In vivo evidence that 5-HT2C receptor antagonist but not agonist modulates cocaine-induced dopamine outflow in the rat nucleus accumbens and striatum.
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During recent years, much attention has been devoted at investigating the modulatory role of central 5-HT(2C) receptors on dopamine (DA) neuron activity, and it has been proposed that these receptors modulate selectively DA exocytosis associated with increased firing of DA neurons. In the present study, using in vivo microdialysis in the nucleus accumbens (NAc) and the striatum of halothane-anesthetized rats, we addressed this hypothesis by assessing the ability of 5-HT(2C) agents to modulate the increase in DA outflow induced by haloperidol and cocaine, of which the effects on DA outflow are associated or not with an increase in DA neuron firing, respectively. The intraperitoneal administration of cocaine (10-30 mg/kg) induced a dose-dependent increase in DA extracellular levels in the NAc and the striatum. The effect of 15 mg/kg cocaine was potentiated by the mixed 5-HT(2C/2B) antagonist SB 206553 (5 mg/kg i.p.) and the selective 5-HT(2C) antagonist SB 242084 (1 mg/kg i.p.) in both brain regions. The mixed 5-HT(2C/2B) agonist, Ro 60-0175 (1 mg/kg i.p.), failed to affect cocaine-induced DA outflow, but reduced significantly the increase in DA outflow induced by the subcutaneous administration of 0.1 mg/kg haloperidol. The obtained results provide evidence that 5-HT(2C) receptors exert similar effects in both the NAc and the striatum, and they modulate DA exocytosis also when its increase occurs independently from an increase in DA neuron impulse activity. Furthermore, they show that 5-HT(2C) agonists, at variance with 5-HT(2C) antagonists, exert a preferential control on the impulse-stimulated release of DA. (+info)
Injection of the 5-HT2C receptor agonist Ro60-0175 into the ventral tegmental area reduces cocaine-induced locomotor activity and cocaine self-administration.
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Previously, we have shown that systemic administration of the 5-HT(2C) receptor agonist Ro60-0175 reduces cocaine-induced locomotor activity and cocaine self-administration. Ro60-0175 also alters the activity of midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), a region where 5-HT(2C) receptors are expressed. The present experiments investigated whether microinjections of Ro60-0175 into the VTA would alter the locomotor stimulant effect of cocaine and cocaine self-administration. In the tests for locomotor activity injection of 3 and 10, but not 1 microg, Ro60-0175 into the VTA reduced the locomotor stimulation resulting from injection of 10 mg/kg cocaine. In tests of cocaine self-administration, rats were trained to lever press for intravenous infusions of 0.25 mg cocaine delivered on either a fixed ratio 5 (FR5) or a progressive ratio schedule. Intra-VTA injection of Ro60-0175 at doses of 3 and 10 microg reduced responding for cocaine on both schedules without significantly altering the latency to initiate responding or the rate of responding. A subsequent experiment determined that the suppressant effect of intra-VTA Ro60-0175 (3 microg) on responding for cocaine was prevented by pretreatment with the selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg/kg). In a final experiment, intra-VTA injection of Ro60-0175 reduced responding for food reinforcement on the same progressive ratio schedule as used for cocaine self-administration. These results demonstrate that stimulation of 5-HT(2C) receptors in the VTA is sufficient to attenuate the stimulant and reinforcing effects of cocaine. These effects complement electrophysiological and neurochemical findings, and indicate that 5-HT(2C) receptors localized within the VTA modulate the activity of mesolimbic DA neurons. (+info)
Stimulation of serotonin2C receptors blocks the hyperactivation of midbrain dopamine neurons induced by nicotine administration.
