buspirone/physiological saline (after one dose) at the very beginning of the experiment, and then at the end of the experiment (after chronic administration). The elevated plus maze test, which is sensitive to the actions of anxiogenic and anxiolytic agents, is among the widely used tests for evaluating anxiety states in rodents [13]. The maze is elevated to 50 cm above the floor and consists of two open and two closed (enclosed on three sides) arms. The cage containing the mouse was placed in a dark room 5 min before the test, and the animal’s behavior in the maze was monitored for 5 min. The animal was placed in the center of the maze with the nose towards a closed arm and the following behavioral parameters were recorded: time spent in the open arms, center, and closed arms of the maze (data are presented as the times spent in each part of the maze as proportions of the total test duration); the number of excursions to the open arms, center, and closed arms, expressed, like time, as percentages; the total number of entries into/exits from the arms and center of the maze; the number of transfers from one closed arm to the other; and the number of glances beneath the maze. The open field test. This test is used to assess motor and investigative activity, as well as anxiety, in rats and mice [14, 38, 39]. The animals’ behavior was monitored in an open field of size 80 × 80 cm with walls of height 25 cm, marked into squares of size 10 × 10 cm. The field was illuminated with a bright light (100 W) at a distance of 1 m from the surface at the center of the field. The mouse was placed in the center of the field and the latent period of the first excursion from the central square (20 × 20 cm) was measured, along with the number of squares crossed by the mouse, the duration and number of rearings onto the hind paws (rearings), and the duration and number of grooming episodes during the 5 min of the test. The Porsolt test is sensitive to the actions of antidepressants [15, 36, 37] and is used to evaluate the state of depressivity in animals [11, 36]. During the 5 min of the test, the number and total duration of episodes of complete immobility of female mice were monitored in conditions of forced

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swimming in a vessel containing water (t = 25 ± 1°C), along with the latent period of the first episode of immobility. All behavioral parameters were recorded using an Etograf apparatus to determine the frequencies and durations of behavioral acts. At the end of psychoemotional stress, vaginal smears were collected from the females after each behavioral test, to identify any possible influences of estral cycle phases on behavioral parameters. Smears were stained with azure eosin by the Romanovskii–Giemsa method after fixation in methanol, and estral cycle phases were identified under a microscope. Results were analyzed statistically using the nonparametric Mann–Whitney U test, the Wilcoxon T test, and analysis of variance for repeat measures run on Statistica 6.0. For analysis of variance, one factor was “measurement number,” i.e., the time factor (seven measurements), and the second factor was “group” (females given the three doses of buspirone and physiological saline). Pairwise comparisons were then performed for independent parameters (within each group) using the Newman–Keuls test.

RESULTS Partition test, one dose of buspirone (Fig. 1). After single doses of buspirone at the lowest dose (0.05 mg/kg), females showed no differences in behavior in the partition test from individuals given physiological saline. Buspirone at 1 mg/kg significantly increased the time spent by the partition by females in response to an unfamiliar male. The most marked effect on the behavior of female mice was produced by the buspirone dose of 10 mg/kg, at which there were decreases (relative to controls) in virtually all parameters studied with the exception of the mean time spent by the partition in response to a familiar male. In addition, females given buspirone at a dose of 10 mg/kg differed from females given smaller doses of buspirone (0.5 and 1 mg/kg) in terms of virtually all parameters of the test. The responses of females to a new social stimulus (an unfamiliar partner) showed some differences in the groups of mice. Thus, substitution of the aggressor with an unfamiliar group male increased the time spent by the partition by females given physiological saline or buspirone at a dose of 0.05 mg/kg (p < 0.002 in both groups), which was accompanied by increases in the mean duration of approaches (p < 0.004 and p < 0.002, respectively). After single doses of buspirone at a dose of 1 mg/kg, there were increases in all three parameters of the test (p < 0.005, p < 0.008, and p < 0.045). After single doses of buspirone at a dose of 10 mg/kg, increases in the number (p < 0.028) and duration (p < 0.037) of approaches were less significant than in the other groups of females; the mean duration of approaches changed at the level of a tendency (p < 0.099).

