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Serotonergic System (serotonergic + system)
Selected AbstractsSerotonin and dopamine transporter binding in children with autism determined by SPECTDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 8 2008Ismo Makkonen MD Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8y 8mo [SD 3y 10mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9y 10mo [SD 2y 8mo]) using single-photon emission computed tomography (SPECT) with [123I] nor-,-CIT. The children, with autism were studied during light sedation. They showed reduced serotonin transporter (SERT) binding capacity in the medial frontal cortex, midbrain, and temporal lobe areas. However, after correction due to the estimated effect of sedation, the difference remained significant only in the medial frontal cortex area (p=0.002). In the individuals with autism dopamine transporter (DAT) binding did not differ from that of the comparison group. The results indicate that SERT binding capacity is disturbed in autism. The reduction is more evident in adolescence than in earlier childhood. The low SERT binding reported here and the low serotonin synthesis capacity shown elsewhere may indicate maturation of a lesser number of serotonergic nerve terminals in individuals with autism. [source] PRECLINICAL STUDY: Effect of cannabinoids on platelet serotonin uptakeADDICTION BIOLOGY, Issue 2 2007Marie Velenovská ABSTRACT Serotonin is involved in many of the same processes affected by cannabinoids; therefore, we investigated in vitro and in vivo effects of these drugs on the function of serotonin transporter. The effect of ,9 -tetrahydrocannabinol (,9 -THC), endocannabinoid anandamide and synthetic cannabinoid receptor agonist WIN 55,212-2 on platelet serotonin uptake and membrane microviscosity was examined in 19 marijuana smokers and 20 controls. (1) Serotonin uptake was inhibited at higher doses of ,9 -THC (IC50 = 139 µmol/l), anandamide (IC50 = 201 µmol/l) or WIN 55,212-2 (IC50 = 17.4 µmol/l); the inhibition was found non-competitive. ,9 -THC, anandamide and WIN 55,212-2 produced different effects on the membrane microviscosity. (2) Maximal velocity of platelet serotonin uptake was significantly increased in a group of chronic marijuana smokers suffering impairment of cognitive functions when compared with controls. Opposite effect of marijuana smoking on the serotonin uptake efficiency was observed in males beside females. In summary, this study provides evidence that (1) Activity of serotonin transporter is acutely affected by cannabinoids at relatively high drug concentrations; this effect is indirect and can be partially accounted for the changes in the membrane microviscosity. (2) Increase of maximal velocity of the serotonin uptake could be understood as adaptation change in the serotonergic system induced by chronic cannabis use. A hypothesis was supported that lowered serotonin uptake may reflect a gender-related differences in effects of psychoactive cannabinoids. [source] Somatodendritic autoreceptor regulation of serotonergic neurons: dependence on l -tryptophan and tryptophan hydroxylase-activating kinasesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2005Rong-Jian Liu Abstract The somatodendritic 5-HT1A autoreceptor has been considered a major determinant of the output of the serotonin (5-HT) neuronal system. However, recent studies in brain slices from the dorsal raphe nucleus have questioned the relevance of 5-HT autoinhibition under physiological conditions. In the present study, we found that the difficulty in demonstrating 5-HT tonic autoinhibition in slice results from in vitro conditions that are unfavorable for sustaining 5-HT synthesis. Robust, tonic 5-HT1A autoinhibition can be restored by reinstating in vivo 5-HT synthesizing conditions with the initial 5-HT precursor l -tryptophan and the tryptophan hydroxylase co-factor tetrahydrobiopterin (BH4). The presence of tonic autoinhibition under these conditions was revealed by the disinhibitory effect of a low concentration of the 5-HT1A antagonist WAY 100635. Neurons showing an autoinhibitory response to l -tryptophan were confirmed immunohistochemically to be serotonergic. Once conditions for tonic autoinhibition had been established in raphe slice, we were able to show that 5-HT autoinhibition is critically regulated by the tryptophan hydroxylase-activating kinases calcium/calmodulin protein kinase II (CaMKII) and protein kinase A (PKA). In addition, at physiological concentrations of l -tryptophan, there was an augmentation of 5-HT1A receptor-mediated autoinhibition when the firing of 5-HT cells activated with increasing concentrations of the ,1 adrenoceptor agonist phenylephrine. Increased calcium influx at higher firing rates, by activating tryptophan hydroxylase via CaMKII and PKA, can work together with tryptophan