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In vivo electrophysiological techniques were used to study the effect of nicotine on the basal activity of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) of chloral hydrate-anesthetized rats. Acute i.v. injections of nicotine (25-400 microg/kg) caused a dose-dependent increase of the firing rate and the bursting activity of DA neurons both in the SNc and the VTA. Repeated daily injection of nicotine (1 mg/kg i.p.) for 10 consecutive days did not cause any significant change in the basal activity of DA neurons in the SNc and the VTA. Acute challenge with nicotine (25-400 microg/kg i.v.) in animals treated repeatedly with this drug caused a dose-related excitation of DA neurons in both areas. To test the hypothesis that stimulation of 5-hydroxytryptamine (5-HT, serotonin)(2C) receptors could affect nicotine-induced stimulation of DA neuronal activity, the selective 5-HT(2C) receptor agonist RO 60-0175 was used. Pretreatment with 100 microg/kg i.v. (S)-2-(chloro-5-fluoro-indo-l-yl)-l-methylethylamine 1:1 C(4)H(4)O(4) (RO 60-0175) prevented the enhancement in DA neuronal firing rate elicited by acute nicotine (25-400 microg/kg i.v.) in the SNc of both drug naive and chronically treated rats but was devoid of any significant effect in the VTA. Moreover, the dose of 300 microg/kg i.v. RO 60-0175 significantly reduced the stimulatory effect of VTA DA neurons induced by acute challenge with nicotine (25-400 microg/kg i.v.) both in drug naive and chronically treated rats. It is concluded that selective activation of 5-HT(2C) receptors can block the stimulatory action of nicotine on midbrain DA neuronal activity. (+info)
Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens.
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Numerous research has pointed out that serotonin2c (5-HT2C) receptor, a subtype of 5-HT receptors belonging to the G-protein-coupled receptor superfamily, modulates the activity of mesencephalic dopamine (DA) neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. In the present study, using in vivo intracerebral microdialysis and Chinese hamster ovary (CHO) cells expressing 5-HT2C receptors to identify appropriate 5-HT2C receptor ligands, we sought to determine whether the property of 5-HT2C receptors to spontaneously activate intracellular signaling pathways in vitro (constitutive activity) participates in the tonic inhibitory control that they exert on DA release in the rat striatum and nucleus accumbens in vivo. In CHO cells, the purported antagonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole hydrochloride (SB 206553), but not 6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridin-3-yl carbamoyl] indoline (SB 242084), decreased basal inositol phosphate accumulation, thus behaving as a 5-HT2C inverse agonist. Its effect was prevented by SB 242084. In vivo, SB 206553 (1-10 mg/kg) elicited a dose-dependent and clear-cut increase in accumbal and striatal DA release compared with SB 242084 (1-10 mg/kg), and the 5-HT2C agonist S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine hydrochloride (Ro-60-0175) (0.3-3 mg/kg) inhibited DA release. Pretreatment by SB 242084 reversed the change in DA release elicited by Ro-60-0175 and SB 206553. Furthermore, SB 206553-stimulated DA release was insensitive to reduction of 5-HT neuronal function induced by the 5-HT1A agonist (+/-)-8-hydroxy-2-dipropylaminotetralin or intra-raphe injections of 5,7-dihydroxytryptamine neurotoxin. The obtained results provide the first in vivo evidence that constitutive activity of the 5-HT2C receptor tonically inhibits mesencephalic DA neurons and underscore the need for a better understanding of the pathophysiological role of constitutive receptor activity. (+info)
A novel antioxidant non-steroidal anti-inflammatory agent protects rat liver against ischemia-reperfusion injury.
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Liver ischemia followed by reperfusion is an important and common clinical event. A major mechanism is leukocyte adhesion to endothelium followed by release of reactive oxygen metabolites. The aim of this study was to determine the effects of a novel antioxidant ethylenediamine derivative with anti-inflammatory properties (compound IA) on an imitated clinical setting of acute hepatic ischemia-reperfusion injury. Eight groups of rats were subjected to a model of hepatic ischemia that was produced by occluding for 30 min the portal vein and hepatic artery. At the end of ischemia, compound IA was administered intravenously and the clamps were removed allowing reperfusion for 60 min or 24 h. The effect of compound IA was evaluated by histopathological examination, lipid peroxidation and plasma levels of liver enzymes. Administration of compound IA resulted in significantly less histological damage in liver tissue after 30-min ischemia followed by 60-min and 24-h reperfusion. Ischemia followed by 60 min of reperfusion increased lipid peroxidation compared to the sham-operated and the non-ischemic group. This increase was attenuated in the group treated with compound IA. Serum enzyme levels were significantly higher in the reperfusion groups compared to the non-ischemic groups and diminished after treatment. Compound IA exerted a protective effect on hepatic reperfusion injury in rats. Compound IA is believed to act by means of its potent antioxidant and anti-inflammatory activities. (+info)
A novel synthetic inhibitor of CDC25 phosphatases: BN82002.
