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Publication
Journal: Brain
June/24/1996
Abstract
Recent studies have delineated a clear role for the trigeminal innervation of pain-sensitive intracranial structures in the pathophysiology of migraine. The development of new compounds for the treatment of the acute attack of migraine has led to a greater understanding of serotonin (5-hydroxytryptamine; <em>5HT</em>) receptor diversity. The ergot alkaloids have been used in the treatment of acute attacks of migraine for many years and parenteral administration of dihydroergotamine (DHE) can be a useful treatment strategy. In this study, the question of a possible central site of action of DHE is considered using both anatomical and physiological approaches. The c-Fos method has been used to map functional activation of central neurons in response to stimulation of the superior sagittal sinus (SSS) in the cat. This structure has been used as it refers pain to the ophthalmic division of the trigeminal nerve in humans, and in cats induces changes in neuropeptides and cranial blood flow similar to those seen in migraine. In addition, the temporal aspects of the effect of DHE have been studied by making extracellular recordings from cells in the most caudal aspect of the trigeminal nuclear complex. Stimulation of the SSS results in Fos expression in the superfical laminae of the trigeminal nucleus caudalis and in the dorsal horn of C1 and C2. This activation is blocked by a clinically relevant dose of DHE. Similarly, cells can be recorded in this region that respond to SSS stimulation. This linked cellular activity can be inhibited by the same intravenous dose of DHE. Together, these studies show that DHE can inhibit activity in central trigeminal neurons. Since the sinus and its nerve supply are directly stimulated, the peripheral nerve/vessel innervation is bypassed and this inhibition cannot have happened at any other site. These data imply that drugs acting at the central trigeminal neurons may have a role in the treatment of acute attacks of migraine.
Publication
Journal: Behavioral Neuroscience
September/13/1999
Abstract
This study describes the development of anxiety and motor activation in mice lacking the serotonin (<em>5HT</em>) 1B receptor and in wild type controls and characterizes their early mother-infant interactions. In the isolation-induced ultrasonic vocalization paradigm, <em>5HT</em>1B knockout pups vocalized less and were hyperactive, rearing, jumping, and rolling more often than wild type pups. One week postpartum, <em>5HT</em>1B knockout mothers spent 20% more of their time outside the nest and were also hyperactive, rearing and climbing to the edge of the cage more often than the wild type mothers. There were no genotype effects on pup retrieval. Knockout adults were less anxious in the elevated plus-maze, defecated less, and head-dipped more, although none of the standard measures of anxiety (time and entries in the open arms) were different. <em>5HT</em>1B knockout mice of both sexes were hyperactive during both the light and the dark phases of the 24-hr cycle. Thus, <em>5HT</em>1B knockout mice show reduced anxiety and are hyperactive throughout their life.
Publication
Journal: Synapse
January/19/1998
Abstract
Local cerebral serotonin synthesis capacity was measured with alpha-[C-11]methyl-L-tryptophan ([C-11]AMT) in normal adult human brain (n = 10; five males, five females; age range, 18-38 years, mean 28.3 years) by using positron emission tomography (PET). [C-11]AMT is an analog of tryptophan, the precursor for serotonin synthesis, and is converted to alpha-[C-11]methyl-serotonin ([C-11]AM-<em>5HT</em>), which is trapped in serotonergic neurons because [C-11]AM-<em>5HT</em> is not degraded by monoamine oxidase. Kinetic analysis of [C-11] activity in brain after injection of [C-11]AMT confirmed the presence of a compartment with unidirectional uptake that represented approximately 40% of the activity in the brain at 50 min after tracer administration. The undirectional rate constant K, which represents the uptake of [C-11]AMT from the plasma to brain tissue followed by the synthesis and physiologic trapping of [C-11]AM-<em>5HT</em>, was calculated using the Patlak graphic approach on a pixel-by-pixel basis, thus creating parametric images. The rank order of K values for different brain regions corresponded well to the regional concentrations of serotonin in human brain (P < .0001). High serotonin synthesis capacity values were measured in putamen, caudate, thalamus, and hippocampus. Among cortical regions, the highest values were measured in the rectal gyrus of the inferior frontal lobe, followed by transverse temporal gyrus; anterior and posterior cingulate gyrus; middle, superior, and inferior temporal gyri; parietal cortex; occipital cortex, in descending order. Values in women were 10-20% higher (P < .05, MANOVA) throughout the brain than those measured in men. Differences in the serotonin synthesis capacity between men and women measured in this study may reflect gender differences of importance to both normal and pathologic behavior. This study demonstrates the suitability of [C-11]AMT as a tracer for PET scanning of serotonin synthesis capacity in human brain and provides normal adult values for future comparison with patient groups.
