Cognitive, Behavioral, and Systems NeuroscienceResearch PaperCitalopram-mediated anxiolysis and differing neurobiological responses in both sexes of a genetic model of depression
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
References (78)
- et al.
Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders
Prog Neuropsychopharmacol Biol Psychiatry
(2004) - et al.
Measuring normal and pathological anxiety-like behaviour in mice: a review
Behav Brain Res
(2001) - et al.
HPA-axis regulation at in-patient admission is associated with antidepressant therapy outcome in male but not in female depressed patients
Psychoneuroendocrinology
(2009) - et al.
Sex differences in forced-swim and open-field test behaviours after chronic administration of melatonin
Eur J Pharmacol
(2000) - et al.
The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine
Biol Psychiatry
(2004) - et al.
Chronic mild stress impact: are females more vulnerable?
Neuroscience
(2005) - et al.
Sex differences in the effects of two stress paradigms on dopaminergic neurotransmission
Physiol Behav
(2008) - et al.
Factor analysis of elevated plus-maze behavior in adolescent and adult rats
Pharmacol Biochem Behav
(2006) - et al.
Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats
Neuroscience
(2004) - et al.
A rapid method for the regional dissection of the rat brain
Pharmacol Biochem Behav
(1980)
Central CRH system in depression and anxiety—evidence from clinical studies with CRH1 receptor antagonists
Eur J Pharmacol
Suppressive effect of mirtazapine on the HPA system in acutely depressed women seems to be transient and not related to antidepressant action
Psychoneuroendocrinology
Involvement of vasopressin V1b receptor in anti-anxiety action of SSRI and SNRI in mice
Neurosci Res
Antagonism of anticholinesterase (DFP) toxicity by donepezil plus scopolamine: a preliminary study
Pharmacol Biochem Behav
Antidepressants induce regionally discrete, sex-dependent changes in brain's glutamate content
Neurosci Lett
Abnormal patterns of maternal behavior in a genetic animal model of depression
Physiol Behav
Regulation of behavioral responses by corticotropin-releasing factor
Gen Comp Endocrinol
Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study
Compr Psychiatry
Gender differences in depression: findings from the STAR*D study
J Affect Disord
Repeated citalopram treatment but not stress exposure attenuates hypothalamic-pituitary-adrenocortical axis response to acute citalopram injection
Life Sci
Influence of oestrogen on spontaneous and diazepam-induced exploration of rats in an elevated plus maze
Neuropharmacology
The Flinders Sensitive Line rat: a selectively bred putative animal model of depression
Neurosci Biobehav Rev
Animal models of anxiety and depression: how are females different?
Neurosci Biobehav Rev
Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat
J Neurosci Methods
Neurochemical and behavioral alterations in an inflammatory model of depression: sex differences exposed
Neuroscience
Gender-related response in open-field activity following developmental nicotine exposure in rats
Pharmacol Biochem Behav
Lack of anxiety in an animal model of depression with cholinergic supersensitivity
Brain Res Bull
Involvement of vasopressin in affective disorders
Eur J Pharmacol
Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress
J Psychosom Res
Elucidation of the neurobiology of depression: insights from a novel genetic animal model
Prog Neurobiol
Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression
Psychoneuroendocrinology
Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project
Acta Psychiatr Scand
Strategies and methods for research on sex differences in brain and behavior
Endocrinology
The CRF system, stress, depression and anxiety-insights from human genetic studies
Mol Psychiatry
Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response
Arch Gen Psychiatry
Do animal models of anxiety predict anxiolytic-like effects of antidepressants?
Psychopharmacol Berl
Corticotrophin-releasing hormone receptor type 1: generation and characterization of polyclonal antipeptide antibodies and their localization in pituitary cells and cortical neurones in vitro
J Neuroendocrinol
Sex differences in animal models of depression and antidepressant response
Basic Clin Pharmacol Toxicol
Sexual differentiation of central vasopressin and vasotocin systems in vertebrates: different mechanisms, similar endpoints
Neuroscience
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