to enhance negative feedback control of the output of the serotonergic system. [source] Distribution and morphology of serotonin-immunoreactive axons in the hippocampal region of the New Zealand white rabbit.HIPPOCAMPUS, Issue 1 2003Abstract This study provides a detailed light microscopic description of the morphology and distribution of immunohistochemically stained serotonergic axons in the hippocampal region of the New Zealand white rabbit. The serotonergic axons were segregated morphologically into three types: beaded fibers, fine fibers, and stem-axons, respectively. Beaded fibers were thin serotonergic axons with large varicosities, whereas thin axons with small fusiform or granular varicosities were called fine fibers. Finally, thick straight non-varicose axons were called stem-axons. Beaded fibers often formed large conglomerates with numerous boutons (pericellular arrays) in close apposition to the cell-rich layers in the hippocampal region, e.g., the granular and hilar cell layers of the dentate area and the pyramidal cell layer ventrally in CA3. The pericellular arrays in these layers were often encountered in relation to small calbindin-D28K -positive cells, as shown by immunohistochemical double staining for serotonin and calbindin-D28K. The beaded and fine serotonergic fibers displayed a specific innervation pattern in the hippocampal region and were encountered predominantly within the terminal field of the perforant path, e.g., the stratum moleculare hippocampi and the outer two-thirds of the dentate molecular layer. These fibers were also frequently seen in the deep part of the stratum oriens and the alveus, forming a dense plexus in relation to large multipolar calbindin-D28K -positive cells and their basal extensions. Stem-axons were primarily seen in the fimbria and alveus. This innervation pattern was present throughout the entire hippocampal formation, but there were considerable septotemporal differences in the density of the serotonergic innervation. A high density of innervation prevailed in the ventral/temporal part of the hippocampal formation, whereas the dorsal/septal part received only a moderate to weak serotonergic innervation. These results suggest that the serotonergic system could modulate the internal hippocampal circuitry by way of its innervation in the terminal field of the perforant path, the hilus fasciae dentatae, and ventrally in the zone closely apposed to the mossy fiber layer and the pyramidal cells of CA3. This modulation could be of a dual nature, mediated directly by single serotonergic fibers traversing the hippocampal layers or indirectly by the pericellular arrays and their close relation to the calbindin-D28K -positive cells. The marked septotemporal differences in innervation density point toward a difference between the ventral and dorsal parts of the hippocampal formation with respect to serotonergic function and need for serotonergic modulation. Hippocampus 2003;13:21,37. © 2003 Wiley-Liss, Inc. [source] Pseudoparadoxical impulsivity in restrictive anorexia nervosa: A consequence of the logic of scarcityINTERNATIONAL JOURNAL OF EATING DISORDERS, Issue 4 2002Daniel M. T. Fessler Abstract Objective To explain an apparently paradoxical pattern wherein sufferers of restrictive anorexia nervosa exhibit both rigorous self-restraint and episodic impulsivity. Method The experimental, historical, and clinical literatures were examined for evidence of psychological and behavioral changes accompanying severe dietary constriction; such changes were noted and compared with those reported to occur in anorexics. Results Increased impulsivity in association with dietary constriction is described in diverse literatures. A number of lines of evidence suggest that the serotonergic system mediates this change. Discussion Many forms of impulsivity can be understood as having once constituted fitness-enhancing responses to resource scarcity. It is suggested that an evolved psychological mechanism calibrates the individual's sensitivity to risk in light of future prospects. Self-injurious behaviors are explicable as misfirings of such a mechanism. Similarly, excessive exercising by anorexics may reflect the misdirection of reward systems that normally encourage adaptive increases in ranging behavior under conditions of scarcity. © 2002 by Wiley Periodicals, Inc. Int J Eat Disord 31: 376,388, 2002. [source] Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Mami Noda Abstract Human serotonin 5A (5-HT5A) receptors were stably expressed in undifferentiated C6 glioma. In 5-HT5A receptors-expressing cells, accumulation of cAMP by forskolin was inhibited by 5-HT as reported previously. Pertussis toxin-sensitive inhibition of ADP-ribosyl cyclase was also observed, indicating a decrease of cyclic ADP ribose, a potential intracellular second messenger mediating