Serotonergic receptor mechanisms underlying antidepressant-like action in the progesterone withdrawal model of hormonally induced depression in rats

Yan Li, Kasper F. Raaby, Connie Sánchez, Maria E. Gulinello

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Hormonally induced mood disorders such as premenstrual dysphoric disorder (PMDD) are characterized by a range of physical and affective symptoms including anxiety, irritability, anhedonia, social withdrawal and depression. Studies demonstrated rodent models of progesterone withdrawal (PWD) have a high level of constructive and descriptive validity to model hormonally-induced mood disorders in women. Here we evaluate the effects of several classes of antidepressants in PWD female Long-Evans rats using the forced swim test (FST) as a measure of antidepressant activity. The study included fluoxetine, duloxetine, amitriptyline and an investigational multimodal antidepressant, vortioxetine (5-HT3, 5-HT7 and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; inhibitor of the serotonin transporter (SERT)). After 14 days of administration, amitriptyline and vortioxetine significantly reduced immobility in the FST whereas fluoxetine and duloxetine were ineffective. After 3 injections over 48h, neither fluoxetine nor duloxetine reduced immobility, whereas amitriptyline and vortioxetine significantly reduced FST immobility during PWD. When administered acutely during PWD, the 5-HT1A receptor agonist, flesinoxan, significantly reduced immobility, whereas the 5-HT1A receptor antagonist, WAY-100635, increased immobility. The 5-HT3 receptor antagonist, ondansetron, significantly reduced immobility, whereas the 5-HT3 receptor agonist, SR-57227, increased immobility. The 5-HT7 receptor antagonist, SB-269970, was inactive, although the 5-HT7 receptor agonist, AS-19, significantly increased PWD-induced immobility. None of the compounds investigated (ondansetron, flesinoxan and SB-269970) improved the effect of fluoxetine during PWD. These data indicate that modulation of specific 5-HT receptor subtypes is critical for manipulating FST immobility in this model of hormone-induced depression.

Original languageEnglish (US)
Pages (from-to)520-528
Number of pages9
JournalBehavioural Brain Research
Volume256
DOIs
StatePublished - 2013

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Antidepressive Agents
Progesterone
Fluoxetine
Depression
Receptor, Serotonin, 5-HT1A
Amitriptyline
Serotonin 5-HT1 Receptor Antagonists
Serotonin 5-HT1 Receptor Agonists
Receptors, Serotonin, 5-HT3
Ondansetron
Mood Disorders
Serotonin 5-HT3 Receptor Agonists
Receptor, Serotonin, 5-HT1D
Receptor, Serotonin, 5-HT1B
Anhedonia
Serotonin 5-HT3 Receptor Antagonists
Long Evans Rats
Serotonin Plasma Membrane Transport Proteins
Affective Symptoms
Serotonin Receptors

Keywords

  • Flesinoxan
  • Forced swim test
  • Ondansetron
  • Premenstrual dysphoric disorder (PMDD)
  • Progesterone withdrawal
  • Vortioxetine

ASJC Scopus subject areas

  • Behavioral Neuroscience

Cite this

Serotonergic receptor mechanisms underlying antidepressant-like action in the progesterone withdrawal model of hormonally induced depression in rats. / Li, Yan; Raaby, Kasper F.; Sánchez, Connie; Gulinello, Maria E.

In: Behavioural Brain Research, Vol. 256, 2013, p. 520-528.

Research output: Contribution to journalArticle

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AB - Hormonally induced mood disorders such as premenstrual dysphoric disorder (PMDD) are characterized by a range of physical and affective symptoms including anxiety, irritability, anhedonia, social withdrawal and depression. Studies demonstrated rodent models of progesterone withdrawal (PWD) have a high level of constructive and descriptive validity to model hormonally-induced mood disorders in women. Here we evaluate the effects of several classes of antidepressants in PWD female Long-Evans rats using the forced swim test (FST) as a measure of antidepressant activity. The study included fluoxetine, duloxetine, amitriptyline and an investigational multimodal antidepressant, vortioxetine (5-HT3, 5-HT7 and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; inhibitor of the serotonin transporter (SERT)). After 14 days of administration, amitriptyline and vortioxetine significantly reduced immobility in the FST whereas fluoxetine and duloxetine were ineffective. After 3 injections over 48h, neither fluoxetine nor duloxetine reduced immobility, whereas amitriptyline and vortioxetine significantly reduced FST immobility during PWD. When administered acutely during PWD, the 5-HT1A receptor agonist, flesinoxan, significantly reduced immobility, whereas the 5-HT1A receptor antagonist, WAY-100635, increased immobility. The 5-HT3 receptor antagonist, ondansetron, significantly reduced immobility, whereas the 5-HT3 receptor agonist, SR-57227, increased immobility. The 5-HT7 receptor antagonist, SB-269970, was inactive, although the 5-HT7 receptor agonist, AS-19, significantly increased PWD-induced immobility. None of the compounds investigated (ondansetron, flesinoxan and SB-269970) improved the effect of fluoxetine during PWD. These data indicate that modulation of specific 5-HT receptor subtypes is critical for manipulating FST immobility in this model of hormone-induced depression.

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