Publication
Journal: European Journal of Pharmacology
July/23/1987
Abstract
CGS 12066B is a novel pyrroloquinoxaline with selectivity for the serotonin-1B (<em>5HT</em>1B) recognition site as assessed by binding, biochemical and electrophysiological studies. The compound had an IC50 value of 51 nM at the <em>5HT</em>1B recognition site as determined using the binding of [3H]<em>5HT</em> in the presence of 1 microM spiperone. At the <em>5HT</em>1A receptor the compound had an IC50 value of 876 nM, providing a <em>5HT</em>1A/<em>5HT</em>1B ratio of 17 in contrast to the putative <em>5HT</em>1B selective agent trifluoromethylphenylpiperazine (TFMPP) which had a corresponding ratio of 3.6. The compound had minimal affinity for alpha 1-, alpha 2- and beta-adrenoceptors and for dopamine D-1 and D-2 receptors. CGS 12066B, in contrast to TFMPP, which was inactive, was found to inhibit dorsal raphe cell firing with an ED50 value of 358 nmol/kg i.v. The corresponding values for the <em>5HT</em>1A selective agonists 8-OH-DPAT and ipsapirone were 1.3 and 33 nmol/kg. CGS 12066B was also effective in decreasing rat brain 5-HTP concentrations and inhibiting in vitro <em>5HT</em> release. The data obtained indicate that CGS 12066B is a reasonably active <em>5HT</em>1B site agonist, which due to its selectivity as compared to compounds such as TFMPP, will be a useful tool for evaluating the physiological role of such receptors in the mammalian CNS.
Publication
Journal: Neuroscience
July/15/1992
Abstract
In this study, we have investigated serotonin hyperalgesia employing the mechanical paw withdrawal nociceptive threshold test in the rat. Intradermally injected serotonin was found to produce a dose-dependent hyperalgesia that was not attenuated by procedures which eliminate the known indirect mechanisms of hyperalgesia such as sympathectomy, polymorphonuclear leukocyte depletion or cyclooxygenase inhibition. In addition, the latency to onset of serotonin hyperalgesia is extremely short, with maximal hyperalgesia observed in less than 1 min, a similar temporal onset to direct-acting hyperalgesic agents such as prostaglandin E2. The results suggest, therefore, that the hyperalgesic effects of serotonin in our animal model are exerted by direct action on primary afferent neurons. Only the intradermal injection of selective serotonin (5-hydroxytryptamine; 5-HT) agonists for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide and N,N-dipropyl-5-carboxamido-tryptamine maleate, produced dose-dependent hyperalgesia. No hyperalgesia was seen after 5-HT1B, CGS-12066B maleate and m-trifluoromethylphenyl-piperazine hydrochloride; 5-HT2+IC, alpha methyl <em>5HT</em> and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; or 5-HT3, 2-methyl-5-hydroxytryptamine maleate and phenylbiguanide, agonists. Similarly, only the 5-HT1A antagonists, spiroxatrine and spiperone, attenuated the hyperalgesia induced by intradermally injected serotonin. 5-HT2+IC antagonists, mesulergine and ketanserin, and 5-HT3 antagonists, quipazine and 3-tropanyl-indole-3-carboxylate, did not significantly attenuate 5-HT hyperalgesia. We conclude that serotonin produces hyperalgesia by a direct action on the primary afferent neuron via the 5-HT1A subset of serotonin receptors.