ryanodine-sensitive Ca2+ mobilization. On the other hand, 5-HT-induced outward currents were observed using the patch-clamp technique in whole-cell configuration. The 5-HT-induced outward current was observed in 84% of the patched 5-HT5A receptor-expressing cells and was concentration-dependent. The 5-HT-induced current was inhibited when intracellular K+ was replaced with Cs+ but was not significantly inhibited by typical K+ channel blockers. The 5-HT-induced current was significantly attenuated by 1,2-bis(2-aminophenoxy)ethane- N,N,N,,N,-tetraacetic acid (BAPTA) in the patch pipette. Depleting intracellular Ca2+ stores by application of caffeine or thapsigargin also blocked the 5-HT-induced current. Blocking G protein, the inositol triphosphate (IP3) receptor, or pretreatment with pertussis toxin, all inhibited the 5-HT-induced current. IP3 showed a transient increase after application of 5-HT in 5-HT5A receptor-expressing cells. It was concluded that in addition to the inhibition of cAMP accumulation and ADP-ribosyl cyclase activity, 5-HT5A receptors regulate intracellular Ca2+ mobilization which is probably a result of the IP3-sensitive Ca2+ store. These multiple signal transduction systems may induce complex changes in the serotonergic system in brain function. [source] Leptin Uptake by Serotonergic Neurones of the Dorsal RapheJOURNAL OF NEUROENDOCRINOLOGY, Issue 6 2002M. C. Fernández-Galaz Abstract The effects of leptin on food intake, metabolism, sleep patterns and reproduction may be mediated, in part, by the midbrain serotonergic systems. Here, we report on the distribution of neurones that accumulate leptin in the raphe nuclei of male and female rats after intracerebroventricular administration of mouse recombinant leptin labelled with digoxigenin. Direct leptin-targeted cells were present in the periventricular grey, pontine and raphe nuclei. Confocal microscopy revealed that raphe neurones which accumulated leptin were predominantly serotonergic. The temporal pattern of leptin accumulation by raphe neurones showed a marked gender difference: 6 h after leptin administration, all male and female rats showed massive leptin binding in the dorsal raphe, while 30 min after leptin treatment, only 10% of male rats exhibited leptin-labelled cells in contrast to 50% of females. The present observations reveal that leptin can be selectively accumulated by serotonergic neurones in the raphe nuclei and that this mechanism is gender specific. These findings support the idea that the midbrain serotonergic system is an important mediator of the effects of leptin on brain function and may provide an explanation for gender differences in metabolism regulation and its coordination with higher functions of the brain. [source] Lateral parabrachial afferent areas and serotonin mechanisms activated by volume expansionJOURNAL OF NEUROSCIENCE RESEARCH, Issue 16 2008Lisandra Oliveira Margatho Abstract Recent evidence has shown that the serotonergic mechanism of the lateral parabrachial nucleus (LPBN) participates in the regulation of renal and hormonal responses to isotonic blood volume expansion (BVE). We investigated the BVE-induced Fos activation along forebrain and hindbrain nuclei and particularly within the serotonergic clusters of the raphé system that directly project to the LPBN. We also examined whether there are changes in the concentration of serotonin (5HT) within the raphé nucleus in response to the same stimulus. With this purpose, we analyzed the cells doubly labeled for Fos and Fluorogold (FG) following BVE (NaCl 0.15 M, 2 ml/100 g b.w., 1 min) 7 days after FG injection into the LPBN. Compared with the control group, blood volume-expanded rats showed a significant greater number of Fos-FG double-labeled cells along the nucleus of the solitary tract, locus coeruleus, hypothalamic paraventricular nucleus, central extended amygdala complex, and dorsal raphé nucleus (DRN) cells. Our study also showed an increase in the number of serotonergic DRN neurons activated in response to isotonic BVE. We also observed decreased levels of 5HT and its metabolite 5-hydroxyindoleacetic acid (measured by high-pressure liquid chromatography) within the raphé nucleus 15 min after BVE. Given our previous evidence on the role of the serotonergic system in the LPBN after BVE, the present morphofunctional findings suggest the existence of a key pathway (DRN-LPBN) that may control BVE response through the modulation of 5HT release. © 2008 Wiley-Liss, Inc. [source] Can Serotonin Transporter Genotype Predict Craving in Alcoholism?ALCOHOLISM, Issue 8 2009Nassima Ait-Daoud Background:, We hypothesize that functional control of the serotonergic system is regulated in part by differential expression of the serotonin (5-HT) transporter (5-HTT). Alcohol-dependent individuals with the LL/LS genotype (L-carriers), compared with those with