Elsevier

Neuroscience

Volume 194, 27 October 2011, Pages 62-71
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
Citalopram-mediated anxiolysis and differing neurobiological responses in both sexes of a genetic model of depression

https://doi.org/10.1016/j.neuroscience.2011.07.077Get rights and content

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.

Highlights

▶Male, but not female, Flinders Sensitive Line (FSL) of rats present anxiety behaviour. ▶Repeated citalopram treatment reduces anxiety levels in both sexes. ▶Citalopram modulates AVPR1b expression in a sex-specific manner. ▶Differing mechanisms converge to produce anxiolysis in FSL rats of both sexes.

Section snippets

Animals

Twenty-four adult male and female FSL rats, weighing 275±17 g and 200±15 g, respectively, and aged 10–11 weeks at the beginning of the experiment, were used. In addition, 24 male and female, similarly aged, SD rats, weighing 325±26 g and 245±20 g, respectively, were used as controls as previously described (Overstreet et al., 2005). Animals were group-housed, according to sex, under controlled 12:12-light/dark cycles (lights on at 7:00 am) and temperature (22±2 °C), with free access to food and

Horizontal activity

Statistical analysis indicated a significant “sex” main effect, as female FSL and SD rats generally showed higher ambulatory counts than their strain-matched male controls [F(1,39)=27.553, P<0.001]. Furthermore, a significant “strain” main effect was observed [F(1,39)=9.259, P=0.004], reflecting the lower ambulatory counts of FSL rats during the 5 min open field test. Male FSL rats displayed considerable lower horizontal activity than their SD counterparts [F(1,10)=46.507, P<0.001] (Fig. 1a).

Vertical activity

Discussion

Although depression and anxiety have greater prevalence and different phenomenology in women, the biological mechanisms underlying such sex differences are not well understood. Likewise, reports on the sex-differentiated antidepressant response remain controversial. The present study used a well-validated model of depression and explored its suitability as a model of comorbid anxious depression, taking into consideration sex-differences in anxiety and depression at baseline and following

Conclusion

In summary, our results suggest that although male and female FSL rats are a good model for research on depression, they are not suitable for accurately modelling comorbid anxious depression, as observed in humans. Interestingly though, SSRI treatment triggers distinct neurobiological mechanisms in male and female rats of this model of depression. These mechanisms result in similarly converging behavioural response in both sexes, although of different magnitude, depending on the pretreatment

Acknowledgments

We thank Dieter Fischer for excellent technical assistance, Carola Hetzel for administrative help, Dr. Linton for providing the CRHR1 antibody, and Drs. Nuno Sousa and Alexandre Patchev for their critical comments and discussions. Citalopram was kindly gifted by Lundbeck SA who nevertheless did not influence the study design and interpretation of results from this work. This research was partly supported through a German-Greek Academic Exchange Programme (DAAD-IKYDA: D/04/42259), an IBRO

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