Search

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]

Abstract: Adaptive changes in serotonin2A (5-HT2A) receptor signaling are associated with the clinical response to a number of psychiatric drugs including atypical antipsychotics and selective serotonin reuptake inhibitors. The present study examined possible mechanisms of agonist-induced desensitization of 5-HT2A receptors in rat hypothalamic paraventricular nucleus (PVN) after 4 and 7 days of treatment with 1mg/kg (−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The magnitude of 5-HT2A receptor-mediated oxytocin release decreased 78% after 4 days and 61% after 7 days of DOI treatment. Similarly, the magnitude of ACTH release following 1mg/kg DOI decreased by 31% after 4 days and 38% after 7 days of DOI treatment. Treatment with DOI for either 4 or 7 days caused a significant decrease (by approximately 50%) in the high-affinity 5-HT2A receptor binding as measured by 125I-DOI binding compared to saline-treated control rats. In contrast, western blot analysis demonstrated a significant increase in 5-HT2A receptor protein levels with 4 or 7 days of DOI treatment to 167% and 191% of control levels, respectively. Real time quantitative RT-PCR analysis revealed a small but nonsignificant increase in the levels of 5-HT2A mRNA following treatment with DOI for 4 or 7 days. Taken together, the 5-HT2A receptor-stimulated hormone responses, agonist binding data and western blot data suggest that although agonist treatment increases the levels of 5-HT2A receptor protein in the cell membrane, there is a reduction in the population of 5-HT2A receptors capable of high-affinity binding and mediating a functional response. [Copyright &y& Elsevier]

Abstract: Serotonin 2A (5-HT2A) receptors are coupled to Gαq and Gα11 proteins to activate phospholipase C (PLC). Regulators of G-protein signaling proteins (RGS) modulate G-protein signaling by accelerating the intrinsic GTPase activity of Gαq and Gα11. This study investigated the effects of over-expression of wild-type Gαq proteins (Gq-Tg) and over-expression of RGS-insensitive Gαq proteins (G188S, RGSi-Tg) on 5-HT2A receptor mediated signaling in transgenic rats. Over-expression of wild-type Gαq and RGS insensitive mutant Gαq did not produce significant alterations in the levels of Gα11, RGS2, RGS4, RGS7, RGS16 or 5-HT2A proteins. RGSi-Tg rats had higher oxytocin and corticosterone responses to (−)DOI, a 5-HT2A/2C receptor agonist, compared to Gq-Tg rats. RGSi-Tg and Gq-Tg rats had higher ACTH responses to (−)DOI compared to control rats. Similarly, 5-HT-stimulated PLC activity in the frontal cortex was higher in RGSi-Tg and Gq-Tg rats compared to control rats. In contrast, GTPγS-stimulated PLC activity was higher in Gq-Tg rats but not in RGSi-Tg rats compared to control rats. There was a small but statistically significant increase in the affinity of [125I]-DOI labeled 5-HT2A receptors in RGSi-Tg rats and Gq-Tg rats compared to controls. There were no significant differences in B max and K d of [3H] ketanserin labeled 5-HT2A receptors among the three groups. These data suggest that the effect of RGS proteins on 5-HT2A receptor signaling is cell type specific. In transgenic rats over-expressing Gαq, endogenous RGS proteins have a negative effect on 5-HT2A receptor-mediated oxytocin release. In contrast, endogenous RGS protein had no impact on 5-HT2A receptor-mediated ACTH release in transgenic rats. [Copyright &y& Elsevier]

This study investigated the ability of prenatal exposure to cocaine to alter serotonin2A (5-HT2A) receptor function and paroxetine-induced desensitization of 5-HT2A receptor function in rat offspring. Following exposure to saline or (−)cocaine (15 mg/kg, s.c., b.i.d.), during gestational days 13–20, adult male offspring were treated with either saline or paroxetine (10 mg/kg/day, i.p. 14 days). Eighteen hours post-treatment, changes in the stimulation of oxytocin, adrenocorticotropic hormone (ACTH) and corticosterone by (−)4-iodo-2,5-dimethoxyphenylisopropylamine (DOI, 0.5 or 2.0 mg/kg, s.c.) and in 5-HT2A receptor densities were determined. Prenatal cocaine exposure did not alter 5-HT2A receptor-mediated neuroendocrine responses or 5-HT2A receptor densities. In contrast, paroxetine treatment reduced cortical 5-HT2A receptors (18–25%) and desensitized 5-HT2A receptor-mediated oxytocin responses in both offspring groups. Furthermore, in cocaine offspring, paroxetine produced an inhibition of 5-HT2A receptor-mediated increase in plasma ACTH levels and a greater attenuation of the oxytocin responses to (−)DOI. Paroxetine-induced reductions in body weight gain (−8.8%) were comparable in both offspring groups. These data, demonstrating that prenatal exposure to cocaine potentiates paroxetine-induced desensitization of 5-HT2A receptor function, may be clinically relevant with respect to treating mood disorders in adults exposed in utero to cocaine. [Copyright &y& Elsevier]