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The aim of this study was to observe the influence of combined zinc and folic acid administration on depression and to explore its mechanism of action. Male Sprague Dawley rats were randomly divided into five groups: control, model, paroxetine (P), zinc + folic acid (ZnY), and zinc + folic acid + paroxetine (ZnYP) groups. Rat models of depression were established by chronic mild unpredictable stress for three weeks. These rats were then treated with different interventions for four weeks and the sucrose preference test was then performed to observe changes in rats’ behavior. An HPLC-electrochemical method was used to detect the levels of 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE) in the frontal cortex. qRT-PCR was employed to detect the mRNA levels of tyrosine kinase receptor B (Trk B) and N-methyl-D-aspartate acid (NMDA) in the frontal cortex; Western blotting was used to detect the protein levels of brain derived neurotrophic factor (BDNF) in the frontal cortex. The results showed that compared with the model group, sucrose consumption, 5-HT, NE and DA levels were significantly increased in the ZnY group ( P  < 0.05). Also the mRNA levels of Trk B and NMDA were significantly increased in the ZnY group compared with the model group ( P  < 0.001). No significant up-regulation of BDNF was observed in the ZnY group. We conclude that combined administration of zinc and folic acid can improve the symptoms of depression-model rats, and its mechanism is related to increased levels of 5-HT, DA and NE in the brain, and to the up-regulation of Trk B and NMDA. [ABSTRACT FROM AUTHOR]

This study investigated the mechanisms underlying regulation of the serotonin system in the rat brain during exercise-induced chronic fatigue. High-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed to measure serum tryptophan of the fatigued rat. HPLC was conducted to measure 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex and hippocampus. In addition, 5-HT 1A receptor and 5-HT transporter (5-HTT) mRNA expressions were measured at the same locations using real-time PCR. The results demonstrated a significant reduction in the serum tryptophan level in rats with exercise-induced chronic fatigue. Moreover, increased 5-HT and decreased 5-HIAA levels were detected in the frontal cortex and hippocampus, and these alterations were significant. Further, 5-HTT expression was significantly increased and 5-HT 1A receptor expression was significantly decreased. These results indicate that the 5-HT system plays an important role in the development of exercise-induced chronic fatigue. The 5-HT levels in different parts of the brain increased simultaneously, especially at synapses, and these alterations were associated with changes in 5-HTT and 5-HT 1A mRNA expressions. [ABSTRACT FROM AUTHOR]

Background: Although pain is one of the most distressing non-motor symptoms among patients with Parkinson's disease, the underlying mechanisms of pain in Parkinson's disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson's disease. Methods: The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results: The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine- treated rats. Conclusions: These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Abdominal expiratory activity is absent at rest and is evoked during metabolic challenges, such as hypercapnia and hypoxia, or after the exposure to intermittent hypoxia (IH). The mechanisms engaged during this process are not completely understood. In this study, we hypothesized that serotonin (5-HT), acting in the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), is able to generate active expiration. In anesthetized (urethane, ip), tracheostomized, spontaneously-breathing adult male Holtzman rats we microinjected a serotoninergic agonist and antagonist bilaterally in the RTN/pFRG and recorded diaphragm and abdominal muscle activities. We found that episodic (3 times, 5 min apart), but not single microinjections of 5-HT (1 mM) in the RTN/pFRG elicited an enduring (>30 min) increase in abdominal activity. This response was amplified in vagotomized rats and blocked by previous 5-HT receptor antagonism with ketanserin (10 µM). Episodic 5-HT microinjections in the RTN/pFRG also potentiated the inspiratory and expiratory reflex responses to hypercapnia. The antagonism of 5-HT receptors in the RTN/pFRG also prevented the long-term facilitation (>30 min) of abdominal activity in response to acute IH exposure (10 x 6-7% O for 45 s every 5 min). Our findings indicate the activation of serotoninergic mechanisms in the RTN/pFRG is sufficient to increase abdominal expiratory activity at resting conditions and required for the emergence of active expiration after IH in anesthetized animals. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the subfornical organ (SFO) is involved in the modulation of sodium intake in rats. To clarify whether serotonergic mechanisms in the SFO participate in the modulatory system, the present study was carried out to examine the effects of sodium and water intake on serotonin (5-hydroxytryptamine, 5-HT) release in the subfornical organ (SFO) in freely moving rats. The ingestion of 0.3 M NaCl and water was induced by subcutaneous injections of the diuretic furosemide (FURO, 10 mg/kg) and the angiotensin converting enzyme inhibitor captopril (CAP, 5 mg/kg), and extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the region of the SFO were measured using intracerebral microdialysis techniques. The combined treatment with FURO and CAP elicited significant decreases in the 5-HT and 5-HIAA levels in the SFO area. The 0.3 M NaCl and water intake caused by the treatment significantly enhanced the 5-HT and 5-HIAA concentrations in the SFO area compared with the basal levels. No significant changes in the 5-HT and 5-HIAA levels caused by either the FURO and CAP treatment or water and NaCl intake were observed in the sites away from the SFO. These results suggest that the serotonergic mechanism in the SFO may be important for the control of sodium appetite and thirst. [ABSTRACT FROM AUTHOR]

Hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the pathogenesis of depression. Dysfunction of the hippocampal serotonin (5-hydroxytryptamine, 5-HT) system has been shown to be a key factor in depression. There is growing evidence that electro-acupuncture (EA) has antidepressant-like effect. However, the effect of EA on HPA axis and hippocampal serotonin system remains unknown. In our study, we investigated the antidepressant-like effect and mechanism of EA for depression rat models. Depression in rats was induced by chronic unpredictable mild stress (CUMS). EA treatment was administered once daily to CUMS rats for 14 days. The acupoints (ST36, bilateral and CV4) were selected. Untreated CUMS rats and normal rats were used as controls. Behavioral tests including forced swim test and open-field test were performed to evaluate the antidepressant effects of EA treatment. Hypothalamic corticotropin-releasing hormone (CRH) mRNA, plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were estimated as indices of HPA axis activity. Enzyme linked immunosorbent assay (ELISA) was performed to determine the concentrations of 5-HT in the hippocampus. Real-time PCR(RT-PCR)and Western blot were respectively used to detect the mRNA and protein levels of 5-hydroxytryptamine 1A receptor (5-HT1AR) in the hippocampus. Our results showed that EA treatment reversed the behavioral deficiency induced by CUMS in rats. EA treatment decreased CRH mRNA expression in the hypothalamic, and ACTH and CORT level in plasma, and markedly increased 5-HT concentration, 5-HT1AR (mRNA and protein) expression in the hippocampus. These results indicated that EA treatment could act on depression by modulating HPA axis and enhancing hippocampal 5-HT/5-HT1AR in CUMS Rats. [ABSTRACT FROM AUTHOR]

Aims In this study we tested the hypothesis that tapentadol inhibits GGRP release from the rat brainstem through a mechanism mediated by the inhibition of NA reuptake; as a second alternative hypothesis, we investigated whether tapentadol inhibits GGRP release via the inhibition of 5-HT reuptake. Methods Rat brainstems were explanted and incubated in short-term experiments. CGRP released in the incubation medium was taken as a marker of CGRP release from the central terminals of trigeminal neurons within the brainstem. CGRP levels were measured by radioimmunoassay under basal conditions or in the presence of tapentadol; NA, 5-HT, clonidine, yohimbine and ondansetron were used as pharmacological tools to investigate the action mechanism of tapentadol. Results The α2-antagonist yohimbine failed to counteract the effects of tapentadol. Moreover, neither NA nor the α 2 -agonist clonidine per se inhibited K + − stimulated CGRP release, thereby indicating that the effects of tapentadol are nor mediated through the block of NA reuptake. Further experiments showed that 5-HT and tramadol, which inhibits both NA and 5-HT reuptake, significantly reduced K + -stimulated CGRP release. Moreover, the 5-HT3 antagonist ondansetron was able to counteract the effects of tapentadol in this system. Significance This study provided pharmacological evidence that tapentadol inhibits stimulated CGRP release from the rat brainstem in vitro through a mechanism involving an increase in 5-HT levels in the system and the subsequent activation of 5-HT3 receptors. [ABSTRACT FROM AUTHOR]

We investigated alterations of cardiac Ca(v)1.2 and 5-hydroxytryptamine (5-HT) associated with positional asphyxia. Male rats were divided into five groups: a control group with no restraint, group 1 restrained for 1 h, group 2 restrained for 2 h, group 3 restrained for 4 h, and group 4 restrained for 8 h. The rats that were restrained for 8 h ultimately suffered fatal asphyxia. After the restraint periods, the rats were sacrificed and immunohistochemistry was performed to evaluate the expressions of Ca(v)1.2 and 5-HT in the heart. Sections were analyzed by digital image analysis. Cardiac expression of Ca(v)1.2 and 5-HT proteins were significantly decreased by positional asphyxia in the rat, shown by integrated optical density (IOD) compared to controls. Our findings indicate that Ca(v)1.2 and 5-HT alterations could cause abnormal cardiac function, and the proteins investigated here may be useful for investigating the mechanisms underlying positional asphyxia. [ABSTRACT FROM AUTHOR]

