Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling.

A major problem with current anti-depressant therapy is that it takes on average 6-7 weeks for remission. Since desensitization of serotonin (5-HT)1A receptor signaling contributes to the anti-depressive response, acceleration of the desensitization may reduce this delay in response to antidepressants. The purpose of the present study was to test the hypothesis that estradiol accelerates fluoxetine-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) of rats, via alterations in components of the 5-HT1A receptor signaling pathway.

5-HT1A receptors mediate (+)8-OH-DPAT-stimulation of extracellular signal-regulated kinase (MAP kinase) in vivo in rat hypothalamus: time dependence and regional differences.

Brain serotonin 1A (5-HT1A) receptors play an important role in mood disorders and can modulate various intracellular signaling mechanisms. We previously reported that systemic administration of either full or partial 5-HT1A agonists increases neuroendocrine responses and that tandospirone, an azapirone partial agonist, can activate (phosphorylate) extracellular signal-regulated kinase (ERK) in the hypothalamic paraventricular nucleus (PVN). In contrast, decreased levels of phosphoERK (pERK) have been reported in hippocampus following in vivo administration of either azapirone or aminotetralin 5-HT1A agonists, such as 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT).

Single exposure to a serotonin 1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, produces a prolonged heterologous desensitization of serotonin 2A receptors in neuroendocrine neurons in vivo.

We previously demonstrated colocalization of serotonin 1A (5-HT(1A)) and serotonin 2A (5-HT(2A)) receptors in oxytocin and corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus (PVN). Because a functional imbalance between hypothalamic 5-HT(1A) and 5-HT(2A) receptors has been implicated in several neuropsychiatric disorders, in this study we investigated whether acute in vivo activation of 5-HT(1A) receptors in the PVN results in desensitization of 5-HT(2A) receptor signaling. Functional desensitization of hypothalamic 5-HT(2A) receptors was assessed via a reduction in oxytocin and adrenocorticotropin (ACTH) responses to the 5-HT(2A/2C) receptor agonist (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl [(-)DOI].

Alterations in 5-HT2A receptor signaling in male and female transgenic rats over-expressing either Gq or RGS-insensitive Gq protein.

Serotonin 2A (5-HT2A) receptors are coupled to Galphaq and Galpha11 proteins to activate phospholipase C (PLC). Regulators of G-protein signaling proteins (RGS) modulate G-protein signaling by accelerating the intrinsic GTPase activity of Galphaq and Galpha11. This study investigated the effects of over-expression of wild-type Galphaq proteins (Gq-Tg) and over-expression of RGS-insensitive Galphaq proteins (G188S, RGSi-Tg) on 5-HT2A receptor mediated signaling in transgenic rats.

Fluoxetine treatment of prepubescent rats produces a selective functional reduction in the 5-HT2A receptor-mediated stimulation of oxytocin.

Various childhood mood disorders are being treated with serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine (Prozac(R)), 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.

Heightened responses to stressors in patients with inflammatory bowel disease.

Objectives: Several studies suggest that stressful situations (stressors) worsen the course of inflammatory bowel disease (IBD), but the mechanism is not known. Based on several lines of evidence, we hypothesized that psychosocial stress activates the brain-gut axis (BGA) and mucosal mast cells (MC), and activated MC produce proinflammatory cytokines. To test this hypothesis, we determined whether stressor-induced activation of BGA is exaggerated in IBD patients.

Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaine.

Rationale: Desensitization of postsynaptic 5-HT(1A) 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 postsynaptic 5-HT(1A) receptors to be desensitized by chronic paroxetine.

Objectives: The aim of the study is to determine (1) prenatal cocaine-induced changes in 5-HT(1A) receptor function and (2) the effectiveness of chronic treatment with paroxetine to produce 5-HT(1A) receptor desensitization in adult offspring exposed to cocaine in utero.

Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT1A receptor mechanisms in vivo.

Tandospirone, an azapirone, is a selective serotonin(1A) (5-HT(1A)) receptor agonist. The effects of tandospirone on plasma hormones and on mitogen-activated protein (MAP) kinase activity in the brain of male rats were studied. Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin, adrenocorticotropin (ACTH), corticosterone, and prolactin.

Chronic mild stress induces behavioral and physiological changes, and may alter serotonin 1A receptor function, in male and cycling female rats.