Publication
Journal: Supportive Care in Cancer
May/12/2013
Abstract
BACKGROUND
Chemotherapy-induced nausea and vomiting (CINV) in cancer patients are common symptoms most feared by patients. The aim of this study was to analyze the impact of CINV associated to moderate/highly emetogenous chemotherapy regimens on patients' quality of life (QoL).
METHODS
Open, multicenter, prospective observational study was performed. Each patient filled out a patient diary for each cycle from the day before chemotherapy and for the next 5 days that included the number of emetic episodes, the intensity of nausea, and QoL evaluation (functional living index-emesis questionnaire).
RESULTS
Data from 202 consecutive patients from nine university hospitals were collected, but only data from 160 were analyzed (79.2 %). Most of the participants (70 %) were women with a mean age of 50 years (SD 1.2 years). The most frequent cancer site was breast (44 %) followed by lung (16 %) and 76.3 % were receiving highly emetogenous chemotherapy. Despite the use of antiemetic prophylaxis, patients experienced significant nausea and vomiting during 31 % (3.2 % during acute, 15.0 % during delayed phase, and 13.2 % during both phases) and 45.1 % (5.1 % only during the acute phase, 23.5 % only during the delayed phase and 16.5 % during both phases) of the cycles, respectively, having 44.5 % (nausea) and 39.3 % (emesis) of the cycles an impact on patients' QoL.
CONCLUSIONS
The results of the study confirm the detrimental effect of CINV on patients' QoL despite the use of antiemetic prophylaxis (<em>5HT</em>(3) receptor antagonist, steroids, and dopamine receptor antagonists). It is mandatory to intensify the detection of CINV in order to improve the management of these important, albeit frequent, side effects of cancer treatments.
Publication
Journal: Journal of Molecular Neuroscience
May/20/1997
Abstract
A cDNA encoding a serotonin receptor has been isolated from a Caenorhabditis elegans mixed stage cDNA library. The nematode serotonin receptor, designated <em>5HT</em>-Ce, was permanently expressed in murine Ltk-cells, where it mediates adenylate cyclase attenuation. Sequence analysis and the pharmacological profiles demonstrate its relatedness not only to Drosophila and Lymnae <em>5HT</em> receptors but also to mammalian <em>5HT</em>1a receptors. The <em>5HT</em>-Ce-gene does not map close to the position of any known serotonergic mutations.
Publication
Journal: Cell Reports
July/23/2015
Abstract
Serotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (<em>5HT</em>) dysregulation are commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of <em>5HT</em> neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections-increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of <em>5HT</em> neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth.
Publication
Journal: Journal of Neurochemistry
August/13/2012
Abstract
Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain <em>5HT</em>) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of <em>5HT</em> levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of <em>5HT</em> was not associated with anxiety-like behaviors. The results indicate that <em>5HT</em> mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.
Publication
Journal: Journal of Pharmacology and Experimental Therapeutics
January/31/1996
Abstract
The behavioral effects of cocaine (0.03-3.0 mg/kg) and several selective serotonin (<em>5HT</em>) uptake inhibitors, direct agonists and antagonists were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of i.v. drug self-administration. Intermediate doses of cocaine increased fixed-interval response rate markedly, and higher doses decreased response rate below control (nondrug) values. The i.v. self-administration of cocaine (0.025-1.0 mg/injection) maintained schedule-appropriate responding over a range of doses, and response rate under the second-order schedule was a function of drug dose. In contrast, none of the <em>5HT</em> uptake inhibitors (alaproclate, clomipramine and fluoxetine) or direct agonists ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, (+/-)-8-hydroxy-2-(di-N-propylamino) tetralin and quipazine) increased fixed-interval response rate, nor did the <em>5HT</em> uptake inhibitors maintain self-administration. In drug interaction studies, the <em>5HT</em> uptake inhibitors and quipazine produced an insurmountable attenuation of the behavioral-stimulant effects of cocaine, whereas the <em>5HT</em> antagonists (ketanserin, mianserin and ritanserin) with high affinity for <em>5HT</em>2 binding sites enhanced the behavioral-stimulant effects of low or intermediate doses of cocaine. Additionally, administration of ritanserin increased response rate for i.v. for self-administration of cocaine over a range of cocaine doses. The pharmacological profile of effects of selective <em>5HT</em> uptake inhibitors and direct agonists indicates that the behavioral-stimulant and reinforcing effects of cocaine do not depend on inhibition of <em>5HT</em> uptake, whereas the drug interactions suggest that the serotonergic system can modulate specific behavioral effects of cocaine.