The role of serotonin (5-hydroxytryptamine [5- HT]) in gastrointestinal motility has been studied for over 50 years. Most of the 5- HT in the body resides in the gut wall, where it is located in subsets of mucosal cells (enterochromaffin cells) and neurons (descending interneurons). Many studies suggest that 5- HT is important to normal and dysfunctional gut motility and drugs affecting 5- HT receptors, especially 5- HT3 and 5- HT4 receptors, have been used clinically to treat motility disorders; however, cardiovascular side effects have limited the use of these drugs. Recently studies have questioned the importance and necessity of 5- HT in general and mucosal 5- HT in particular for colonic motility. Recent evidence suggests the importance of 5- HT3 and 5- HT4 receptors for initiation and generation of one of the key colonic motility patterns, the colonic migrating motor complex ( CMMC), in rat. The findings suggest that 5- HT3 and 5- HT4 receptors are differentially involved in two different types of rat CMMCs: the long distance contraction ( LDC) and the rhythmic propulsive motor complex (RPMC). The understanding of the role of serotonin in colonic motility has been influenced by the specific motility pattern(s) studied, the stimulus used to initiate the motility (spontaneous vs induced), and the route of administration of drugs. All of these considerations contribute to the understanding and the controversy that continues to surround the role of serotonin in the gut. [ABSTRACT FROM AUTHOR]

5-HT is a powerful vasoconstrictor substance in renal vasculature (mainly by 5-HT2 activation). Nevertheless, 5-HT is notable for its dual cardiovascular effects, producing both vasodilator and vasoconstrictor actions. This study aimed to investigate whether, behind the predominant serotonergic vasoconstrictor action, THE 5-HT system may exert renal vasodilator actions, and, if so, characterize the 5-HT receptors and possible indirect pathways. Renal perfusion pressure ( PP), systemic blood pressure ( SBP) and heart rate ( HR) measurement in in situ autoperfused rat kidney was determined in phenylephrine infused rats. Intra arterial (i.a.) bolus administration of 5-HT (0.00000125-0.1 μg/kg) decreased renal PP in the presence of a phenylephrine continuous infusion (phenylephrine-infusion group), without modifying SBP or HR. These vasodilator responses were potentiated by 5-HT2 antagonism (ritanserin, 1 mg/kg i.v.), whereas the responses were abolished by 5-HT1/7 antagonist (methiothepin, 100 μg/kg i.v.) or 5-HT1D antagonist (LY310762, 1 mg/kg i.v.). The i.a. administration (0.00000125 to 0.1 μg/kg) of 5-CT or L-694,247 (5-HT1D agonist) mimicked 5-HT vasodilator effect, while other agonists (1-PBG, α-methyl-5-HT, AS-19 (5-HT7), 8-OH-DPAT (5-HT1A) or CGS-12066B (5-HT1B)) did not alter baseline haemodynamic variables. L-694,247 vasodilation was abolished by i.v. bolus of antagonists LY310762 (5-HT1D, 1 mg/kg) or L-NAME (nitric oxide, 10 mg/kg), but not by i.v. bolus of indomethacin (cyclooxygenase, 2 mg/kg) or glibenclamide (ATP-dependent K+ channel, 20 mg/kg). These outcomes suggest that 5-HT1D activation produces a vasodilator effect in the in situ autoperfused kidney of phenylephrine-infusion rats mediated by the NO pathway. [ABSTRACT FROM AUTHOR]

5-hydroxytryptamine (5-HT) is involved in the stress-induced alteration of colonic functions, specifically motility and secretion, but its precise mechanisms of regulation remain unclear. In the present study, we have investigated the effects of 5-HT on rat colonic mucosal secretion after acute water immersion restraint stress, as well as the underlying mechanism of this phenomenon, using short circuit current recording (ISC), real-time polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbance assays. After 2h of water immersion restraint stress, the baseline ISC and 5-HT-induced ISC responses of the colonic mucosa were significantly increased. Pretreatment with selective 5-HT4 receptor antagonist, SB204070, inhibited the 5-HT-induced colonic ISC response by 96% in normal rats and 91.2% in acute-stress rats. However, pretreatment with the selective antagonist of 5-HT3 receptor, MDL72222 or Y-25130, had no obvious effect on 5-HT-induced ISC responses under either set of conditions. Total protein expression of both the mucosal 5-HT3 receptors and the 5-HT4 receptors underwent no significant changes following acute stress. Both colonic basal cAMP levels and foskolin-induced ISC responses were significantly enhanced in acute stress rats. 5-HT significantly enhanced the intracellular cAMP level via 5-HT4 receptors in the colonic mucosa from both control and stressed animals, and 5-HT-induced cAMP increase in stressed rats was not more than that in control rats. Taken together, the present results indicate that acute water immersion restraint stress enhances colonic secretory responses to 5-HT in rats, a process in which increased cellular cAMP accumulation is involved. [ABSTRACT FROM AUTHOR]

Disorders caused by the malfunction of the serotonergic system in the central nervous system show sex-specific prevalence. Many studies have reported a relationship between sex steroid hormones and the brain serotonergic system; however, the interaction between sex steroid hormones and the number of brain neurons expressing serotonin has not yet been elucidated. In the present study, we determined whether sex steroid hormones altered the number of serotonergic neurons in the dorsal raphe nucleus (DR) of adult rat brains. Animals were divided into five groups: ovariectomized (OVX), OVX + low estradiol (E2), OVX + high E2, castrated males, and intact males. Antibodies against 5-hydroxytryptamine (5-HT, serotonin) and tryptophan hydroxylase (Tph), an enzyme for 5-HT synthesis, were used as markers of 5-HT neurons, and the number of 5-HT-immunoreactive (ir) or Tph-ir cells was counted. We detected no significant differences in the number of 5-HT-ir or Tph-ir cells in the DR among the five groups. By contrast, the intensity of 5-HT-ir showed significant sex differences in specific subregions of the DR independent of sex steroid levels, suggesting that the manipulation of sex steroid hormones after maturation does not affect the number and intensive immunostaining of serotonergic neurons in rat brain. Our results suggest that, the sexual dimorphism observed in the serotonergic system is due to factors such as 5-HT synthesis, transportation, and degradation but not to the number of serotonergic neurons. [ABSTRACT FROM AUTHOR]

Summary Previous studies have shown that diet-induced obesity is associated with insulin resistance and impaired feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. The objective of this study was to test the hypothesis that hyper-secretion of glucocorticoid, evoked by feeding rats a high fat (HF) diet for 12 weeks, also influences behavioural and neural responses to the elevated plus-maze (EPM) test of anxiety. HF-fed animals exhibited anxiolytic-like behaviour in the EPM but were also hyperactive in this test. Covariant analysis established that the anxiolytic-like behaviour was not secondary to the increase in activity. The HF diet significantly increased basal levels of plasma corticosterone. The groups exposed to the EPM also displayed increased plasma corticosterone levels compared to the relevant control group, although the increment was smaller in the HF-fed animals. Glucocorticoid receptor (GR) immunoreactivity in the cytoplasmic fraction of parietal cortex and hypothalamus and the particulate fraction of the parietal cortex were increased by HF feeding. The behavioural changes evoked by HF feeding did not correlate significantly with changes in GR immunoreactivity in each treatment group or 5-HT turnover in the brain areas studied. It is concluded that anxiolytic properties evoked in the EPM by high fat feeding are unlikely to be related to the changes in HPA function seen in animals fed this diet. [ABSTRACT FROM AUTHOR]

This study was aimed to test the authors' hypothesis stating that the developing brain before the closure of the blood brain barrier (BBB) operates as an endocrine organ that secretes classical neurotransmitters and neuropeptides into the general circulation. 5-Hydroxytryptamine (5-HT) was selected as a marker of brain endocrine activity though it is also secreted by peripheral organs. 5-HT was detected in blood of rats in a biologically active concentration at any studied age, from the 21st embryonic day till the 30th postnatal day. The brain was proven to be a source of circulating 5-HT before the BBB closure by showing that the 5-HT concentration in blood decreased significantly after the inhibition of 5-HT synthesis in the brain of neonates. The 5-HT concentration in blood was not diminished after the BBB closure, apparently due to compensatory increase of 5-HT secretion by peripheral sources. Thus, brain-derived 5-HT is delivered to the general circulation before the BBB closure being potentially capable of providing endocrine regulation of target organs. [ABSTRACT FROM AUTHOR]

Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p -methoxyamphetamine, PMA; p -methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5 mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150–290%) but remarkably increased 5-HT levels (540–900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para -mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC 50 values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs. [ABSTRACT FROM AUTHOR]

We have demonstrated that the antagonism of 5-HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect by 5-HT1D and 5-HT7 activation. The aim of this work was to determine mechanisms involved in the 5-hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in pithed rats treated with a 5-HT2 receptor blocker. The blockade of 5-HT2 receptors was induced by orally sarpogrelate treatment (30mg/kg/day). Two weeks later, animals were anaesthetized and pithed. A bolus injection of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10µg/kg), a guanylyl cyclase inhibitor, or indomethacin (2mg/kg), a non-selective COX inhibitor, prior to the infusion of (2S)(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin, AS-19 (5µg/kg/min) were not able to abolish its inhibitory action. However, i.v. administration of glibenclamide (20mg/kg), a blocker of ATP-sensitive K+ channels, completely reversed AS-19 sympathoinhibitory action. The inhibitory effect of 2-[5-[3-(4-methylsulfonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3-yl]ethanamine, L-694,247 (5µg/kg/min) was abolished by indomethacin, whereas pretreatment with ODQ had no effect. Nimesulide (3mg/kg), a COX-2 inhibitor, completely reversed the inhibitory action of L-694,247, whereas 1-[[4,5-bis (4-methoxyphenyl)-2-thiazolyl]carbonyl]-4-methylpiperazine hydrochloride (FR122047) (3mg/kg), a COX-1 inhibitor, partially blocked this action. The sympathoinhibition by 5-HT (20µg/kg/min) could not be elicited after i.v. treatment with indomethacin plus glibenclamide. In conclusion, these results suggest that in chronic sarpogrelate-treated rats, the inhibitory serotonergic effect of the pressor responses induced by electrical stimulation of the sympathetic outflow via 5-HT7 and 5-HT1D receptor activation is mediated by KATP channel-mediated smooth muscle hyperpolarization and the COX pathway, respectively. [ABSTRACT FROM AUTHOR]

Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects. [ABSTRACT FROM PUBLISHER]

In our previous work, we found that feeding Lactobacillus johnsonii to BioBreeding diabetes-prone (BBDP) rats decreased the incidence of diabetes development. The aim of this study was to investigate host pathways affected by L. johnsonii, with specific focus on the rate-limiting enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO). Suspensions of L. johnsonii or an equal volume of vehicle were orally administered to BBDP rats. Tissue IDO was investigated using quantitative RT-PCR and Western blot, whereas tryptophan, kynurenine, and 5-hydroxytryptamine (5-HT) concentrations were quantified by HPLC and ELISA. IDO activity was also investigated using L. johnsonii culture cell-free supernatant (CFS) with affinity-purified IDO and HT-29 intestinal epithelial cells. L. johnsonii feeding resulted in a 17% reduction in serum kynurenine compared with that in vehicle-fed controls, correlating with a 1.4-fold elevation in 5-HT levels. H2O2 produced by L. johnsonii abolished IDO activity in vitro, and L. johnsonii feeding resulted in a 3.9-fold increase in ileum lumen H2O2. L. johnsonii CFS significantly reduced IDO activity in HT-29 intestinal epithelial cells (47% reduction) compared with that in vehicle-treated controls, an effect abolished by catalase treatment. These data support the role of H2O2 in commensal bacteria-host interactions and highlight the influence of commensal bacteria-derived H2O2 on host physiology. [ABSTRACT FROM AUTHOR]

We investigated the mechanisms involved in the 5-hydroxytriptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in long-term-diabetic pithed rats. Diabetes was induced in rats by alloxan administration. Eight weeks later, the animals were anaesthetized and pithed. The action and mechanisms of 5-HT were analysed based on the pressor responses induced by sympathostimulation. In 8-week-diabetic animals, 5-HT (20 μg/kg/min) inhibits the pressor effect of sympathostimulation which is reproduced by two selective 5-HT1A and 5-HT2 receptor agonists: 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT, 5 μg/kg/min) and α-methyl-5-HT (5 μg/kg/min). A bolus injection of 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 10 μg/kg), or L-arginine HCl, Nω-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg), an inhibitor of NO production, prior to the infusion of 8-OH-DPAT (5 μg/kg/min) reversed the inhibitory effect of 8-OH-DPAT. The inhibitory effect of infusion of α-methyl 5-HT (5 μg/kg/min) was abolished in the presence of indomethacin (2 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, or FR 122047 (1.5 mg/kg) or nimesulide (1.5 mg/kg), two selective COX-1 and COX-2 inhibitors, respectively, in long-term-diabetic pithed rats. Our results indicate that 5-HT inhibition of the pressor responses induced by electrical stimulation is mediated both by the NO and COX pathways in long-term-diabetic rats. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We investigated the mechanisms involved in the 5-hydroxy-triptaminergic inhibitory action on the pressor responses elicited by sympathostimulation in long-term-diabetic pithed rats. Diabetes was induced in rats by alloxan administration. Eight weeks later, the animals were anaesthetized and pithed. The action and mechanisms of 5-HT were analysed based on the pressor responses induced by sympathostimulation. In 8-week-diabetic animals, 5-HT (20 &mgr;g/kg/min) inhibits the pressor effect of sympathostimulation which is reproduced by two selective 5-HT1A and 5-HT2 receptor agonists: 8-hydroxydipropylaminotetralin hydrobro-mide (8-OH-DPAT, 5 &mgr;g/kg/min) and &agr;-methyl-5-HT (5 &mgr;g/kg/min). A bolus injection of 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 10 &mgr;g/kg), or L-arginine HCl, Νω-L,-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg), an inhibitor of NO production, prior to the infusion of 8-OH-DPAT (5 &mgr;g/kg/min) reversed the inhibitory effect of 8-OH- DPAT. The inhibitory effect of infusion of α-methyl 5-HT (5 &mgr;g/kg/min) was abolished in the presence of indomethacin (2 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, or FR 122047 (1.5 mg/kg) or nimesulide (1.5 mg/kg), two selective COX-1 and COX-2 inhibitors, respectively, in long-term-diabetic pithed rats. Our results indicate that 5-HT inhibition of the pressor responses induced by electrical stimulation is mediated both by the NO and COX pathways in long-term-diabetic rats. [ABSTRACT FROM AUTHOR]

Summary: The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Previous work has shown that the dorsal raphe nucleus (DR)-5-HT system is inhibited by swim stress via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor (CRF). Additionally, the DR 5-HT system is regulated by opioids. The present study tests the hypothesis that the DR 5-HT system regulates stress-induced opioid relapse. In the first experiment, electrophysiological recordings of GABA synaptic activity in 5-HT DR neurons were conducted in brain slices from Sprague-Dawley rats that were exposed to swim stress-induced reinstatement of previously extinguished morphine conditioned place preference (CPP). Behavioral data indicate that swim stress triggers reinstatement of morphine CPP. Electrophysiology data indicate that 5-HT neurons in the morphine-conditioned group exposed to stress had increased amplitude of inhibitory postsynaptic currents (IPSCs), which would indicate greater postsynaptic GABA receptor density and/or sensitivity, compared to saline controls exposed to stress. In the second experiment, rats were exposed to either morphine or saline CPP and extinction, and then 5-HT DR neurons from both groups were examined for sensitivity to CRF in vitro. CRF induced a greater inward current in 5-HT neurons from morphine-conditioned subjects compared to saline-conditioned subjects. These data indicate that morphine history sensitizes 5-HT DR neurons to the GABAergic inhibitory effects of stress as well as to some of the effects of CRF. These mechanisms may sensitize subjects with a morphine history to the dysphoric effects of stressors and ultimately confer an enhanced vulnerability to stress-induced opioid relapse. [Copyright &y& Elsevier]

Abstract: We compared the neurotoxic effects of 14nm silver nanoparticles (AgNPs) and ionic silver, in the form of silver acetate (AgAc), in vivo and in vitro. In female rats, we found that AgNPs (4.5 and 9mg AgNP/kg bw/day) and ionic silver (9mg Ag/kg bw/day) increased the dopamine concentration in the brain following 28 days of oral administration. The concentration of 5-hydroxytryptamine (5-HT) in the brain was increased only by AgNP at a dose of 9mg Ag/kg bw/day. Only AgAc (9mg Ag/kg bw/day) was found to increase noradrenaline concentration in the brain. In contrast to the results obtained from a 28-day exposure, the dopamine concentration in the brain was decreased by AgNPs (2.25 and 4.5mg/kg bw/day) following a 14-day exposure. These data suggest that there are differential effects of silver on dopamine depending on the length of exposure. In vitro, AgNPs, AgAc and a 12kDa filtered sub-nano AgNP fraction were used to investigate cell death mechanisms in neuronal-like PC12 cells. AgNPs and the 12kDa filtered fraction decreased cell viability to a similar extent, whereas AgAc was relatively more potent. AgNPs did not induce necrosis. However, apoptosis was found to be equally increased in cells exposed to AgNPs and the 12kDa filtered fraction, with AgAc showing a greater potency. Both the mitochondrial and the death receptor pathways were found to be involved in AgNP- and AgAc-induced apoptosis. In conclusion, 14nm AgNPs and AgAc affected brain neurotransmitter concentrations. AgNP affected 5-HT, AgAc affected noradrenaline, whereas both silver formulations affected dopamine. Furthermore, apoptosis was observed in neuronal-like cells exposed to AgNPs, a 12kDa filtered fraction of AgNP, and AgAc. These findings suggest that ionic silver and a 14nm AgNP preparation have similar neurotoxic effects; a possible explanation for this could be the release and action of ionic silver from the surface of AgNPs. [Copyright &y& Elsevier]

The article offers information on a study that established a model of migraine by electrical simulation of the superior sagittal sinus in rats. The study reveals the analgesic effects of paroxetine in a rat migraine model. After treatment, the study finds higher mechanical withdrawal thresholds and extracellular concentrations of 5-hydroxytryptamine in the periaqueductal grey matter and nucleus reticularis gigantocellularis.