Rationale: Interactions among stress, serotonin 1A (5-HT(1A)) receptors, and the hypothalamic-pituitary-adrenocortical (HPA) system have been proposed to influence the development of depression in humans. The investigation of depression-relevant behaviors and physiological responses to environmental stressors in animal models of depression may provide valuable insight regarding these mechanisms.

Objectives: The purpose of these experiments was to investigate the interactions among central 5-HT(1A) receptors, endocrine function, and behavior in an animal model of depression, chronic mild stress (CMS).

Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.

Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted.

Estrogen reduces serotonin-1A receptor-mediated oxytocin release and Galpha(i/o/z) proteins in the hypothalamus of ovariectomized rats.

The present study examined the effect of estradiol on hypothalamic serotonin-1A (5-HT(1A)) receptor signaling in female rats. We first examined the time-course effects of a single injection of the 5-HT(1A) 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 microg/kg, s.c.

Repeated administration of the 5-HT(1B) receptor antagonist SB-224289 blocks the desensitisation of 5-HT(1B) autoreceptors induced by fluoxetine in rat frontal cortex.

Desensitisation of 5-HT(1A) and 5-HT(1B) autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin re-uptake inhibitors (SSRIs) when these are administered chronically, while blockade of these autoreceptors occurring on administration of an SSRI together with an autoreceptor antagonist is responsible for the acute increase in 5-HT levels in vivo observed under these circumstances. The effects of repeated administration of SSRIs together with 5-HT(1B) receptor antagonists on 5-HT levels and autoreceptor activity have not been studied previously with an in vivo method. In this work we found, using in vivo microdialysis that the effect of fluoxetine (5 mg/kg i.

Effects of triiodothyronine on 5-HT(1A) and 5-HT(1B) autoreceptor activity, and postsynaptic 5-HT(1A) receptor activity, in rat hypothalamus: lack of interaction with imipramine.

Triiodothyronine (T3) is effective in both augmenting and accelerating the therapeutic response to antidepressant drugs, especially tricyclics, and there is evidence from both human and animal studies that it acts on serotonergic neurotransmission. In this work we examined the effects of T3 alone and together with imipramine on 5-HT levels in the hypothalamus and on 5-HT(1A) and 5-HT(1B) autoreceptor sensitivity, using in vivo microdialysis in the rat. The effects of T3 on postsynaptic 5-HT(1A) receptor activity in the hypothalamus were also determined using a neuroendocrine challenge procedure.

Short-term cocaine treatment causes neuroadaptive changes in Galphaq and Galpha11 proteins in rats undergoing withdrawal.

One of the characteristics of drug dependence is that a drug has to be administered repeatedly before withdrawal effects can be observed. We have previously shown that withdrawal after 14 days of cocaine treatment produces a supersensitivity of hypothalamic 5-hydroxytryptamine (serotonin) 2A (5-HT(2A)) receptors, which is accompanied by increases in the levels of Galpha(q) and Galpha(11) proteins. Unfortunately, the exact duration of cocaine treatment necessary to induce alterations in G protein levels during cocaine withdrawal is unknown.

Prenatal cocaine exposure potentiates paroxetine-induced desensitization of 5-HT2A receptor function in adult male rat offspring.

This study investigated the ability of prenatal exposure to cocaine to alter serotonin(2A) (5-HT(2A)) receptor function and paroxetine-induced desensitization of 5-HT(2A) receptor function in rat offspring. Following exposure to saline or (-)cocaine (15 mg/kg, s.c.

Desensitization of 5-HT1A receptors by 5-HT2A receptors in neuroendocrine neurons in vivo.

An imbalance between serotonin-2A (5-HT2A) and 5-HT1A receptors may underlie several mood disorders. The present studies determined whether 5-HT2A receptors interact with 5-HT1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 microg/kg s.

Chronic fluoxetine-induced desensitization of 5-HT1A and 5-HT1B autoreceptors: regional differences and effects of WAY-100635.

Desensitization of 5-HT(1A) and 5-HT(1B) autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin reuptake inhibitors when these are administered chronically. The blockade of 5-HT(1A) autoreceptors occurring on administration of a selective serotonin reuptake inhibitor together with a 5-HT(1A) autoreceptor antagonist is responsible for the acute increase in 5-hydroxytryptamine (serotonin, 5-HT) levels observed under these circumstances. The effects of repeated administration of selective serotonin reuptake inhibitors together with 5-HT(1A) receptor antagonists have not been widely studied.