Publication
Journal: Blood
November/5/1975
Abstract
The influence of freshly purified ATP on the effects of aggregating agents on human platelets was studied. ATP inhibited aggregation induced by ADP competitively (Ki = 20 muM) and immediately without need for prior incubation. ATP had no effect on primary aggregation induced by adrenaline, thrombin, vasopressin, or 5-hydroxytryptamine (<em>5HT</em>). ATP inhibited the shape change and the consumption of metabolic ATP induced by ADP but did not inhibit these effects when induced by thrombin, vasopressin, or <em>5HT</em>. ATP counteracted the inhibition by ADP of PGE1-stimulated cyclic AMP production in platelets but did not reduce inhibition by adrenaline. It is concluded that adrenaline, thrombin, <em>5HT</em>, and vasopressin each can induce primary aggregation of human platelets by a mechanism independent of extracellular ADP.
Publication
Journal: Journal of Pharmacology and Experimental Therapeutics
September/22/1996
Abstract
The substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) has been shown to be neurotoxic to serotonin (<em>5HT</em>) terminals in the rat, and rat body temperature (TEMP) has been shown to affect this neurotoxicity. This study looked at the effect on CORE TEMP of three drugs that protect against MDMA neurotoxicity in the rat. Male Holtzmann rats were injected with a control saline (SAL) injection or with ketanserin (KET; 6 mg/kg), alpha-methyl-p-tyrosine (AMPT; 75 mg/kg) or fluoxetine (FLUOX; 10 mg/kg) before a 40-mg/kg MDMA or SAL injection. CORE TEMP was recorded throughout the study using a noninvasive peritoneally implanted temperature probe. Rats pretreated with KET had no change in CORE TEMP until MDMA was injected, at which time an immediate hypothermia was seen that continued for 180 minutes, with a peak low of 34.7 degrees C. Rats treated with AMPT had no change in CORE TEMP until the MDMA was injected, at which time an immediate hypothermia was seen that continued for 240 min., with a peak low of 34.3 degrees C. Two weeks later, brain regions were analyzed for 5-HT and 5-hydroxindole acetic acid levels. MDMA produced significant (P < .05) decreases in 5-HT and 5-hydroxindole acetic acid levels in the frontal cortex, somatosensory cortex, striatum and hippocampus, and pretreatment with KET or AMPT prevented these depletions. When rats were given the KET/MDMA or AMPT/MDMA drug injections and warmed to prevent hypothermia, the protection against neurotoxicity was removed, which indicated that the hypothermia mediated the protective effects of KET and AMPT. In comparison with the hypothermia seen with AMPT or KET pretreatment, pretreatment with FLUOX had no effect on CORE TEMP. The rats given the FLUOX/MDMA treatment did not have different CORE TEMPs than rats given SAL/MDMA. The FLUOX pretreatment protected against MDMA-induced 5-HT and 5-hydroxindole acetic acid depletions in the frontal cortex, somatosensory cortex, striatum and hippocampus. This study suggests that a decrease in CORE TEMP may be a mechanism of protection against MDMA neurotoxicity by some drugs but that there is also a mechanism of protection that is independent of a change in body temperature.