Studies suggest that like selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors, antagonists at neurokinin-1 receptors (NK1Rs) may have antidepressant and anxiolytic properties. NK1Rs are present in 5-HT innervated forebrain regions which may provide a common point of interaction between these two transmitter systems. This study aimed to investigate for cellular co-localization between NK1Rs and 5-HT receptor subtypes in mood-related brain regions in the rat forebrain. With experiments using fluorescence immunocytochemistry, double-labelling methods demonstrated a high degree of co-localization between NK1Rs and 5-HT1A receptors in most regions examined. Co-localization was highest in the medial septum (88% NK1R expressing cells were 5-HT1A receptor-positive) and hippocampal regions (e.g. dentate gyrus, 65%), followed by the lateral/basolateral amygdala (35%) and medial prefrontal cortex (31%). In contrast, co-localization between NK1Rs and 5-HT2A receptors was infrequent (< 8%) in most areas examined except for the hippocampus (e.g. CA3, 43%). Overall co-localization between NK1Rs and 5-HT1A receptors was much greater than that between NK1Rs and 5-HT2A receptors. Thus, these experiments demonstrate a high degree of co-localization between NK1Rs and 5-HT1A receptors in cortical and limbic regions of the rat forebrain. These findings suggest a novel site of interaction between NK1R antagonists and the 5-HT system. [ABSTRACT FROM PUBLISHER]

The relevance of age on serotonergic involvement in the control of alimentary contractility has not been pharmacologically described. Experiments were performed to investigate the effects of acetylcholine, atropine, 5-hydroxytryptamine (5-HT) and its related drugs on intestinal segments taken from the neonatal and adult ileum. 5-HT induced concentration-dependent contractions of ileum irrespective of age; however, these contractions were diminished by pretreatment with atropine only in neonatal tissues. In tissues taken from both the neonatal and adult ileum, methysergide (5-HT1/2/5-7 receptor antagonist), ritanserin (5-HT2 receptor antagonist), and RS23597-190/SB204070 (5-HT4 receptor antagonists) all differentially reduced 5-HT-induced contractions at a concentration <100 μmol/l. At higher concentrations, the contractions were comparable to those in control tissues. Granisetron and ondansetron (5-HT3 receptor antagonists) significantly reduced contractions induced by 5-HT at concentrations >30 μmol/l in both neonatal and adult ileum. Combined treatments with ritanserin, granisetron, plus RS23597-190 reduced or abolished contraction responses induced in neonatal ileum by 5-HT. SB269970A (5-HT7 receptor antagonist) and WAY100635 (5-HT1A receptor antagonist) failed to influence contractile responses induced by 5-HT or 5-HT receptor agonists. Pretreatments with WAY100635 and SB267790A also had no influence on the contractile responses induced by 5-HT1A/7 receptor agonist, 5-CT, and 5-HT1A receptor agonist, 8-OH-DPAT, which itself failed to induce a measurable response. It is concluded that the 5-HT-induced contractions in segments taken from both the neonatal and adult rat ileum were mediated via 5-HT2 receptors, 5-HT3 receptors and 5-HT4 receptors. However, the effect of atropine on the neonatal rat intestine indicates that the mechanism of serotonergic involvement in ileal contractility is influenced by age. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

It has been rereported that axons which display 5-hydroxytryptamine (5-HT) immunoreactivity are abundant in the pancreas and the majority of serotonergic axons terminate within intrapancreatic ganglia, islet and acini. This histological result strongly suggests that intrapancreatic serotonergic nerves could affect to the pancreatic endocrine and exocrine secretion. Thus, this study was aimed to investigate whether intrapancreatic serotonergic nerves could affect pancreatic exocrine secretion and an action mechanism of the intrapancreatic serotonergic nerves. The rats were anesthetized with a single injection of urethane. The median line and the abdominal aorta was carefully dissected and cannulated with PE-50 tubing just above the celiac artery, and then tightly ligated just below the superior mesenteric artery. The pancreatic duct was also cannulated with Tygon microbore tubing. With the addition of serotonin, pancreatic volume flow and amylase output were significantly inhibited electrical field stimulation (EFS). On the other hand, pancreatic volume flow and amylase output were significantly elevated in EFS with the addition of spiperone. EFS application, however, pancreatic volume flow and amylase output had no significant change in cholecystokinin (CCK) alone when serotonin was applied under a 5.6 mM glucose background. Pancreatic volume flow and amylase output under 18 mM glucose background were significantly elevated in CCK plus serotonin than in CCK alone. These data suggest that intrapancreatic serotonergic nerves play an inhibitory role in pancreatic exocrine secretion and an important role in the insulin action or release. [ABSTRACT FROM AUTHOR]

Abstract: Serotonin (5HT) is a biologically active amine present in mammals in the brain and the peripheral tissues. Autism is a neurodevelopmental disorder in which 5HT homeostasis is disturbed both centrally and peripherally, but the relationship between the 5HT disturbances in the two compartments is not understood. In an attempt to explore the relationship between the disturbed peripheral 5HT homeostasis and central 5HT functioning, we exposed the developing rat brain to increased 5HT concentrations, by treatment of rats with subcutaneous injections of the immediate 5HT precursor 5-hydroxy-l-tryptophan (5HTP, 25mg/kg), or the non-selective MAO inhibitor tranylcypromine (TCP, 2mg/kg), during the period of the most intensive development of 5HT neurons – from gestational day 13 to post-natal day 21. The effects of the mentioned treatments on peripheral and central 5HT levels were then studied in adult rats. Platelet and plasma 5HT concentrations (measured by ELISA), as well as cortical and midbrain 5HT, tryptophan and 5-hydroxyindoleacetic acid levels (measured by HPLC) were determined in twelve 5HTP treated and eight TCP treated rats, and compared with the values measured in 10 control, saline treated rats. Treatment with 5HTP significantly raised peripheral but not central 5HT concentrations. At adult age, peripheral 5HT homeostasis was re-established, while modest decrease in 5HT concentration was observed in frontal cortex, presumably due to hyperserotonemia-induced loss of 5HT terminals during brain development. Treatment with TCP induced significant 5HT elevations in both compartments. At adult age, permanent changes in 5HT homeostasis were observed, both peripherally (as hyperserotonemia) and centrally (as altered 5HT metabolism with decreased 5HT concentrations). Further studies are planned in order to explore the nature of the different disturbances of 5HT homeostasis induced by the two compounds, and their results are expected to shed some light on the role of hyperserotonemia in autism. [Copyright &y& Elsevier]

The article presents a study on the impacts of habenular nucleus (Hb) excitation on 5-hydroxytryptamine (5-HT) and genioglossus electromyogram (EMG). The study stimulates Hb of adult Wistar rats using L-glutamate and evaluates the changes on 5-HT release, abnormalities on genioglossus EMG performance, and changes in the respiration. Result shows that Hb stimulation lead to the apnea development similar to obstructive sleep apnea syndrome and plasma 5-hydroxytryptamine content reduction.

