Chronic Fluoxetine Differentially Affects 5-Hydroxytryptamine_2A Receptor Signaling in Frontal Cortex, Oxytocin- and Corticotropin-Releasing Factor-Containing Neurons in Rat Paraventricular Nucleus

Abstract

Differential adaptive changes in serotonin 2A 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 (Ϯ)-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 ␣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 5Ј-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.

Sustained treatment with a 5-HT2A receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT2A receptors despite increases in receptor protein levels in rats

“…For example, several antipsychotic drugs, such as olanzapine, desensitize 5-HT 2A receptors (Kuoppamaki, et al, 1995;Roth and Ciaranello, 1991) while serotonin reuptake blockers (e.g., fluoxetine), alter the maximal efficacy of 5-HT 2A receptor signaling (Damjanoska, et al, 2003;Li, et al, 1993;Tilakaratne, et al, 1995). Although the molecular mechanisms that underlie the adaptive changes in 5-HT 2A receptor signaling are not well understood, they may contribute to the clinical effectiveness of these drugs.…”

5-HT2A receptor antagonist M100907 reduces serotonin synthesis: An autoradiographic study

“…Long-term treatment with SSRIs produces a desensitization of hypothalamic 5-HT 1A receptors, both in humans and rats [9,39,61] and alters the function of 5-HT 2A receptors [16,73,20]. Recent studies suggest that the activation of 5-HT 2A receptors induces a desensitization of the 5-HT 1A receptors [77,81].…”

Chronic olanzapine activates the Stat3 signal transduction pathway and alters expression of components of the 5-HT2A receptor signaling system in rat frontal cortex

“…PLC activity was measured in membrane fractions of rat frontal cortex as previously described using an ED50 concentration of GTPγS and an Emax concentration of serotonin (Damjanoska, et al, 2003;Wolf and Schutz, 1997). 5-HT-stimulated PLC activity in the frontal cortex is almost entirely mediated by 5-HT 2A receptors, as pretreatment with 5-HT 2A receptor antagonists (ketanserin, spiperone, or mianserin) inhibits most of the 5-HT-stimulated PLC activity in the frontal cortex of rats (Wolf and Schutz, 1997).…”

“…Immunoblot analysis of proteins has been described previously in detail (Damjanoska, et al, 2003). Briefly, the membrane or cytosolic proteins (10-2.5μg/lane depending on the antibody used) were resolved by SDS-PAGE and electrophoretically transferred to nitrocellulose membranes.…”

“…For example, several antipsychotic drugs, such as olanzapine, desensitize both 5-HT 2A and 5-HT 2C receptors (Roth, et al, 1998) while 5-HT uptake blockers (e.g., fluoxetine), can increase the maximal efficacy of 5-HT 2A receptor signaling (Damjanoska, et al, 2003;Tilakaratne, et al, 1995).These adaptive changes may explain the 2-3 week delay in full symptom improvement seen with these drug treatments. However, the molecular mechanisms that underlie these adaptive changes in 5-HT 2A receptor signaling are not well understood.…”