Chronic Fluoxetine Differentially Affects 5-Hydroxytryptamine2A Receptor Signaling in Frontal Cortex, Oxytocin- and Corticotropin-Releasing Factor-Containing Neurons in Rat Paraventricular Nucleus

• Published in: The Journal of pharmacology and experimental therapeutics 2003-08, Vol.306 (2), p.563
• Main Authors: K. J. Damjanoska, L. D. Van de Kar, G. H. Kindel, Y. Zhang, D. N. D'Souza, F. Garcia, G. Battaglia, N. A. Muma
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.050534

Differential adaptive changes in serotonin 2A [5-hydroxytryptamine (5-HT) 2A ] receptor signaling during treatment may be one mechanism involved in the latency of therapeutic improvement with antidepressants, such as fluoxetine. We examined the effects of fluoxetine (2, 3, 7, 21, or 42 days) on hypothalamic 5-HT 2A receptor signaling. The hormone responses to an injection of the 5-HT 2A receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) were used as an index of hypothalamic 5-HT 2A receptor function. Treatment with fluoxetine for 21 or 42 days produced diminished adrenocorticotropic hormone (ACTH) and oxytocin (but not corticosterone) responses to DOI injections (2.5 mg/kg i.p.; 15 min postinjection). Regulators of G protein signaling 4 and G α q protein levels in the hypothalamic paraventricular nucleus were not altered during fluoxetine treatment. Because previous studies indicate that treatment with fluoxetine for 21 days resulted in increased hormone responses to DOI when measured at 30 min after injection, we examined the effect of fluoxetine (21 days) on DOI-induced increase hormone levels at 15, 30, and 60 min after DOI injection. Fluoxetine decreased the oxytocin response at 15 but not at 30 min post-DOI injection, and potentiated the ACTH and corticosterone responses at 30 min post-DOI injection. For comparison, we examined the effect of fluoxetine on 5-HT 2A receptor-mediated increase in phospholipase C (PLC) activity in the frontal cortex. 5-HT-stimulated, but not guanosine 5′- O -(3-thio)triphosphate-stimulated PLC activity was increased after 21 days of fluoxetine-treatment. Overall, these results indicate that chronic fluoxetine treatment can potentiate 5-HT 2A receptor signaling in frontal cortex but differentially alters 5-HT 2A receptor signaling in oxytocin-containing neurons and corticotropin-releasing factor-containing neurons in the paraventricular nucleus.