Abstract: We attempted to characterize the 5-hydroxytryptamine (5-HT) receptor type/subtype and mediator mechanisms involved in the contractile effects of 5-HT in the in situ autoperfused kidney of long-term diabetic rats. Diabetes was induced in male Wistar rats by a single subcutaneous injection of alloxan. Intra-arterial (i.a.) bolus injection of 5-HT (0.00000125 to 0.1μg/kg) increased renal perfusion pressure in a dose dependent way but did not affect the systemic blood pressure in long-term diabetic rats. The selective 5-HT2 receptor agonist, α-methyl-5-HT, caused a local vasoconstrictor effect in the in situ autoperfused rat kidney similar to 5-HT. However, BW723C86, a selective 5-HT2B receptor agonist, m-CPP (1-(3-chlorophenyl)piperazine), a selective 5-HT2B/2C receptor agonist, the 5-HT1 receptor agonist, 5-carboxamidotryptamine (5-CT), and the selective 5-HT3 receptor agonist, 1-phenylbiguanide did not modify the renal perfusion pressure. In long-term diabetic rats, vasoconstriction elicited by 5-HT and α-methyl-5-HT was significantly decreased by ritanserin (a 5-HT2 receptor antagonist), spiperone (a 5-HT2A receptor antagonist), and the cyclooxygenase (COX) inhibitors, indomethacin (non-selective COX inhibitor), FR 122047 or nimesulide (selective COX-1 and COX-2 inhibitors, respectively), but was not modified by pretreatment with SB 206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2.b:4,5-b′]dipyrrole(1H)-carboxamide hydrochloride), a non-selective 5-HT2C receptor antagonist, prazosin, propranolol, enalapril or losartan. The results of protein expression support these results: COX-1 and COX-2 are expressed in renal tissue. Inducible COX (COX-2) is overexpressed in long-term diabetes. Our data suggest that, in the in-situ autoperfused kidney of long-term diabetic rats, 5-HT vasoconstrictor action is mediated, through cyclooxygenase pathway, by local activation of 5-HT2A receptors. [Copyright &y& Elsevier]

Abstract: We have demonstrated that the activation of 5-hydroxytryptamine (5-HT) receptor 3 in the submucosal plexus suppresses 5-HT-induced colonic ion secretion by increasing submucosal somatostatin release. A number of psychological and physical stresses have impacts on the intestinal mucosal functions, including secretion and the epithelial barrier. Whether the 5-HT3 receptor-mediated somatostatin-dependent secretoinhibitory pathway in the rat distal colon is involved in the stress process is still unknown. The present study aims to investigate the effect of the water-immersion restraint stress on this inhibitory pathway and its underlying mechanisms. Mucosa/submucosa preparations from the rat distal colon were mounted in the Ussing chambers for the measurement of short-circuit current (I SC). Real-time PCR and western blot were performed to study the expression of the 5-HT3 receptor, 5-HT4 receptor, and somatostatin receptor 2. Radioimmunoassay was used to measure somatostatin release. After 2h of water-immersion restraint stress, the membrane resistance (Rte) of rat mucosa/submucosa preparations was significantly decreased, but the baseline I SC and 5-HT-induced I SC responses were significantly increased. The protein expression of the submucosal 5-HT3 receptors and mucosal somatostatin receptor 2 were down-regulated, and the 5-HT-induced somatostatin release from the mucosa/submucosa preparations was significantly reduced in the stress group. Taken together, these results suggest that the 5-HT3 receptor-mediated somatostatin-dependent secretoinhibitory pathway is suppressed in the water-immersion restraint stressed rats, which may contribute to the acute stress-induced increase in colonic secretion. [Copyright &y& Elsevier]

Abstract: Considering the importance of 5-hydroxytryptamine (5-HT) and cyclooxygenase (COX) products in vascular pathology, we investigated the effects of 5-HT on COX expression in rat vascular smooth muscle cells (VSMCs), and to provide mechanistic insights into these effects. VSMCs were enzymatically isolated from aortic media of Wistar rats. Incubation of VSMCs with 5-HT for 24h stimulated prostaglandin I2 production, but this stimulation was completely suppressed by NS-398, a selective COX-2 inhibitor. 5-HT induced transient COX-2, but not COX-1, protein and mRNA expression in concentration- and time-dependent manners. This effect of 5-HT was completely inhibited by sarpogrelate, a 5-HT2A receptor antagonist. 5-HT-induced COX-2 expression was markedly blunted by Ca2+ depletion; GF 109203X, a protein kinase C (PKC) inhibitor; PP2, an inhibitor of Src-family tyrosine kinase (Src); PD 98059, an inhibitor of extracellular signal-regulated kinase (ERK) activation; SB 203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK); and SP 600125, an inhibitor of c-Jun N-terminal kinase (JNK). 5-HT activated ERK and p38 MAPK, followed by JNK activation. PP2 inhibited these activations, while GF 109203X inhibited only JNK activation. Furthermore, PD 98059 inhibited JNK activation. These results suggest that 5-HT induces COX-2 expression in rat VSMCs, and that PKC, Src, and MAPK activation are each essential for the full expression of COX-2 pathways. [Copyright &y& Elsevier]

Abstract: We analysed the type and/or subtype of 5-hydroxytryptamine (5-HT) receptors involved in the inhibitory mechanisms of 5-HT on the pressor responses induced by stimulation of sympathetic vasopressor outflow in long-term diabetic pithed rats. Diabetes was induced in male Wistar rats by a single subcutaneous injection of alloxan. Eight weeks later, rats were anaesthetized, pre-treated with atropine, and pithed. The effect of 5-HT on the pressor responses elicited by stimulation of the sympathetic outflow was analysed in eight-week alloxan-induced diabetic pithed rats. 5-HT (20μg/kg/min) reduced the pressor action obtained by electrical stimulation of the sympathetic outflow. However, there was no effect on exogenous noradrenaline-induced pressor responses. 5-CT (5μg/kg/min), 8-OH-DPAT (5μg/kg/min), and α-methyl-5-HT (5μg/kg/min), selective 5-HT1, 5-HT1A and 5-HT2 receptor agonists, respectively, reproduced the 5-HT inhibitory action. Nevertheless, infusion of 5μg/kg/min of 1-phenylbiguanide, CGS-12066B, L-694,247, BW273C86 or MK212 (5-HT3, 5-HT1B, 5-HT1D, 5-HT2B and 5-HT2C receptor agonists, respectively) had no effect on the pressor responses elicited by stimulation of the sympathetic outflow. Methiothepin (100μg/kg) and a cocktail of WAY-100,635 (100μg/kg) and spiperone (125μg/kg) blocked the 5-HT inhibitory effect on the pressor action obtained by sympathetic stimulation. Moreover, WAY-100, 635 abolished the 8-OH-DPAT inhibitory effect and spiperone blocked α-methyl-5-HT action. In conclusion, this study revealed that long-term experimental diabetes induces changes in the receptor type/subtype involved in the 5-HT inhibitory action on the sympathetic pressor responses produced by electrical stimulation. This is mainly mediated by pre-junctional 5-HT1A and 5-HT2A receptors. [Copyright &y& Elsevier]

Abstract: This report investigates acute changes in the sensitivity of 5-HT1A receptors in dorsal raphe (dr) neurons in response to elevated serotonin. DR neurons were isolated from adult rats and measurements of inhibition of Ca2+ current by 5-HT were obtained using the whole cell patch clamp technique. During a 10-min application of 5-HT (with normal [Ca2+]i∼100 nM) a desensitization occurred. The response to 20 nM 5-HT decreased by 66% relative to control and remained depressed for about 30 min. When the internal [Ca2+] was buffered to <1 nM only a weak transient desensitization occurred that was surmountable with higher [5-HT]. Adenylyl cyclase activation with forskolin mimicked the desensitization and selective inhibition of protein kinase A (PKA), but not protein kinase C (PKC), partially antagonized the desensitization induced by 5-HT. To measure the activity of PKA and phosphatase enzymes, dr slices were incubated with the selective agonist dipropyl-5-carboxamidotryptamine (DP-5-CT, 1 μM) for 10 min and the phosphorylation of the PKA substrate Kemptide was followed using ATP-γ32P. DP-5-CT inhibited the cAMP stimulated maximal activity of PKA but raised basal PKA activity, thus increasing the percentage of PKA in the active state (activity ratio), an effect that was prevented by the selective 5-HT1A antagonist WAY100635. DP-5-CT also caused a significant inhibition of phosphatase activity. These data support a model in the dr where 5-HT1A-receptor stimulation of PKA promotes phosphorylation of a target and phosphatase inhibition leading to heterologous desensitization. The effect would be expected to have physiological consequences for 5-HT-mediated inhibitory post synaptic potentials and the Ca2+ component of the action potentials of dr neurons. [Copyright &y& Elsevier]