Chronic rTMS induces subsensitivity of post-synaptic 5-HT1A receptors in rat hypothalamus.

Chronic administration of several antidepressants, notably the selective serotonin re-uptake inhibitors (SSRIs) induces sub-sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus. Chronic repetitive transcranial magnetic stimulation (rTMS) is a form of treatment for depression which is often compared to electroconvulsive shock therapy (ECT). rTMS was applied to rats either on a single occasion (acute) or daily for 8 d (chronic).

A region-specific increase in Galphaq and Galpha11 proteins in brains of rats during cocaine withdrawal.

Serotonin 2A (5-HT2A) receptor-mediated increases in plasma hormone levels become supersensitive after 42 h of withdrawal from cocaine treatment. The present study investigated which components of the 5-HT2A receptor signaling system are associated with this supersensitivity. Rats were injected daily for 14 days with either saline or cocaine (15 mg/kg i.

Plasma oxytocin in response to pharmaco-challenge to D-fenfluramine and placebo in healthy men.

The neuropeptide oxytocin is produced in the hypothalamus and released centrally and peripherally in response to serotonergic stimulation. Plasma oxytocin levels may be a candidate as a biological index of serotonergic function in response to pharmacological challenge by serotonergic agents. Fourteen male healthy subjects underwent a placebo challenge and a D-fenfluramine (D-FEN) (0.

Brain region-specific alterations of 5-HT2A and 5-HT2C receptors in serotonin transporter knockout mice.

The aim of the present studies was to determine the effects of reduced or absent serotonin (5-HT) transporters (5-HTTs) on 5-HT2A and 5-HT2C receptors. The density of 5-HT2C receptors was significantly increased in the amygdala and choroid plexus of 5-HTT knockout mice. On the other hand, the density of 5-HT2A receptors was significantly increased in the hypothalamus and septum, but reduced in the striatum, of 5-HTT knockout mice.

Neuroendocrine pharmacology of stress.

Exposure to hostile conditions initiates responses organized to enhance the probability of survival. These coordinated responses, known as stress responses, are composed of alterations in behavior, autonomic function and the secretion of multiple hormones. The activation of the renin-angiotensin system and the hypothalamic-pituitary-adrenocortical axis plays a pivotal role in the stress response.

Ovariectomy-induced increases in hypothalamic serotonin-1A receptor function in rats are prevented by estradiol.

The present study investigated the effects of long-term estradiol withdrawal (ovariectomy) on hypothalamic serotonin-1A (5-HT(1A)) receptor signaling. Changes in neuroendocrine responses to the 5-HT(1A) agonist 8-OH-DPAT and levels of G(z) protein in the hypothalamus were used to examine 5-HT(1A) receptor signaling. Five days following ovariectomy, rats received daily injections of either 2 microg of beta-estradiol 3-benzoate or vehicle (subcutaneously) for 2, 4 or 14 days.

Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (-)DOI.

The present study determined whether the serotonin2A (5-HT2A) receptors in the hypothalamic paraventricular nucleus mediate the neuroendocrine responses to a peripheral injection of the 5-HT2A/2C receptor agonist (-)DOI [(-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]. The 5-HT2A receptor antagonist MDL100,907 ((+/-)-alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol), the 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), or vehicle were microinjected bilaterally through a chronically implanted double-barreled cannula into the hypothalamic paraventricular nucleus 15 min before a peripheral injection of (-)DOI in conscious rats. (-)DOI significantly elevated plasma levels of oxytocin, prolactin, ACTH, corticosterone, and renin.

Functional effects of chronic electroconvulsive shock on serotonergic 5-HT(1A) and 5-HT(1B) receptor activity in rat hippocampus and hypothalamus.

The aims of this work were to determine the influence of chronic electroconvulsive shock (ECS) on presynaptic 5-HT(1A) receptor function, postsynaptic 5-HT(1A) receptor function in hippocampus and hypothalamus, and presynaptic 5-HT(1B) receptor function in hippocampus and hypothalamus. This represents part of an on-going study of the effects of ECS on serotonergic receptor activity in selected brain areas which may be relevant to the effects of electroconvulsive therapy (ECT) in humans. Chronic ECS reduced the ability of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) (0.