Fig. 1. Effects of single doses of buspirone (0.05, 1, and 10 mg/kg) on the behavior of female mice in the partition test. 1) Physiological saline (controls); 2) buspirone 0.05 mg/kg; 3) buspirone 1 mg/kg; 4) buspirone 10 mg/kg. *p < 0.05, ***p < 0.001 compared with controls; vp < 0.05, vvp < 0.01, vvvp < 0.001 compared with buspirone 0.05 mg/kg; +p < 0.05, ++p < 0.01, +++p < 0.001 compared with buspirone 1 mg/kg.

Partition test, chronic administration of buspirone (Fig. 2). On chronic administration of any dose of buspirone on the background of long-term psychoemotional stress, the four groups of females showed no difference from each other in terms of test parameters, with the exception of a smaller number of approaches to the partition in response to an unfamiliar male in the group of females given chronic buspirone at a dose of 1 mg/kg, as compared with females given buspirone at a dose of 0.05 mg/kg.

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Fig. 2. Effects of chronic buspirone (0.05, 1, and 10 mg/kg) on the behavior of female mice in the partition test. For further details see caption to Fig. 1. vp < 0.05 compared with buspirone 0.05 mg/kg.

Fig. 3. Effects of chronic buspirone (0.05, 1, and 10 mg/kg) on the behavior of female mice in the elevated plus maze test. For further details see caption to Fig. 1. *p < 0.05 compared with controls, vp < 0.05, vvp < 0.01 compared with buspirone 0.05 mg/kg.

In all four groups, responses to an unfamiliar partner were greater than those to a familiar partner: the duration spent by the partition (p < 0.004 for all) and the mean duration of each approach (p < 0.006 for all) increased. In addition, mice given chronic buspirone at doses of 0.05 and 10 mg/kg showed increased numbers of approaches to the partition (p < 0.021 and p < 0.033, respectively). The elevated plus maze test (Fig. 3). The elevated plus maze test showed larger numbers of excursions into the open arms and increases in the time spent in them by female mice

given chronic buspirone at a dose of 1 mg/kg as compared with control animals (p < 0.034 for the number, p < 0.011 for the duration) and females given buspirone at a dose of 0.05 mg/kg (p < 0.020 for the number, p < 0.008 for the duration). The groups of females given buspirone (0.05 and 10 mg/kg) showed no differences in any of the behavioral parameters studied in the maze, either from the control group or from each other. The open field test (Table 1). There were no differences in behavior in the groups of female mice in the open

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Avgustinovich and Vishnivetskaya TABLE 1. Effects of Chronic Buspirone on the Behavior of Female Mice in the Open Field Test

field test: animals given chronic buspirone at the three doses used showed no differences from controls or from each other in terms of any of the parameters studied. The Porsolt test (Fig. 4). In the Porsolt test, as in the elevated plus maze test, significant changes were seen in the group of females given chronic buspirone at a dose of 1 mg/kg. Buspirone at this dose decreased the number (p < 0.035) of immobility postures, with some (p < 0.076) increase in the duration of immobility. Buspirone at doses of 0.05 and 10 mg/kg had no effect in this test. Analysis of changes in body weight in female mice of the four groups during the experiments showed that this measure was related to both the time factor (“measurement number”) (F6,294 = 26.31, p < 0.001) and the interaction of the “measurement number” and “group” factors (F18,294 = 1.9, p < 0.017) (Fig. 5; Table 2). Pairwise comparison of values showed (Table 2) that on the background of prolonged psychoemotional stress, there was a gradual increase in body weight in females given chronic administration of physiological saline and low doses of buspirone (0.05 mg/kg) by 20 days of psychoemotional stress, while stable increases in body weight occurred later with higher doses of buspirone (1 mg/kg) – at 30 days. Females given buspirone at a dose of 10 mg/kg gained virtually no weight. Analysis of vaginal smears did not identify any influence of estral cycles on the behavioral parameters studied in the tests.