the SS genotype, have a lower 5-HT neurotransmission, which we hypothesize would be associated with higher craving for alcohol among L-carriers. We hypothesize further that acute peripheral depletion of tryptophan (5-HT's precursor), while further reducing 5-HT function, might decrease auto-inhibition of 5-HT neuronal firing, thereby increasing 5-HT neurotransmission transiently and lowering alcohol craving. Methods:, We tested these hypotheses by examining whether in 34 Hispanic alcohol-dependent individuals subjective and physiological cue craving for alcohol differed by genotype, age of onset of problem drinking, and tryptophan availability. Results:, On subjective "urge to drink" and "crave for a drink," we found a significant (p < 0.05) main effect of genotype and cue, as well as an interaction among genotype, age of onset of problem drinking, and tryptophan depletion. For the physiological measure of pulse, there was a main effect of genotype. L-carriers had higher craving than their SS counterparts, an effect that decreased under tryptophan depletion. While craving in L-carriers increased with an earlier age of onset of problem drinking, the opposite effect was seen in those with the SS genotype. Conclusion:, These results not only provide support for the hypothesis that alcoholics who are L-carriers have greater alcohol craving and possibly greater propensity for drinking but also propose that there is an important 5-HTT gene-by-environment interaction that alters cue craving response for alcohol. [source] An Association Study Between Alcoholism and the Serotonergic Receptor GenesALCOHOLISM, Issue 3 2000Akio Himei Background: Linkage and association studies of alcoholism using DNA makers have been conducted without conclusive results. The comorbidity of alcoholism with affective disorder indicates that dysfunction of the serotonergic system may play an important role in developing alcoholism. Methods: We studied the genetic association between alcoholism and alleles of the HTR1A, HTR2A, and HTR2C genes. The subjects were 91 biologically unrelated alcoholics and 90 controls. Polymorphisms of these genes were determined by polymerase chain reaction restriction fragment length polymorphisms, and the data were analyzed by X2 tests. Results: We found no significant association between alcoholism and the HTR1A, HTR2A, and HTR2C genes. Conclusions: The study results suggest that these serotonergic receptor genes may not directly contribute to the etiology of alcoholism. [source] Effects of two new steroids and cyproterone on some biomarkers of oxidative stress and serotonergic system on rat prostate and brainANDROLOGIA, Issue 1 2009G. D. Calderón Summary The purpose of this study was to evaluate the effect of cyproterone acetate (CPA, A) compared with new synthetic steroids 3,-acetoxy-5,6-epoxy-16-pregnen-20-one (B) and 17,-hydroxy-16,-methyl-1,4,6-pregnatriene-3,20-dione (C) in rat prostate and brain. Groups of animals were treated either with A, B or C (4 mg kg,1 day,1) by the intraperitoneal route for 5 days. Levels of reduced glutathione (GSH), 5-hydroxy-indole acetic acid (5-HIAA), lipid peroxidation (as thiobarbituric acid reactive substances, TBARS) and the activities of Na+, K+ - and total ATPases were assayed in prostate and brain for each group of animals including a control group. No appreciable changes were shown in Na+, K+ -ATPase and total ATPases and TBARS on prostate and brain of rats that received A, B and C steroids. However, the levels of GSH and 5-HIAA decreased significantly (P < 0.05) in both tissues for the steroids assayed. It is concluded that CPA and the homologues B and C steroids induce changes in the levels of GSH and serotonin in rat prostate and brain. [source] Association between brain-derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter geneBIPOLAR DISORDERS, Issue 5 2008Ilona Vincze Background:, Recent data suggest that brain-derived neurotrophic factor (BDNF) and the serotonergic system are involved and interact in major depressive disorder and suicidal behavior (SB). Several family and population-based studies have reported associations between the BDNF gene and serotonin-related genes, specifically the serotonin transporter (5HTT) gene, with bipolar disorder (BD) and SB. However, despite the fact that gene-by-gene interaction between BDNF and 5HTT has been demonstrated in monoamine deficiencies in animals, this kind of interaction has never been tested in humans. Our hypothesis is that some BDNF and 5HTT polymorphisms might confer increased risk for BD and SB and that both genes may interact with each other. Methods:, To test this hypothesis, we genotyped the most common BDNF polymorphisms, G196A (Val66Met), A-633T and BDNF-LCPR, as well as 5HTT (5HTT-LPR), in 447 BD patients and 370 controls. Results:, We replicated the association previously reported