Abstract: The 5-HT4 receptor modulates activity of serotonergic neurons and is a new potential target for antidepressant treatment. This microdialysis study evaluated the effect of the 5-HT4 receptor agonist, RS67333, on extracellular serotonin (5-hydroxytryptamine, 5-HT) and 5-HIAA levels in rat ventral hippocampus during chloral hydrate anaesthesia, and explored the ability of RS67333 to augment the effect of the selective serotonin reuptake inhibitor paroxetine. The effect of RS67333 was examined after acute and subchronic (3 days) administration. Acute RS67333 (1.5mg/kg i.v.) had no effect on extracellular 5-HT or 5-HIAA levels, while acute paroxetine (0.5mg/kg i.v.) increased 5-HT levels by 299±16% and decreased 5-HIAA levels by 25±4%. Administration of RS67333 80min after paroxetine caused an additional transient increase in 5-HT levels (to 398±52% of baseline). Subchronic RS67333 administration (1.5mg/kg i.p.) increased basal 5-HT levels by 73±15% and decreased 5-HIAA levels by 27±13%. In conclusion, the 5-HT4 receptor agonist RS67333 augmented the acute effect of paroxetine on extracellular 5-HT levels in the ventral hippocampus, and after 3 days increased basal hippocampal 5-HT levels. [Copyright &y& Elsevier]

Abstract: The descending serotonergic (5-HT) system is shown to be plastically altered under pathological conditions such as inflammation or peripheral nerve lesion. Although much evidence indicates that the potentiation of descending facilitatory 5-HT pathways may contribute to the development of chronic pain, the inhibition of descending inhibitory 5-HT system may be functionally more important to the development of central sensitization and neuropathic pain. In the present study, we observed that the inhibitory effects of 5-HT and its receptor agonists including 1A, 1B, 3, 4, and probably 2C receptor agonists, on the C-fiber responses of dorsal horn wide dynamic range (WDR) neurons in the spinal cord decreased significantly following spinal nerve ligation (SNL). Furthermore, we found that the antagonistic effects of 5-HT 1B, 2C, 3, and 4 receptor antagonists on the 5-HT-induced inhibition of C-fiber responses of WDR neurons were also attenuated after SNL. In consistent with these observations, we also found an obvious decrease in the content of 5-HT and 5-HIAA, and a marked increase in the turnover rate of 5-HT (5-HIAA/5-HT) in the ipsilateral dorsal half of the lumbar spinal cord after SNL. These data indicate that a loss or decrease in the descending inhibitory 5-HT system upon the spinal processing of nociceptive information appears to occur following spinal nerve injury, and this kind of decrease in the descending inhibitory 5-HT system is proposed to be involved in the development of central sensitization and ultimately to the nerve injury-induced neuropathic pain. [Copyright &y& Elsevier]

Abstract: The effects of chronic pre-treatment with a standardised extract of Curcuma longa on learning and spatial memory in aged 24-month old male Wistar rats were estimated in a Morris water maze paradigm. Animals received the extract orally for two months in prepared rodent chow to obtain the doses 10 and 50mg/kg/day. At the end of behavioural trials the concentration of neurotransmitters, their metabolites and amino acids in selected brain regions were estimated. There was a significant decrease in escape latency over four days of training in both treated groups in comparison to the control group. In a probe trial on the 5th day the C10 group crossed the target area more often and spent more time in the SE quadrant than control group. Significant differences in brain monoamines and amino acid levels between groups were noticed. The increase in the 5-HT (5-hydroxytryptamine) level in the prefrontal cortex correlated positively with the number of crossings over the target area during the first probe trial in both pre-treated groups. The plasma corticosterone level was lower in both pre-treated groups than in the control group. This suggests enhanced learning ability and spatial memory after C. longa extract treatment with the modulation of central serotoninergic system activity, and may be linked with an increased tolerance to stress conditions. A decrease in hippocampal glutamate in animals given plant extract compared to control rats was observed. It is possible that extract may influence a reduction in glutamate-induced excitotoxicity and consequently the neurodegeneration processes in the hippocampus. [Copyright &y& Elsevier]

Abstract: Aim: To determine if central serotonin (5-HT)-induced satiety is altered in obesity. Methods: Obese and lean Zucker rats received infusion of 5-HT (5μg/0.5μl/h) or saline into the ventromedial nucleus of the hypothalamus (VMN) for 2 weeks. Results: In lean rats, 5-HT decreased body weight (7%) and total food intake (15%) which was due to a decreased meal size during the dark phase. In obese rats, a decrease of food intake was also observed in the dark phase, but it was compensated by an increased food intake during the light phase, resulting in no significant changes of total food intake and body weight. In obese rats, meal number but not meal size was affected by 5-HT delivery. Body fat content was not affected by 5-HT in obese rats, while cessation of 5-HT delivery in lean rats resulted in 13% increase. Conclusion: Intra-VMN 5-HT in obese rats did not increase meal-associated satiety as it did in lean rats, but modulated hunger. These results show that the Zucker obese phenotype is characterized by VMN resistance to 5-HT, which may contribute to neurobiological mechanisms of increased meal size and food intake and may diminish anti-obesity effects of serotonergic anorexiants. [Copyright &y& Elsevier]

Abstract: The effects of nociceptin/orphanin FQ on putative serotonin (5HT) neurons of the dorsal raphe nucleus (DRN), known to modulate the behavioral responses to stress, were investigated in vivo and in vitro. In DRN slices from unstressed rats, nociceptin/orphanin FQ concentration-dependently inhibited the firing rate of putative 5HT neurons (EC50 = 21.6 ± 1.21 nM) and the selective NOP receptor antagonist UFP-101 shifted the concentration-response curve to the right (estimated pA2 6.86). Nociceptin/orphanin FQ potency was enhanced in slices prepared from rats previously subjected to a 15 min swim stress (EC50 = 1.98 ± 0.11 nM). Swim stress did not change the number or affinity of NOP receptors in DRN. Stress-elicited potentiation involved corticotropin-releasing factor (CRF)1 receptors, GABA signaling and protein synthesis, being attenuated by pre-treatment with antalarmin (20 mg/kg, i.p.), diazepam (2.4 mg/kg, i.p.) and cycloheximide (2.5 mg/kg, i.p.), respectively. In anesthetized unstressed rats, locally applied nociceptin/orphanin FQ (0.03 and 0.1 ng/30 nl) inhibited the firing rate of DRN neurons (to 80 ± 7 and 54 ± 10% of baseline, respectively). Nociceptin/orphanin FQ inhibition was potentiated both 24 h after swim stress and 1 h after CRF (30 ng/30 nl intra-DRN). Stress-induced potentiation was prevented by the selective CRF1 receptor antagonist, NBI 30755 (20 mg/kg, i.p.). In contrast, the inhibitory response of DRN neurons to the 5HT1A agonist, 8OH-DPAT (1μg/1 μl, intra-DRN) was not potentiated by swim stress, ruling out a non-specific enhanced permeability of GIRK channel. Together, these findings suggest that CRF and the nociceptin/orphanin FQ/NOP system interact in the DRN during stress to control 5HT transmission; this may play a role in stress-related neuropsychopathologies. [Copyright &y& Elsevier]

Serotonin (5-hydroxytryptamine; 5-HT) has been shown to produce vascular sympatho-inhibi-tion in a wide variety of isolated blood vessels by activation of prejunctional 5-HT1 receptors. After considering the mechanisms involved in modulating neuroeffector transmission, the present review analyzes the experimental findings identifying the pharmacological profile of the 5-HT receptors that inhibit the sympathetically-induced vasopressor responses in pithed rats. Thus, 5-HT-induced sympatho-inhibition has been shown to be: (i) unaffected by physiological saline or by the selective antagonists ritanserin (5-HT2), MDL72222 (5-HT3) or tropisetron (5-HT3/4); (ii) blocked by methysergide, a non-selective 5-HT1/2 receptor antagonist; and (iii) potently mimicked by 5-carboxamidotryptamine (5-CT), a non-selective 5-HT1 receptor agonist, as well as by the selective agonists 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP93,129 (5-HT1B), and sumatriptan (5-HT1B/1D). These findings show the involvement of prejunctional 5-HT1 receptors. With the use of selective antagonists, it has been shown subsequently that the sympatho-inhibition induced by indorenate, CP93,129, and sumatriptan was selectively antagonized by WAY100635 (5-HT1A), cyanopindolol (5-HT1A/1B), and GR127935 (5-HT1B/1D), respectively. These results demonstrate that the 5-HT1 receptors mediating sympatho-inhibition on the systemic vasculature of pithed rats resemble the pharmacological profile of the 5-HT1A, 5-HT1B, and 5-HT1D subtypes [ABSTRACT FROM AUTHOR]

Previous studies demonstrated the efficacy of electro-acupuncture (EA) in relieving chronic visceral hypersensitivity (CVH) in IBS rats. However, ST25 which is a key acupoint for patients with IBS has not been reported in these experiments. Eight CVH rats were treated by EA at both ST25 and ST37 for 20 min, once daily for seven consecutive days, model rats ( n = 8) and normal rats ( n = 8) as controls. After the first EA treatment, the abdominal withdrawal reflex scores were investigated to evaluate the pain threshold. After seven EA treatments, the concentrations of 5-hydroxytryptamine (5-HT), 5-HT3 receptor (5-HT3R) and 5-HT4 receptor (5-HT4R) in colon tissue were assayed quantitatively by enzyme-linked immunosorbent assay. The results showed that EA improved the pain threshold of CVH rats, reduced the 5-HT concentration and increased the 5-HT4R concentration, but had no effect on the 5-HT3R concentration. Further studies are needed to optimize the choice of two-matching points for EA in the treatment of CVH rats. [ABSTRACT FROM AUTHOR]