DISCUSSION These experiments showed that the effects of buspirone on the behavior of females in the partition test depended on the buspirone dose and the treatment conditions (singledose, chronic). Single doses of buspirone at a dose of 1 mg/kg had positive effects on communicativeness in intact females, increasing their interest in unfamiliar males on the other side of the partition. In this, females differed from males, which have been shown to display decreases in behavioral parameters in the partition test after single doses of buspirone (1 mg/kg) [2]. A larger dose of buspirone (10 mg/kg) had a negative effect, with decreases in both the

Fig. 4. Effects of chronic buspirone (0.05, 1, and 10 mg/kg) on the behavior of female mice in the Porsolt test. For further details see caption to Fig. 1. *p < 0.05 compared with controls.

number of approaches to the partition and the time spent by the partition in both situations – with familiar and unfamiliar males. These results are analogous to those obtained previously in mice of this strain [2]. This may be associated with inhibition of the animals’ motor activity, especially when the effects of buspirone were assessed 30 min after administration, as shown by other investigators [29, 45]. Thus, single doses of buspirone (1 mg/kg) had opposite

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Fig. 5. Changes in the body weight of females during chronic administration of buspirone (0.05, 1, and 10 mg/kg) and physiological saline. The intervals between measurements were five days.

TABLE 2. Levels of Significance on Comparison of Initial Body Weights in Females and Weights Measured Every Five Days for One Month (Newman–Keuls test)

effects on communicative behavior in intact C57BL/6J mice – positive in females and negative in males [2]. As the effects of chronic and single-dose administration of buspirone can differ significantly [17], the effects of chronic administration of buspirone on the behavior of females in conditions of prolonged psychoemotional stress were studied further. Buspirone is known to be an anxiolytic and is used in clinical practice [16] and in animal experiments [22, 29]. Furthermore, the anxiolytic effects of buspirone have been shown to depend on social context in both humans and rats and mice [23, 29]. For example, in animals kept individually, when all social interactions from littermates are removed, the anxiolytic effect of buspirone increases [29]. Our previous studies showed that in male C57BL/6J mice subjected to prolonged social stress via intermale confrontations, chronic buspirone had significant positive effects, improving communicativeness and decreasing anxi-

ety in stressed animals [6]. Thus, the effects of buspirone were significant even on the background of ongoing negative stress. The present studies therefore suggest that in female mice of the same strain (C57BL/6J), in which prolonged psychoemotional stress induced anxiety and impairments to communicativeness [1, 3, 4], chronic buspirone also had positive effects. These studies showed that at one month of psychoemotional stress, the three groups of females given chronic buspirone at doses of 0.05, 1, and 10 mg/kg showed no differences in behavior in the partition test from animals chronically given physiological saline. In other words, prolonged administration of buspirone at any of these doses failed to improve their communicativeness impaired by prolonged psychoemotional stress. Thus, like single-dose administration of buspirone, chronic administration was found to have significantly different effects on the behavior of male and female C57BL/6J mice in the partition test.