between BDNF G196A (Val66Met) polymorphism and BD. We also observed a correlation between the number of G196 alleles and short alleles of 5HTT-LPR and the severity of SB in BD. However, we found no significant interaction between these two markers. Conclusions:, These results suggest that BDNF G196A as well as 5HTT-LPR polymorphisms confer risk for SB in BD, but we did not observe any evidence for an interaction between them. [source] The effects of chronic administration of sumatriptan and dipyrone on serotonergic system in the rat brain: an immunohistochemical studyACTA NEUROLOGICA SCANDINAVICA, Issue 4 2009E. Genç Objective,,, To investigate the effects of chronic high dose sumatriptan and dipyrone treatment on central serotonergic system in rats. Materials and methods,,, Male Sprague,Dawley rats (seven per group) were daily injected with sumatriptan (3 mg/kg), dipyrone (400 mg/kg) or saline for 30 days. The brains of animals were surgically removed and immunohistochemically stained for serotonin. Serotonin-positive stained cells were counted automatically by using a computerized image analysis program. Statistical analysis carried out using one-way ANOVA followed by post hoc Tukey test. Results,,, A significant decrease in serotonin-positive cells in the brainstem was observed after chronic sumatriptan administration while chronic use of dipyrone induced a significant increase in serotonin-positive cells both in the cortex and midbrain. Conclusion,,, Our data suggest that central serotonergic system might be modified by chronic use of sumatriptan and dipyrone. [source] Influence of metyrapone treatment during pregnancy on the development and maturation of brain monoaminergic systems in the ratACTA PHYSIOLOGICA, Issue 4 2009M. L. Leret Abstract Aim:, This study examines the effect of reducing the corticosterone levels of gestating rat dams on the postnatal development and maturation of monoaminergic systems in their offspring's brains. Methods:, Metyrapone, an inhibitor of CORT synthesis, was administered to pregnant rats from E0 to E17 of gestation. Monoamine concentrations were determined in male and female offspring at postnatal days (PN) 23 and 90 in the hippocampus, hypothalamus and striatum. Results:, Reducing maternal corticosterone (mCORT) during gestation led to alterations in dopamine and serotonin levels in all three brain areas studied at PN 23. Alterations persisted until at least PN 90 in the serotonergic systems; the dopamine content of the hippocampus also remained modified. Reduced mCORT during gestation also led to alterations in the development and maturation of the hypothalamic noradrenergic systems. Sexually dimorphic responses were observed in all these monoaminergic systems at different times. Conclusion:, These results suggest that while they are still developing, brain monoaminergic systems are particularly sensitive to epigenetic influences. An adequate foetal level of CORT is required for the normal ontogeny of brain monoaminergic systems. The present data also provide that during the critical period of brain development, maternal CORT plays an important role in the sexual differentiation of monoaminergic systems, with particular influence on brain serotonergic neurones. [source] Circuits and systems in stress.DEPRESSION AND ANXIETY, Issue 1 2002Abstract This paper follows the preclinical work on the effects of stress on neurobiological and neuroendocrine systems and provides a comprehensive working model for understanding the pathophysiology of posttraumatic stress disorder (PTSD). Studies of the neurobiology of PTSD in clinical populations are reviewed. Specific brain areas that play an important role in a variety of types of memory are also preferentially affected by stress, including hippocampus, amygdala, medial prefrontal cortex, and cingulate. This review indicates the involvement of these brain systems in the stress response, and in learning and memory. Affected systems in the neural circuitry of PTSD are reviewed (hypothalamic-pituitary-adrenal axis (HPA-axis), catecholaminergic and serotonergic systems, endogenous benzodiazepines, neuropeptides, hypothalamic-pituitary-thyroid axis (HPT-axis), and neuro-immunological alterations) as well as changes found with structural and functional neuroimaging methods. Converging evidence has emphasized the role of early-life trauma in the development of PTSD and other trauma-related disorders. Current and new targets for systems that play a role in the neural circuitry of PTSD are discussed. This material provides a basis for understanding the psychopathology of stress-related disorders, in particular PTSD. Depression and Anxiety 16:14,38, 2002. © 2002 Wiley-Liss, Inc. [source] Recreational ecstasy use and the neurotoxic potential of MDMA: current status of the controversy and methodological issuesDRUG AND ALCOHOL