Users of the popular party drug 3,4-methylenedioxymethamphetamine (MDMA) sometimes report combining MDMA with γ-hydroxybutyrate (GHB) to enhance the pleasurable effects of both drugs. However, very few studies have examined the influences of this drug combination. The present study investigated the development of locomotor sensitization in laboratory rats given 7 once-weekly exposures to either MDMA, GHB or their combination (MDMA/GHB). The drugs were administered at a high ambient temperature (28°C) to mimic nightclub conditions. MDMA (5 mg/kg), given once weekly, produced a progressively greater locomotor and hyperthermic response over time. In contrast, GHB (500 mg/kg) administered weekly produced consistent low levels of locomotor activity and few changes in body temperature. Rats receiving the mixture of MDMA (5 mg/kg) and GHB (500 mg/kg) showed asymptotic levels of sensitized locomotor activity similar to those seen in rats given MDMA alone, but the development of locomotor sensitization was delayed by coadministered GHB. GHB also delayed the development of MDMA-induced hyperthermia. After a washout period of 5 weeks, rats pre-exposed to MDMA, GHB and MDMA/GHB showed no hyperactivity when tested drug-free in the context in which they had previously received drugs, but displayed a sensitized locomotor response to a low challenge dose of MDMA (2.5 mg/kg). The response to a low dose of methamphetamine (0.5 mg/kg) did not differ among groups. Neurochemical analysis using high-performance liquid chromatography revealed few lasting changes in serotonin, dopamine or their metabolites in the striatum or prefrontal cortex of MDMA- or GHB-pre-exposed rats. These results indicate that GHB modulates the locomotor and hyperthermic response to acute MDMA and that pre-exposure to GHB can sensitize the locomotor response to low doses of MDMA. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the renal vascular effects of serotonin in Nω-Nitro-l-arginine-hypertensive rats (L-NAME, 30mg/kg/day, administered over 21days in drinking water), a model of systemic hypertension with glomerular capillary hypertension and renal disease due to chronic blockade of endogenous synthesis of nitric oxide (NO) and compared with those obtained in normotensive rats. Using several agonists and antagonists of 5-hydroxytryptamine (5-HT), we characterized the receptor subtypes involved in the contractile response to 5-HT in the in-situ autoperfused rat kidney. An intra-arterial (i.a.) bolus injection of 5-HT (0.00000125–0.1µg/kg) increased renal perfusion pressure in a dose-dependent manner, but did not affect systemic blood pressure. The selective 5-HT2 receptor agonist α-methyl-5-hydroxytryptamine (α-methyl-5-HT) caused a local vasoconstrictor effect in the autoperfused rat kidney. The selective 5-HT2B receptor agonist BW723C86, the non-selective 5-HT2C receptor agonist (1-(3-chlorophenyl) piperazine), m-CPP, the 5-HT1 receptor agonist 5-carboxamidotryptamine (5-CT) and the selective 5-HT3 receptor agonist (1-(m-chlorophenyl)-biguanide), m-CPBG, did not modify renal perfusion pressure. The vasoconstrictor effect elicited by α-methyl-5-HT was significantly decreased by the 5-HT2 receptor antagonist ritanserin and the 5-HT2A receptor antagonist spiperone, but was not modified by pretreatment with the selective 5-HT2B/2C receptor antagonist (3,5-dihydro-5-methyl-N-3pyridinylbenzo[1,2.b:4,5-b′]dipyrrole(1H)-carboxamide hydrochloride), SB206553. The results of protein expression analyses allow us to postulate that the 5-HT2A receptor protein 5HT-SRC is expressed in renal tissue and differentially expressed in the renal artery of hypertensive (L-NAME) rats. Our data suggest that the serotonergic vasoconstrictor response induced in the in-situ autoperfused hypertensive rat kidney would be mediated by local activation of the 5-HT2A receptor. [Copyright &y& Elsevier]

Abstract: The changes in the firing rate and firing pattern of pyramidal neurons in medial prefrontal cortex (mPFC) and the effects of selective 5-hydroxytryptamine-1A (5-HT1A) receptor agonist (R)-(+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridylcyclohexane carboxamide maleate salt (WAY-100635) on the firing activity of the neurons were studied in sham-lesioned rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc increased the firing rate of pyramidal neurons significantly compared to sham-lesioned rats, and the firing pattern of these neurons also changed significantly towards a more burst-firing. The systemic administration of 8-OH-DPAT at doses in the range of 0.5–128 μg/kg showed an excitatory-inhibitory effect on the firing rate of pyramidal neurons in mPFC of sham-lesioned rats. At lower doses, 0.5–32 μg/kg, it evoked excitation of the neurons, and at a high dose, i.e. 128 μg/kg, inhibited the activity of the neurons. In contrast to sham-lesioned rats, 8-OH-DPAT, at the same doses, showed no excitatory effect in the lesioned rats although the inhibitory phase of the effect of 8-OH-DPAT on the firing rate of pyramidal neurons in mPFC was still present. Furthermore, the local application of 8-OH-DPAT, 5 μg, in mPFC inhibited the firing rate of pyramidal neurons in sham-lesioned rats, while having no effect on firing rate in the lesioned rats. The excitatory or inhibitory effects of 8-OH-DPAT were reversed by WAY-100635, indicating that these effects are mediated by 5-HT1A receptor. Altogether, these results indicate that the lesion of the SNc leads to hyperactivity of pyramidal neurons in mPFC and the abnormality of response of these neurons to 5-HT1A receptor stimulation, suggesting that mPFC may be involved in the pathophysiology of the psychiatric disturbance of Parkinson''s disease. [Copyright &y& Elsevier]

Abstract: In the present study, we examined changes in the firing rate and firing pattern of pyramidal neurons in medial prefrontal cortex (mPFC), and the effects of 5-HT2A/2C receptor agonist DOI and antagonist ritanserin on the neuronal firing in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta by using extracellular recording. The unilateral lesion of the nigrostriatal pathway significantly increased the mean firing rate of pyramidal neurons compared to sham-operated rats, and the firing pattern of these neurons also changed significantly towards a more bursty one. Systemic administration of DOI (20–320 μg/kg, i.v.) increased the mean firing rate of pyramidal neurons in sham-operated and the lesioned rats. The excitation was significant only at doses higher than 160 μg/kg and 320 μg/kg in sham-operated and the lesioned rats, respectively. In addition, the local application of DOI, 5 μg, in mPFC inhibited the firing rate of pyramidal neurons in sham-operated rats, while having no effect on firing rate in the lesioned rats. After treatment with GABAA receptor antagonist picrotoxinin, the local application of DOI, at the same dose, increased the mean firing rate of the neurons in sham-operated rats; however, DOI did not alter the firing activity of the neurons in the lesioned rats. These results indicate that the lesion of the nigrostriatal pathway leads to hyperactivity of pyramidal neurons in mPFC, and the decreased response of pyramidal neurons to DOI, suggesting dysfunction of 5-HT2A and 5-HT2C receptors on pyramidal neurons and GABAergic interneurons in the 6-OHDA-lesioned rats. [Copyright &y& Elsevier]

Quantal release of adenosine triphosphate (ATP) was monitored in rat pancreatic β-cells expressing P2X2 receptors. Stimulation of exocytosis evoked rapidly activating and deactivating ATP-dependent transient inward currents (TICs). The unitary charge ( q) of the events recorded at 0.2 μM [Ca2+]i averaged 4.3 pC. The distribution of the 3√q of these events could be described by a single Gaussian. The rise times averaged ∼5 ms over a wide range of TIC amplitudes. In β-cells preloaded with 5-hydroxytryptamine (5-HT; accumulating in insulin granules), ATP was coreleased with 5-HT during >90% of the release events. Following step elevation of [Ca2+]i to ∼5 μM by photo release of caged Ca2+, an increase in membrane capacitance was observed after 33 ms, whereas ATP release first became detectable after 43 ms. The step increase in [Ca2+]i produced an initial large TIC followed by a series of smaller events that echoed the changes in membrane capacitance (Δ Cm). Mathematical modeling suggests that the large initial TIC reflects the superimposition of many unitary events. Exocytosis, measured as Δ Cm or TICs, was complete within 2 s after elevation of [Ca2+]i with no sign of endocytosis masking the capacitance increase. The relationship between total charge ( Q) and Δ Cm was linear with a slope of ∼1.2 pC/fF. The latter value predicts a capacitance increase of 3.6 fF for the observed mean value of q, close to that expected for exocytosis of individual insulin granules. Our results indicate that measurements of ATP release and Δ Cm principally (≥85–95%) report exocytosis of insulin granules. [ABSTRACT FROM AUTHOR]