Publication
Journal: British Journal of Pharmacology
June/18/2008
Abstract
Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABA(A), glycine and <em>5HT</em>(3) receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long-term alterations in the function of NMDA and GABA(A) receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development.
Publication
Journal: Acta Neuropathologica
April/21/2009
Abstract
The immunoreactivity of the serotoninergic receptor subtype 1A (<em>5HT</em>(1A)R) was quantitatively analyzed in the human infant brainstem medulla (caudal and rostral levels). We hypothesized that immunoreactivity of <em>5HT</em>(1A)R would be reduced in infants diagnosed with sudden infant death syndrome (SIDS). In particular that those infants with known clinical risk factors (including cigarette smoke exposure, bed sharing and sleep position) would have greater changes than those without clinical risks. Comparing SIDS (n = 67) to infants who died suddenly with another diagnosis (non-SIDS, n = 25), we found decreased <em>5HT</em>(1A)R immunoreactivity in the majority of the nuclei studied at the rostral medulla level including dorsal motor nucleus of the vagus (DMNV), nucleus of the solitary tract, vestibular, and inferior olivary nucleus (ION). There was a significant relationship with all risk factors for <em>5HT</em>(1A)R, especially for DMNV, suggesting that <em>5HT</em>(1A)Rs are highly vulnerable to various insults within the SIDS DMNV. This study not only provides further evidence of abnormalities within the brainstem serotoninergic system of SIDS infants, but also shows that these changes may be associated with exposure to clinical risk factors.
Publication
Journal: Cellular and Molecular Neurobiology
August/12/2003
Abstract
1. AMPA receptor potentiators (ARPs) exhibit antidepressant-like activity in preclinical tests (for example, the forced swim test) that are highly predictive of efficacy in humans. Unlike most currently used antidepressants, ARPs do not elevate extracellular levels of biogenic amines (e.g., <em>5HT</em>, NE) in prefrontal cortex at doses that are active in the forced swim test. 2. The present series of experiments examined the effects of combining the ARP, LY 392098, with biogenic amine-based antidepressants in the forced swim test. Male, NIH Swiss mice were placed in a cylinder of water and observed for attempted escape behaviors and immobility. 3. LY 392098 dose-dependently decreased immobility as did a range of classical antidepressants. At doses of LY 392098 below those that decreased immobility, this compound significantly increased the potency with which fluoxetine and citalopram (SSRI antidepressants), imipramine (tricyclic antidepressant), duoxetine (norepinephrine/serotonin uptake blocker), nisoxetine (norepinephrine uptake inhibitor), and rolipram (PDE4 inhibitor) decreased immobility in the forced swim test with potency shifts upward of 5-fold (fluoxetine, imipramine, and rolipram). Likewise, ineffective doses of the traditional antidepressants potentiated the effects LY 392098 with shifts in the dose-effect functions that were 10-fold or more for citalopram, fluoxetine, imipramine, and duloxetine. 4. Combined with other evidence for a role of AMPA receptors in the efficacy of antidepressants, the current data suggest that the addition of an ARP may augment the activity and perhaps the onset of the therapeutic effects of biogenic amine and second messenger-based antidepressants.
Publication
Journal: Journal of Pathology
November/6/1975
Abstract
A study has been made of the exudate provoked by intrapleural carrageenan in rats. Various parameters have been measured including volume of exudate, numbers and types of cells. Pharmacological assay has shown the early release of histamine and <em>5HT</em> into the exudate followed at later times by a release of prostaglandins, and a second release of histamine. The role of complement has been studied. Intrapleural injection of carrageenan after complement depletion produced a reduced migration of polymorphonuclear cells and also a reduction in volume of exudate. Prostaglandins remained unaffected by this treatment.
