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Various childhood mood disorders are being treated with serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine (Prozac®), yet limited data are available on their effects on serotonergic systems prior to maturation. This study investigated the effects of chronic fluoxetine treatment on 5-HT2A serotonin receptor-mediated neuroendocrine responses in young male rats. Prepubescent male rats were treated with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days, a treatment regimen producing maximal changes in postsynaptic 5-HT2A function in adults. Eighteen hours post-treatment, the rats received saline or increasing doses (0.5, 2.0, or 5.0 mg/kg, i.p.) of the 5-HT2 receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl ((±)-DOI). Trunk blood was obtained to determine changes in oxytocin, ACTH, corticosterone, and renin responses. Fluoxetine produced a small (∼6%) but significant reduction in body weight gain, but no changes were observed in basal hormone levels. In both saline- and fluoxetine-treated rats, (±)-DOI increased plasma oxytocin levels in a dose-dependent manner. However, the magnitude of the oxytocin responses to all doses of (±)-DOI were markedly attenuated (∼50%) in the fluoxetine-treated rats, indicating a functional reduction in the Emax of 5-HT2A receptor-mediated oxytocin responses. In contrast, fluoxetine did not alter the (±)-DOI-induced increases in plasma ACTH, corticosterone, or renin. These data provide the first demonstration of selective neuroadaptive responses in 5-HT2A serotonin receptor function due to prepubescent treatment with fluoxetine. These data may be clinically relevant with respect to the use of selective serotonin reuptake inhibitors in children and adolescents. Synapse 58:102-109, 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Rationale: Desensitization of postsynaptic 5-HT1A receptors may be responsible for the therapeutic effectiveness of serotonin selective uptake inhibitors (SSRIs). As prenatal cocaine exposure produces long-term deficits in 5-HT neurons in offspring, it may alter the ability of post-synaptic 5-HT1A receptors to be desensitized by chronic paroxetine. Objectives: The aim of the study is to determine (1) prenatal cocaine-induced changes in 5-HT1A receptor function and (2) the effectiveness of chronic treatment with paroxetine to produce 5-HT1A receptor desensitization in adult offspring exposed to cocaine in utero. Methods: Pregnant rats received saline or (−)cocaine (15 mg/ kg, s.c.) twice daily from gestational days 13 through 20. Adult male offspring from each of prenatal groups were treated with saline or paroxetine (10 mg/kg/day; i.p.) for 14 days. Eighteen hours post-treatment, rats were challenged with saline or the 5-HT1A receptor agonist (+)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.04 or 0.2 mg/kg, s.c.). Plasma oxytocin, adrenocorticotropic hormone (ACTH), corticosterone, renin and prolactin were determined. Results: Prenatal cocaine exposure did not alter 5-HT1A receptor-mediated neuroendocrine responses. Paroxetine treatment desensitized 5-HT1A receptor-mediated increases in oxytocin, ACTH and corticosterone to a comparable extent in all offspring and reduced the Emax for ACTH only in prenatal cocaine-exposed offspring. Cortical [³H]-8-OH-DPAT- or [³H]-WAY100635-labeled 5-HT1A receptors were unaltered by prenatal cocaine or subsequent paroxetine treatment. Conclusions: Postsynaptic 5-HT1A receptor function is unaltered by prenatal cocaine exposure and paroxetine can effectively desensitize 5-HT1A receptor function in adult cocaine-exposed offspring. These data suggest that paroxetine may be clinically... [ABSTRACT FROM AUTHOR]

