Article

Citalopram-mediated anxiolysis and differing neurobiological responses in both sexes of a genetic model of depression

Department of Pharmacology, Medical School, University of Athens, 11527 Athens, Greece.
Neuroscience (Impact Factor: 3.36). 08/2011; 194:62-71. DOI: 10.1016/j.neuroscience.2011.07.077
Source: PubMed

ABSTRACT

Disorders such as depression and anxiety exhibit strong sex differences in their prevalence and incidence, with women also differing from men in their response to antidepressants. Furthermore, receptors for corticotrophin releasing hormone (CRHR1) and arginine vasopressin receptor subtype 1b (AVPR1b) are known to contribute to the regulation of mood and anxiety. In the present study, we compared the anxiety profile and CRHR1 and AVPR1b expression levels in control Sprague-Dawley (SD) rats and rats of the SD-derived Flinders Sensitive Line (FSL), a genetic model of depression. Additionally, given the apparent sex differences in the therapeutic efficacy of antidepressants and because antidepressants are commonly used to treat comorbid anxiety and depressive symptoms, we assessed whether the anxiolytic effects of an antidepressant occur in a sex-dependent manner. Male and female FSL rats were treated with citalopram 10 mg/kg once daily for 14 days and were then tested in the open field and the elevated plus maze paradigms. Upon completion of the behavioural analysis, AVPR1b and CRHR1 expression levels were monitored in the hypothalamus and the prefrontal cortex (PFC) using Western blotting. According to our results, male FSL rats were more anxious than control SD rats, a difference abolished by citalopram treatment. Baseline anxiety levels were similar in female FSL and SD rats, and citalopram further reduced anxiety in female FSL rats. Importantly, whereas citalopram altered AVPR1b expression in the hypothalamus of male FSL rats, its actions on this parameter were restricted to the PFC in female FSL rats. In both sexes of FSL rats, citalopram did not alter CRHR1 expression in either the hypothalamus or PFC. Our results demonstrate that antidepressant treatment reduces anxiety levels in FSL rats of both sexes: the magnitude of treatment effect was related to the starting baseline level of anxiety and the antidepressant elicited sexually differentiated neurobiological responses in specific brain regions.

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    • " between FSL and SD rats were found ( Table S1 ) . FSL rats were charac - terized by more time spent in the corridors and lower velocity . These results together with generally longer latency measures in FSL rats indicate a slightly lower exploratory drive compared to SD rats , in line with the previous finding that FSL rats display hypoactivity ( Kokras et al . , 2011 ) . In the MCSF , the rat could choose between three corridors to leave the center and the choice of corridor affects the time for reaching the other zones . There - fore , a lack of a statistical difference in latency to the first visit of the corridors was to be expected and proved that there was no bias between the groups in choosing"
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    ABSTRACT: Modeling depression in animals is based on the observation of behaviors interpreted as analog to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL), a rat model of depression, compared to the Sprague-Dawley (SD) rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field ™ (MCSF) and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered exploratory behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests.
    Full-text · Article · May 2015 · Frontiers in Behavioral Neuroscience
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    • " between FSL and SD rats were found ( Table S1 ) . FSL rats were charac - terized by more time spent in the corridors and lower velocity . These results together with generally longer latency measures in FSL rats indicate a slightly lower exploratory drive compared to SD rats , in line with the previous finding that FSL rats display hypoactivity ( Kokras et al . , 2011 ) . In the MCSF , the rat could choose between three corridors to leave the center and the choice of corridor affects the time for reaching the other zones . There - fore , a lack of a statistical difference in latency to the first visit of the corridors was to be expected and proved that there was no bias between the groups in choosing"
    [Show abstract] [Hide abstract]
    ABSTRACT: Modeling depression in animals is based on the observation of behaviors interpreted as analog to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL), a rat model of depression, compared to the Sprague-Dawley (SD) rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field ™ (MCSF) and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered exploratory behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests.
    Full-text · Article · May 2015 · Frontiers in Behavioral Neuroscience
    • "Sex differences have been observed in FSL rats, with male rats being less active and more anxious in the open field and the elevated plus maze tests, in comparison with Sprague-Dawley controls, whereas there are no differences in female rats. Treatment with the SSRI citalopram decreased anxiety levels in both sexes (Kokras et al., 2011b). "
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    ABSTRACT: Psychiatric disorders are characterized by sex differences in their prevalence, symptomatology and treatment response. Animal models have been widely employed for the investigation of the neurobiology of such disorders and the discovery of new treatments. However, mostly male animals have been used in preclinical pharmacological studies. In this review, we highlight the need for the inclusion of both males and females in experimental studies aiming at gender-oriented prevention, diagnosis and treatment of psychiatric disorders. We present behavioural findings on sex differences from animal models of depression, anxiety, post-traumatic stress disorder, substance related disorders, obsessive-compulsive disorder, schizophrenia, bipolar disorder, and autism. Moreover, when available, we include studies conducted across different stages of the estrous cycle. By inspection of the relevant literature, it is obvious that robust sex differences exist in models of all psychiatric disorders. However, many times results are conflicting and no clear conclusion regarding the direction of sex differences and the effect of the estrous cycle is drawn. Moreover, there is a lack of considerable amount of studies using psychiatric drugs in both males and females, in order to evaluate the differential response between the two sexes. Notably, while in most cases animal models successfully mimic drug response in both sexes, test parameters and treatment-sensitive behavioural indices are not always the same for male and female rodents. Thus, there is an increasing need to validate animal models for both sexes and use standard procedures across different laboratories.
    No preview · Article · Apr 2014 · British Journal of Pharmacology
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