Publication
Journal: Journal of Neuroscience Research
April/23/2003
Abstract
The serotonin (<em>5HT</em>) transporter (<em>5HT</em>T) regulates serotonergic neurotransmission by mediating the reuptake of <em>5HT</em> from the synaptic cleft. Although lacking the high affinity and selectivity of the <em>5HT</em>T, the brain expresses a large number of other transporters, including the polyspecific organic cation transporters (OCTs). OCT1 and OCT3, members of the potential-sensitive organic cation transporter gene family, physiologically transport a wide spectrum of organic cations. In addition, both transporters mediate low-affinity <em>5HT</em> transport and, therefore, may participate in the clearance of excessive <em>5HT</em>. Because concentrations of extracellular <em>5HT</em> are increased in the brain of <em>5HT</em>T-deficient mice, they are a model for investigating the role of OCTs in <em>5HT</em> system homeostasis. Here, we analyzed OCT1 and OCT3 gene expression in the brain of <em>5HT</em>T knockout mice by semiquantitative competitive polymerase chain reaction and in situ hybridization. We demonstrate that, in <em>5HT</em>T-deficient mice, OCT3 mRNA concentrations were significantly increased in the hippocampus, but not in other brain regions, including cortex, striatum, cerebellum, and brainstem. In contrast, no difference in OCT1 expression was detected between <em>5HT</em>T knockout and control mice. Up-regulation of OCT3 expression and enhanced low-affinity <em>5HT</em> uptake may limit the adverse effects of elevated extracellular <em>5HT</em> and may play a critical role in maintaining <em>5HT</em>-dependent functions of the hippocampus in the absence of <em>5HT</em>T.
Publication
Journal: Brain Research Bulletin
December/28/2008
Abstract
Although developmental exposures of rats to low levels of the organophosphate pesticides (OPs), chlorpyrifos (CPF) or diazinon (DZN), both cause persistent neurobehavioral effects, there are important differences in their neurotoxicity. The current study extended investigation to parathion (PTN), an OP that has higher systemic toxicity than either CPF or DZN. We gave PTN on postnatal days (PND) 1-4 at doses spanning the threshold for systemic toxicity (0, 0.1 or 0.2 mg/kg/day, s.c.) and performed a battery of emotional and cognitive behavioral tests in adolescence through adulthood. The higher PTN dose increased time spent on the open arms and the number of center crossings in the plus maze, indicating greater risk-taking and overall activity. This group also showed a decrease in tactile startle response without altering prepulse inhibition, indicating a blunted acute sensorimotor reaction without alteration in sensorimotor plasticity. T-maze spontaneous alternation, novelty-suppressed feeding, preference for sweetened chocolate milk, and locomotor activity were not significantly affected by neonatal PTN exposure. During radial-arm maze acquisition, rats given the lower PTN dose committed fewer errors compared to controls and displayed lower sensitivity to the amnestic effects of the NMDA receptor blocker, dizocilpine. No PTN effects were observed with regard to the sensitivity to blockade of muscarinic and nicotinic cholinergic receptors, or serotonin <em>5HT</em>(2) receptors. This study shows that neonatal PTN exposure evokes long-term changes in behavior, but the effects are less severe, and in some incidences opposite in nature, to those seen earlier for CPF or DZN, findings consistent with our neurochemical studies showing different patterns of effects and less neurotoxic damage with PTN. Our results reinforce the conclusion that low dose exposure to different OPs can have quite different neurotoxic effects, obviously unconnected to their shared property as cholinesterase inhibitors.
Publication
Journal: Biological Psychiatry
March/5/1992
Abstract
m-Chlorophenylpiperazine (mCPP) is the most extensively used probe of serotonin function in psychiatry. This article reviews its in vitro and in vivo properties in animals, normal human subjects, and psychiatric patients. mCPP is a safe, reliable, direct 5-hydroxytryptamine (<em>5HT</em>) agonist, which may be used to evaluate <em>5HT</em> receptor sensitivity. It causes a consistent, dose-dependent elevation of ACTH, cortisol, and prolactin levels in both animals and humans, as well as increased body temperature in man. It also causes a variety of behavioral effects, depending on the population studied. These effects are probably <em>5HT</em> receptor-related, although specific <em>5HT</em> receptor subtype mechanisms have not yet been established. mCPP may be considered an important addition to armamentarium of <em>5HT</em> receptor probes, which is especially useful until more selective <em>5HT</em> receptor agonists have been tested.