REVIEW, Issue 3 2006MICHAEL LYVERS Abstract The controversy over possible MDMA-induced serotonergic neurotoxicity in human recreational ecstasy users is examined critically in light of recent research findings. Although the designs of such studies have improved considerably since the 1990s, the evidence to date remains equivocal for a number of reasons, including (1) inconsistent findings on the existence and reversibility of persistent ecstasy-related serotonergic and cognitive deficits; (2) lack of clear association between changes in brain imaging measures and functional deficits attributed to MDMA-induced neurotoxicity; (3) the contribution of concomitant cannabis or other drug use to both brain imaging abnormalities and cognitive deficits; (4) methodological shortcomings such as failure to adequately match samples of ecstasy users and controls; (5) the questionable relevance of animal models of MDMA-induced neurotoxicity to typical human patterns of ecstasy use; and (6) the potential role of inherent pre-drug deficits in serotonergic systems, impulse control and executive cognitive function that may predispose to excessive use of drugs including ecstasy. Given the retrospective nature of nearly all studies of ecstasy users to date, the controversy over whether MDMA has ever caused neurotoxicity or cognitive deficit in human ecstasy users is likely to continue for some time without resolution. [source] PRECLINICAL STUDY: FULL ARTICLE: Tolerance to 3,4-methylenedioxymethamphetamine is associated with impaired serotonin releaseADDICTION BIOLOGY, Issue 3 2010Karen Jones ABSTRACT Tolerance to the behavioural effects of 3,4-methylenedioxymethamphetamine (MDMA) following high dose exposure has been attributed to alterations in serotonergic systems. The present study aimed to determine whether decreased 5-HT release and/or 5-HT2A/C receptor desensitization might play a role in tolerance by measuring the response to selective ligands following MDMA exposure. To this end, the latency to nose poke and emerge from a hide box to an open field arena following administration of various ligands to MDMA pre-treated and control rats was measured. Acute exposure to MDMA (0.0,3.3 mg/kg), the 5-HT releasing stimulant fenfluramine (0.0,2.0 mg/kg) and the 5-HT2 receptor agonist m-CPP (0.0,1.25 mg/kg) increased nose poke and emergence latency. Following administration of doses that produce 5-HT2A receptor-mediated behaviours, the 5-HT2 receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane failed to alter nose poke and emergence latency, suggesting a limited role of this receptor subtype in these behaviours. Activation of 5-HT2C receptors was implicated in the behavioural response to both MDMA and m-CPP since the increased emergence latency was dose-dependently attenuated by pre-treatment with the selective 5-HT2C receptor antagonist RS102221 (0.0,1.0 mg/kg). Tolerance to the behavioural effect of MDMA and fenfluramine but not m-CPP was produced by prior exposure to MDMA (10 mg/kg administered at two-hour intervals, total 40 mg/kg), and tissue levels of 5-HT and 5-HIAA were decreased. These findings suggest that tolerance to the increased nose poke and emergence latency produced by MDMA is due to impaired 5-HT release. [source] Serotonin norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders: a comprehensive review of their clinical efficacyHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 1 2010Bernardo Dell'Osso Abstract Anxiety disorders are common psychiatric conditions that typically require long-term treatment. This review summarizes current knowledge of the pharmacological treatment of anxiety disorders with serotonin norepinephrine reuptake inhibitors (SNRIs) with specific emphasis on the findings of recent randomized clinical trials and relevant neurobiological investigations. It is now well established that gabaergic, noradrenergic and serotonergic systems play a critical role in the pathophysiology of anxiety disorders, abnormalities in these systems being related to structural and functional alterations in specific brain areas such as the amygdala, prefrontal cortex, locus coeruleus and hippocampus, as repeatedly shown by neuroimaging studies. SNRIs selectively inhibit norepinephrine and serotonin reuptake and have shown to be efficacious and generally well tolerated treatments in patients with anxiety disorders, with some potential clinical advantages over selective serotonin reuptake inhibitors (SSRIs), which are considered by many to represent first-line pharmacological treatments in patients with anxiety disorders. Anxiety disorders are characterized by a typically chronic course, high rates of comorbidity and frequent partial response to standard treatments, and the increasing use of SNRIs reflects currently unmet clinical need, in terms of overall response, remission rates and treatment