640 As demonstrated here, chronic administration of buspirone at a dose of 1 mg/kg (but not at 0.05 or 10 mg/kg) had anxiolytic effects on the behavior of females in the elevated plus maze test: they showed more excursions into the open arms of the maze and spent longer within them. We have previously noted that the partition and elevated plus maze tests evaluate two types of anxiety in mice [7]. In the partition test, the animals were in familiar home cage conditions. Testing consisted of simple observation of the animals’ behavior in these cages. The communicative behavior displayed by the animals in this test reflected the anxiety component developing on the background of psychoemotional stress. This is to a large extent what is known as basal anxiety [31]. In the elevated plus maze, the animals were in the unfamiliar conditions of the test, with greater manifestation of situational anxiety [9, 31]. As the three groups of females showed no differences from animals given physiological saline in the partition test after 30 days of psychoemotional stress, it would appear that buspirone is unable to decrease basal anxiety in female mice after being increased by prolonged intermale confrontations. In its turn, situational anxiety apparent in the plus maze was suppressed by buspirone correction at 1 mg/kg. It is interesting to note that in the open field test, which is also used by investigators to assess levels of situational anxiety in rodents [14, 31, 38, 39], there were also no differences between the study groups of females. This test has greater aversiveness than the elevated plus maze, mainly because of the bright illumination of the surface of the field [33]. It can therefore be suggested that increases in aversiveness on testing the animals could prevent detection of the effects of chronic buspirone administration. The conditions of the Porsolt test are even more aversive than those of the open field test, as the animals are placed in conditions of the unavoidable need to swim. This test is used to evaluate levels of depressivity in animals [28] on the grounds that the main measure of the test – the duration of immobility – is sensitive to the actions of many antidepressants [37]. In our studies, the females of the study groups showed no significant differences in behavior in the Porsolt test, though there was a minor increase in the duration of immobility in the group of females given buspirone at a dose of 1 mg/kg, which should be evaluated as a prodepressive effect. Thus, it can be suggested that increases in the aversiveness of the test conditions, for example in the open field test or Porsolt test, as compared with the less aversive conditions of the elevated plus maze test, eliminated the effects of buspirone in female mice subjected to prolonged psychoemotional stress. The fact that stress factors can modulate the effects of 5-HT1A receptor agonists on behavior in mice has been demonstrated elsewhere [12, 45]. In addition, a negative characteristic of buspirone seen in the present experiments should be emphasized, i.e., the absence of any weight gain in the animals during chronic administration

Avgustinovich and Vishnivetskaya of the high dose of buspirone (10 mg/kg) for 30 days. This is important, given that buspirone is used clinically for prolonged periods, often together with antidepressants [16, 32], some of which also produce weight loss in patients [44]. Weight loss on the background of buspirone administration for 3–4 weeks has also been noted in animals [26]. As buspirone is a partial agonist of 5-HT1A receptors in the brain, these changes in behavior may be due to changes occurring in these receptors. In turn, it has been shown that 5-HT1A receptors are closely linked with the regulation of anxiety and depression in animals [19]. It has been suggested that prolonged activation of 5-HT1A autoreceptors in the dorsal cervical nucleus with 5-HT1A receptor agonists such as buspirone and its analogs leads to receptor desensitization and, thus, increased serotonin release in the limbic parts of the brain [10], providing grounds for the anxiolytic effect of buspirone. Furthermore, it has been noted that prolonged administration of buspirone has a region-specific effect on brain 5-HT1A receptors: desensitization occurs in the dorsal nucleus and the septum of the brain, but not in the hippocampus, entorhinal cortex, or prefrontal cortex [42]. This may be because the buspirone affinity of 5-HT1A receptors is 3–4 times greater in the dorsal nucleus than in the hippocampus [47]. It has also been shown that at low blood concentrations (0.45–1.3 mg/kg/h), the occupancy of 5-HT1A receptors by agonist in the dorsal nucleus is two times higher than in the hippocampus, while higher concentrations (12 mg/kg/h) gave equal levels of 5-HT1A receptor occupancy by buspirone in both brain structures [47]. Considering these data and our results, it can be suggested that both auto- and postsynaptic 5-HT1A receptors are involved in the mechanisms of development of anxiety and depression in female mice in conditions of prolonged psychoemotional stress. Overall, our results suggest that some of the effects of chronic administration of buspirone in mice in conditions of prolonged negative psychoemotional conditions depend on the gender of the animals. Apart from the nonspecific influences of buspirone, typical of both male [6] and female mice, we observed behavioral changes seen only in females. Furthermore, buspirone was found to have different effects on behavior in females, depending on dose and the test conditions. Thus study was supported by the Russian Foundation for Basic Research (Grant No. 08-04-00225).

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