Publication
Journal: Journal of the American Chemical Society
February/28/2010
Abstract
Myeloperoxidase (MPO) is increasingly being recognized as an important factor in many inflammatory diseases, particularly cardiovascular and neurological diseases. MPO-specific imaging agents would thus be highly useful to diagnose early disease, monitor disease progression, and quantify treatment effects. This study reports in vitro and in vivo characterizations of the mechanism of interaction between MPO and paramagnetic enzyme substrates based on physical and biological measurements. We show that these agents are activated through a radical mechanism, which can combine to form oligomers and, in the presence of tyrosine-containing peptide, bind to proteins. We further identified two new imaging agents, which represent the near extremes in either oligomerization (mono-<em>5HT</em>-DTPA-Gd) or protein-binding in their activation mechanism (bis-o-dianisidine-DTPA-Gd). On the other hand, we found that the agent bis-<em>5HT</em>-DTPA-Gd utilizes both mechanisms when activated. These properties yield distinct in vivo pharmacokinetics profiles for each of these agents that may be exploited for different applications. Specificity studies show that only MPO, but not eosinophil peroxidase, can highly activate these agents, and that MPO activity as low as 0.005 U/mg of tissue can be detected. Gd kinetic lability and cytotoxicity studies further confirm stability of the Gd ion and low toxicity for the <em>5HT</em>-based agents, suggesting that these agents are suitable for translational in vivo studies.
Publication
Journal: Journal of Physiology
August/31/1994
Abstract
The involvement of the 5-HT-1A receptor in serotoninergic responses of stage 2 expiratory (E-2) neurones was investigated in pentobarbitone-anaesthetized, mechanically ventilated cats. The specific agonist of the 5-HT-1A receptor, 8-hydroxy-diproplaminotetralin (8-OH-DPAT), administered systemically or by ionophoresis directly on to the neurones, had a clear depressant effect. Administration of 8-OH-DPAT at doses of 10-50 micrograms kg-1 (I.V.) increased the membrane hyperpolarizations of E-2 neurones during the inspiratory and postinspiratory phases, and shortened their duration of activity in association with shortening of phrenic nerve activity. Discharges of E-2 neurones were also less intense. At doses of 50-90 micrograms kg-1, 8-OH-DPAT reduced or abolished inspiratory hyperpolarizations, and reduced expiratory depolarizations of membrane potential and discharge in parallel with inhibition of phrenic nerve discharges. The effects of the larger doses were reversed by I.V. injection of NAN-190, an antagonist at the 5-HT-1A receptor. Dose-dependent effects on the membrane potential and discharge of E-2 neurones, but not on phrenic nerve activity, were also seen by ionophoretic administration of 8-OH-DPAT on to E-2 neurones. At low currents, ejection of 8-OH-DPAT hyperpolarized the neurones without affecting the duration of inspiratory hyperpolarization and expiratory depolarization. This hyperpolarization depressed the intensity and the duration of expiratory discharges. Ejection with larger currents hyperpolarized the E-2 neurones further, and depressed expiratory depolarization leading to blockade of expiratory discharges. The effects on membrane potential were accompanied by decreased neuronal input resistance. This depressed the excitability of E-2 neurones as tested by discharge evoked by intracellular current injection. The amplitudes of action potentials decreased in parallel with the changes in input resistance. The effects were attributed to a postsynaptic effect of 8-OH-DPAT leading to a gradually developing inhibition by activation of 5-HT-1A receptors. Hyperventilatory apnoea depressed on-going synaptic activity and unmasked the effect of ionophoretically applied 8-OH-DPAT. The responses of the E-2 neurone were enhanced, as evidenced by increased membrane hyperpolarization and greater reduction of input resistance. Both responses faded appreciably, indicating receptor desensitization. The degree and rate of apparent desensitization depended on the dose/ejecting current. The greater sensitivity and faster desensitization to 8-OH-DPAT were attributed to the hyperventilatory alkalinization of the extracellular fluid, which might influence agonist binding to <em>5HT</em>-1A receptors and/or receptor properties.