tolerability. Copyright © 2009 John Wiley & Sons, Ltd. [source] Leptin Uptake by Serotonergic Neurones of the Dorsal RapheJOURNAL OF NEUROENDOCRINOLOGY, Issue 6 2002M. C. Fernández-Galaz Abstract The effects of leptin on food intake, metabolism, sleep patterns and reproduction may be mediated, in part, by the midbrain serotonergic systems. Here, we report on the distribution of neurones that accumulate leptin in the raphe nuclei of male and female rats after intracerebroventricular administration of mouse recombinant leptin labelled with digoxigenin. Direct leptin-targeted cells were present in the periventricular grey, pontine and raphe nuclei. Confocal microscopy revealed that raphe neurones which accumulated leptin were predominantly serotonergic. The temporal pattern of leptin accumulation by raphe neurones showed a marked gender difference: 6 h after leptin administration, all male and female rats showed massive leptin binding in the dorsal raphe, while 30 min after leptin treatment, only 10% of male rats exhibited leptin-labelled cells in contrast to 50% of females. The present observations reveal that leptin can be selectively accumulated by serotonergic neurones in the raphe nuclei and that this mechanism is gender specific. These findings support the idea that the midbrain serotonergic system is an important mediator of the effects of leptin on brain function and may provide an explanation for gender differences in metabolism regulation and its coordination with higher functions of the brain. [source] Neural Circuits Regulating Pulsatile Luteinizing Hormone Release in the Female Guinea-Pig: Opioid, Adrenergic and Serotonergic InteractionsJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2001A. C. Gore Abstract We studied three neurotransmitters involved in the regulation of pulsatile luteinizing hormone (LH) release: opioid peptides, serotonin and norepinephrine, using the ovariectomized guinea-pig. This is an attractive animal model due to the regularity of its LH pulses, enabling any disruptions to be clearly ascertained. In all experiments, a specific agonist or antagonist was administered, either alone or serially to enable detection of interactions, and effects on mean LH concentrations, pulse amplitude and interpulse interval were determined by PULSAR analysis. In the ovariectomized guinea-pig, catecholamines are stimulatory (acting through the ,1 and ,2 but not , receptors, unlike other species), opioids inhibitory and serotonin permissively stimulatory to pulsatile LH release. Stimulatory effects of the opiate antagonist were not blocked by pretreatment with an ,1 - or ,2 -adrenergic antagonist. Similarly, pretreatment with the opiate antagonist did not prevent the suppression of LH release by ,1 and ,2 antagonists. This suggests that, in the guinea-pig, effects of opiates and catecholamines on LH release are exerted by independent pathways to luteinizing hormone releasing hormone (LHRH) neurones. For the opiate,serotonin interactions, pretreatment with the serotonergic antagonist did not block the stimulatory effect of the opiate antagonist on LH release. However, pretreatment with the opiate agonist could not be overcome by the serotonergic agonist. This suggests that the effects of the serotonin system on LHRH release may be indirectly mediated by opioid neurones. Taken together, these studies demonstrate that the three neurotransmitter systems studied are critically involved in normal pulsatile LH release in the female guinea-pig, and demonstrate novel functional relationships between the opioid and the adrenergic and serotonergic systems. [source] Stress, norepinephrine and depressionACTA NEUROPSYCHIATRICA, Issue 4 2002Brian E. Leonard Experimental and clinical evidence implicates stress as a major predisposing factor in depression and other severe psychiatric disorders. In this review, evidence is presented to show how the impact of stress on the central sympathetic system leads to changes in the endocrine, immune and neurotransmitter axes which underlie the main clinical symptoms of depression. Thus it can be shown that the noradrenergic system is dysfunctional in depression, a situation which reflects the chronic hypersecretion of glucocorticoids and inflammatory mediators within the brain in addition to an enhanced activity of the locus ceruleus. With regard to the actions of antidepressants in modulating the stress response and alleviating depression it is now evident that, irrespective of the presumed specificity of the antidepressants for the noradrenergic or serotonergic systems, they all normalize noradrenergic function. This action is due partly to the regulation of tyrosine hydroxylase activity in the locus ceruleus but also enhances neuronal sprouting which counteracts the neurodegenerative effects of chronic stress. [source] | ||||||||||||||||||||||||||||