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CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models. BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro. It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G1-S, in S phase and at the G2-M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G1 phase. Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice. BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target. (+info)
Testicular sulfoconjugation of the 16-androstene steroids by hydroxysteroid sulfotransferase: its effect on the concentrations of 5alpha-androstenone in plasma and fat of the mature domestic boar.
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This study examined the relationship between sulfoconjugation and the degree to which 5alpha-androstenone can accumulate in fat. Analysis of the unconjugated and sulfoconjugated fractions of peripheral plasma from 25 mature Yorkshire boars and testicular vein plasma from an additional 20 mature Yorkshire boars revealed that the majority of 5alpha-androstenone is present as a sulfoconjugate, reaching levels up to 69 +/- 4.3 and 72 +/- 6.2%, respectively, relative to its unconjugated form. The presence of this steroid in the sulfoconjugate fraction was confirmed by gas chromatography-mass spectrometry. Plasma concentrations of 5alpha-androstenone in the sulfoconjugate fraction were negatively correlated (r = -0.36; P < 0.01) with the concentrations of 5alpha-androstenone in fat. High concentrations of 5alpha-androstenone in the sulfate fraction were only associated with animals that had fat androstenone concentrations < 0.5 microg/g. In addition, there was a positive correlation (r = 0.31; P < 0.01) between the concentrations of unconjugated 5alpha-androstenone in plasma and 5alpha-androstenone in fat. These findings indicate that the levels of the sulfoconjugated form present in the peripheral plasma influence the accumulation of 5alpha-androstenone in fat. The specific sulfotransferase enzyme involved in sulfoconjugating these steroids was identified by incubating Leydig cells with specific sulfotransferase inhibitors for 8 h. It was discovered that the enzyme responsible for the sulfoconjugation of the 16-androstene steroids is hydroxysteroid sulfotransferase. Hydroxysteroid sulfotransferase may play a significant role in determining the levels of sulfated 16-androstene steroids present in plasma. The results of this study indicate that sulfoconjugation may serve to regulate the quantity of unconjugated 5alpha-androstenone present in the circulation and thus available for accumulation. Animals with a decreased ability to sulfoconjugate 5alpha-androstenone would have a subsequent increase in the levels of unconjugated 5alpha-androstenone in circulation, allowing for the accumulation of high levels in fat and thereby potentially leading to the development of boar taint. (+info)
Positive interaction of the beta2-agonist CHF 4226.01 with budesonide in the control of bronchoconstriction induced by acetaldehyde in the guinea-pigs.
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Pretreatment of anaesthetized guinea-pigs with either CHF 4226.01 (8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(p-methoxyphenyl)-1-methylethyl]amino]e thyl] carbostyril hydrochloride), formoterol or budesonide reduced acetaldehyde (AcCHO)-evoked responses in the lungs with a rank order of potency CHF 4226.01 (ED(50) values, from 1.88 to 3.31 pmol) > formoterol (ED(50) values, from 3.03 to 5.51 pmol) >> budesonide (ED(50) values, from 335 to 458 nmol). The duration of action of CHF 4226.01 in antagonizing the airway obstruction elicited by AcCHO was also substantially longer than formoterol (area under the curve) at 10 pmol, 763+/-58 and 480+/-34, respectively; P<0.01). Continuous infusion of a subthreshold dose of AcCHO enhanced the intratracheal pressure (ITP) increases caused by subsequent challenges with substance P (from 9.7+/-0.8 to 27.5+/-1.6 cm H(2)O as a peak, P<0.001). Pretreatment with either CHF 4226.01 or formoterol prevented the sensitizing effect of AcCHO on substance P responses (ED(50) values, 2.85 and 6.11 pmol, respectively; P<0.01). The ED(50) value of budesonide (396 nmol) in preventing AcCHO-evoked ITP increase was reduced when this glucocorticoid was combined with 0.1 pmol CHF 4226.01 (ED(50) 76 nmol; P<0.001). CHF 4226.01/budesonide was two-fold more effective (P<0.01) than the formoterol/budesonide combination. These results suggest that CHF 4226.01/budesonide, by optimizing each other's beneficial potential in the control of pulmonary changes caused by AcCHO in the guinea-pigs, may represent a new fixed combination in asthma. (+info)