Abstract: The dorsomedial hypothalamus (DMH) plays an important role in coordinating physiological and behavioral responses to stress-related stimuli. In vertebrates, DMH serotonin (5-HT) concentrations increase rapidly in response to acute stressors or corticosterone (CORT). Recent studies suggest that CORT inhibits postsynaptic clearance of 5-HT from the extracellular fluid in the DMH by blocking organic cation transporter 3 (OCT3), a polyspecific CORT-sensitive transport protein. Because OCTs are low-affinity, high-capacity transporters, we hypothesized that CORT effects on extracellular 5-HT are most pronounced in the presence of elevated 5-HT release. We predicted that local application of CORT into the DMH would potentiate the effects of d-fenfluramine, a 5-HT-releasing agent, on extracellular 5-HT. These experiments were conducted using in vivo microdialysis in freely-moving male Sprague–Dawley rats implanted with a microdialysis probe into the medial hypothalamus (MH), which includes the DMH. In Experiment 1, rats simultaneously received intraperitoneal (i.p.) injections of 1 mg/kg d-fenfluramine or saline and either 200 ng/mL CORT or dilute ethanol (EtOH) vehicle delivered to the MH by reverse-dialysis for 40 min. In Experiment 2, 5 μM d-fenfluramine and either 200 ng/mL CORT or EtOH vehicle were concurrently delivered to the MH for 40 min using reverse-dialysis. CORT potentiated the increases in extracellular 5-HT concentrations induced by either i.p. or intra-MH administration of d-fenfluramine. Furthermore, CORT and d-fenfluramine interacted to alter home cage behaviors. Our results support the hypothesis that CORT inhibition of OCT3-mediated 5-HT clearance from the extracellular fluid contributes to stress-induced increases in extracellular 5-HT and 5-HT signaling. [Copyright &y& Elsevier]

Abstract: It is firmly established that women experience major depression (MD) at roughly twice the rate of men and that dysregulation of the immune system is associated with the appearance and course of this condition. In the present study, we sought to identify whether “sickness behavior”, an inflammatory model of MD, is characterized by sexual dimorphism by focusing on both neurochemical and behavioral responses. Therefore, we investigated the serotonergic and dopaminergic activity of various brain regions implicated in the pathophysiology of affective disorders (hypothalamus, hippocampus, prefrontal cortex, amygdala and striatum) in response to a mild lipopolysaccharide (LPS) challenge, in rats of both sexes. According to our results, at 2 h post-LPS administration (100 μg/kg i.p.), the neurochemical substrate was primarily altered in female rats with the serotonergic function being markedly enhanced in all brain regions examined. Dopaminergic activation following immune system sensitization with LPS was not apparent in male rats and only modest in female rats with the exception of striatum. LPS administration also affected sickness-associated behaviors to a different extent in male and female rats, as assessed in the forced swim test (FST), the hot plate test (HPT) and the open-field arena. LPS-treated female rats coped better with the stressful FST procedure, as evidenced by an increase in swimming duration. The effects of LPS treatment appeared to be more robust in male rats, as far as suppression of locomotor activity is concerned, while the antinociceptive properties of LPS were evident in both sexes though showing sex-dependent kinetics. Moreover, when traditional measures of sickness (i.e. sucrose consumption, social exploration, food intake) were assessed, males and females appeared to be similarly affected, except for food intake. These data are the first to demonstrate that the serotonergic system is affected to a greater extent in female rats at 2 h post-LPS administration and further contribute to our understanding regarding sexual dimorphism upon sickness establishment. [Copyright &y& Elsevier]

Abstract: Experiments in rats have shown that chronic visceral hyperalgesia can be relieved by electro-acupuncture, but the efficacy of suspended moxibustion for relieving chronic visceral hyperalgesia is still unclear. The present study aimed to evaluate the effect of suspended moxibustion on rectal sensory thresholds and to analyze its possible mechanisms when treating chronic visceral hypersensitivity rats. Suspended moxibustion was administered once daily to 37-day-old chronic visceral hypersensitivity rats for 7 days. The two acupoints (ST25, bilateral) were simultaneously given suspended moxibustion. Each treatment lasted for 15min. Rats in treatment of suspended moxibustion was not anesthetized. Untreated chronic visceral hypersensitivity rats and normal rats were used as controls. The abdominal withdrawal reflex was determined during 30–90min after the first treatment. A 5-cm long segment of distal colon was harvested after seven treatments and 5-hydroxytryptamine concentrations in the colon were assayed by enzyme-linked immunosorbent assay. Abdominal withdrawal reflex scores from the rectus abdominis in response to colorectal distention were increased in rats with chronic visceral hypersensitivity, and the stimulation at strength of 20mmHg was significantly depressed by suspended moxibustion. Suspended moxibustion increased the pain threshold and restored normal sensitivity by reducing 5-hydroxytryptamine concentrations in the colon of chronic visceral hypersensitivity rats. [Copyright &y& Elsevier]

Abstract: The anorectic drug, dexfenfluramine has been associated with an increase in the relative risk of developing pulmonary hypertension. 5-hydroxytryptamine (5-HT) is a mitogen for smooth muscle cell, an effect that relies on 5-HT transporter expression and which has been proposed to explain pulmonary side effect of dexfenfluramine, and more particularly its effect on vascular remodeling. However recent data supported a major role of pulmonary artery vasoconstriction through the RhoA/Rho-kinase pathway. We questioned whether or not anorectic treatment aggravates pulmonary hypertension through vascular remodeling and if RhoA/Rho-kinase (ROCK) was potentially involved. In rats exposed to hypoxia, concomitant dexfenfluramine treatment (5 mg/kg/day, i.v.) for 4 weeks had no effect on pulmonary hypertension development. When exposure to 2 weeks of chronic hypoxia followed discontinuation of dexfenfluramine treatment (dexfenfluramine-hypoxic rats), echocardiographic parameters of pulmonary artery flow and right ventricle were further altered (P <0.05) as well as right ventricle systolic pressure was further increased (P <0.001) when compared to hypoxic rats treated with vehicle (hypoxic rats). However, the total number of muscularized distal pulmonary arteries artery was similar in dexfenfluramine-hypoxic vs. hypoxic rats (P >0.05). Western blot, RT-PCR and immunofluorescence analysis revealed a greater expression of 5-HT transporter and ROCK, as well as a greater activation of RhoA in dexfenfluramine-hypoxic rats compared to hypoxic rats. These data show that increased 5-HT transporter expression that follows dexfenfluramine discontinuation is not associated to a greater vascular remodeling despite worsening the development of pulmonary hypertension. Furthermore dexfenfluramine discontinuation promotes a greater RhoA/ROCK pathway activation. This pathway, involved in many cardiovascular diseases, might explain the cardiac and pulmonary toxicity of serotoninergic agonists. [Copyright &y& Elsevier]

Aim: To study the synaptic mechanisms involved in the 5-hydroxytryptamine 1A/7 (5-HT1A/7) receptor-mediated reflex control of cardiac vagal preganglionic neurons (CVPN). Methods: CVPN were retrogradely labeled and identified in brain stem slices of newborn rats, and their synaptic activity was examined using whole-cell patch-clamp. Results: 8-Hydroxy-2-(di- N-propylamino) tetralin (8-OH-DPAT), an agonist of 5-HT1A/7 receptors, had no effect on the glutamatergic inputs of CVPN. In contrast, it significantly decreased the frequency and the amplitude of both the GABAergic and the glycinergic spontaneous inhibitory postsynaptic currents (sIPSC). 8-OH-DPAT also caused significant amplitude decrease of the GABAergic currents evoked by stimulation of the nucleus tractus solitarius. Both the frequency inhibition and the amplitude inhibition of the GABAergic and the glycinergic sIPSC by 8-OH-DPAT had dose-dependent tendencies and could be reversed by WAY-100635, an antagonist of 5-HT1A/7 receptors. In the pre-existence of tetrodotoxin, 8-OH-DPAT had no effect on the GABAergic or the glycinergic miniature inhibitory postsynaptic currents, and had no effect on the GABAergic or the glycinergic currents evoked by exogenous GABA or glycine. Conclusion: The 5-HT1A/7 receptor agonist excites CVPN indirectly via the inhibition of both the GABAergic and glycinergic inputs. These findings have at least in part revealed the synaptic mechanisms involved in the 5-HT1A/7 receptor-mediated reflex control of cardiac vagal nerves in intact animals. [ABSTRACT FROM AUTHOR]