The present study examined the effect of estradiol on hypothalamic serotonin-1A (5-HT1A) receptor signaling in female rats. We first examined the time-course effects of a single injection of the 5-HT1A receptor agonist (±)8-OH-DPAT (5, 15 or 30 min prior to decapitation), and dose response of (+)8-OH-DPAT (50, 100, 200 or 500 μg/kg, s.c.) on plasma hormones in ovariectomized rats that received a daily injection of β-estradiol 3-benzoate (10 μg/day, s.c.) or vehicle (sesame oil) for 2 days. In vehicle- and estrogen-treated rats, the peak response of hormones occurred at 15 min after injection and the time-course of oxytocin and adrenocorticotropic hormone (ACTH) responses to an injection of 8-OH-DPAT were comparable. However, only the oxytocin response was reduced by estrogen treatment. A second experiment compared the ACTH and oxytocin responses with doses of 50 or 200 μg/kg, s.c. of (+)8-OH-DPAT vs. (±)8-OH-DPAT in ovariectomized rats that were treated with oil or β-estradiol 3-benzoate (10 μg/day, s.c.) for 2 days. (+)8-OH-DPAT and (±)8-OH-DPAT produced a similar magnitude of increase in plasma levels of ACTH and oxytocin. Treatment with β-estradiol 3-benzoate produced a significant and comparable reduction in the oxytocin response to the highest dose (200 μg/kg, s.c.) of both (+)8-OH-DPAT and (±)8-OH-DPAT but did not alter the ACTH response to either (+)8-OH-DPAT or (±)8-OH-DPAT. In the dose-response experiment, a dose of 50 μg/kg of (+)8-OH-DPAT produced a maximal increase in plasma levels of ACTH, while the maximal oxytocin response was achieved with a dose of 200 μg/kg, s.c. Treatment with β-estradiol 3-benzoate reduced the maximal oxytocin response to (+)8-OH-DPAT (by 29%) but did not alter the ACTH response to any doses of (+)8-OH-DPAT. To examine potential mechanisms mediating the effects of estrogen on 5-HT1A receptor signaling, we measured the levels of Gαi, Gαo and Gαz proteins, which couple 5-HT1A receptors to their effector enzymes, in two subregions of the hypothalamus. The levels of Gαz protein were reduced in the mediobasal hypothalamus (containing the ventromedial and arcuate nuclei), which mainly expresses estrogen receptor-α, but not in the paraventricular hypothalamus, which mainly expresses estrogen receptor-β. Estradiol reduced the levels of Gαi2 and Gαi3 proteins in both hypothalamic regions but did not affect Gαi1 levels in either area. Combined, the data suggest that racemic and stereoselective 8-OH-DPAT have similar neuroendocrine effects and that both estrogen receptor-α and estrogen receptor-β mediate the reduction in levels of Gαi2,3 proteins. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The present study investigated the effects of long-term estradiol withdrawal (ovariectomy) on hypothalamic serotonin-1A (5-HT[sub 1A] ) receptor signaling. Changes in neuroendocrine responses to the 5-HT[sub 1A] agonist 8-OH-DPAT and levels of G[sub z] protein in the hypothalamus were used to examine 5-HT[sub 1A] receptor signaling. Five days following ovariectomy, rats received daily injections of either 2 μg of β-estradiol 3-benzoate or vehicle (subcutaneously) for 2, 4 or 14 days. Twenty-four hours after the last injection, and 15 min prior to sacrifice, rats were injected with (±)8-OH-DPAT (50 μg/kg, s.c.) or saline. Estradiol treatment did not alter basal corticotropin (ACTH) or oxytocin levels. Injection of (±)8-OH-DPAT produced significant increases in plasma ACTH and oxytocin levels. In the vehicle-treated rats, hormone responses to 8-OH-DPAT were enhanced in rats that received injections for 14 days compared with rats that received injections for either 2 or 4 days. Estradiol treatment for 4 or 14 days blunted this enhanced ACTH response to 8-OH-DPAT, whereas the oxytocin response to 8-OH-DPAT was only blunted after 14 daily injections of β-estradiol 3-benzoate. The treatment with β-estradiol 3-benzoate (2 μg/rat) did not reduce membrane-associated G[sub z] protein levels in the paraventricular nucleus of the hypothalamus. Hence, the inhibitory influence of a low dose of β-estradiol 3-benzoate on 5-HT[sub 1A] receptor signaling in the hypothalamus is not accompanied by a change in the levels of G[sub z] protein in the paraventricular hypothalamic nucleus. Results from the present study indicate a supersensitivity of 5-HT[sub 1A] receptors after withdrawal of estradiol and suggest that estradiol suppresses 5-HT[sub 1A] receptor signaling. Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]