Publication
Journal: Neurogastroenterology and Motility
May/11/2009
Abstract
Gut mucosal enterochromaffin (EC) cells are regarded as key regulators of intestinal motility and fluid secretion via secretion of serotonin (<em>5HT</em>), are increased in numbers in mucosal inflammation and located in close proximity to immune cells. We examined whether interleukin (IL)1beta and Escherichia coli lipopolysaccharide (LPS) induced EC cell <em>5HT</em> release through Toll-like/IL-1 (TIL) receptor activation, nuclear factor kappa B (NFkappaB) and mitogen-activated protein kinase (MAPK) phosphorylation and evaluated whether somatostatin could inhibit this phenomenon. Pure (>98%) human intestinal EC cells were isolated by fluorescent activated cell sorting from preparations of normal (n = 5) and Crohn's colitis (n = 6) mucosa. <em>5HT</em> release was measured (ELISA), and NFkappaB and ERK phosphorylation quantitated (ELISA) in response to IL1beta and LPS. <em>5HT</em> secretion was increased by both E. coli LPS (EC(50) = 5 ng mL(-1)) and IL1beta (EC(50) = 0.05 pmol L(-1)) >2-fold (P < 0.05) in Crohn's EC cells compared with normal EC cells. Secretion was reversible by the TLR4 antagonist, E. coli K12 LPS (IC(50) = 12 ng mL(-1)) and the IL1beta receptor antagonist (ILRA; IC(50) = 3.4 ng mL(-1)). IL1beta caused significant (P < 0.05) NFkappaB and MAPK phosphorylation (40-55%). The somatostatin analogue, lanreotide inhibited IL1beta-stimulated secretion in Crohn's (IC(50) = 0.61 nmol L(-1)) and normal EC cells (IC(50) = 1.8 nmol L(-1)). Interleukins (IL1beta) and bacterial products (E. coli LPS) stimulated <em>5HT</em> secretion from Crohn's EC cells via TIL receptor activation (TLR4 and IL1beta). Immune-mediated alterations in EC cell secretion of <em>5HT</em> may represent a component of the pathogenesis of abnormal bowel function in Crohn's disease. Inhibition of EC cell-mediated <em>5HT</em> secretion may be an alternative therapeutic strategy in the amelioration of inflammatory bowel disease symptomatology.
Publication
Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December/6/2009
Abstract
Agomelatine is a novel antidepressant acting as a melatonergic receptor agonist and serotonergic (5-HT(2C)) receptor antagonist. In adult rats, chronic agomelatine treatment enhanced cell proliferation and neurogenesis in the ventral hippocampus (VH), a region pertinent to mood disorders. This study compared the effects of agomelatine on cell proliferation, maturation, and survival and investigated the cellular mechanisms underlying these effects. Agomelatine increased the ratio of mature vs immature neurons and enhanced neurite outgrowth of granular cells, suggesting an acceleration of maturation. The influence of agomelatine on maturation and survival was accompanied by a selective increase in the levels of BDNF (brain-derived neurotrophic factor) vs those of VEGF (vascular endothelial factor) and IGF-1 (insulin-like growth factor 1), which were not affected. Agomelatine also activated several cellular signals (extracellular signal-regulated kinase1/2, protein kinase B, and glycogen synthase kinase 3beta) known to be modulated by antidepressants and implicated in the control of proliferation/survival. Furthermore, as agomelatine possesses both melatonergic agonist and serotonergic (5-HT(2C)) antagonist properties, we determined whether melatonin and 5-HT(2C) receptor antagonists similarly influence cell proliferation and survival. Only the 5-HT(2C) receptor antagonists, SB243,213 or S32006, but not melatonin, mimicked the effects of agomelatine on cell proliferation in VH. The promoting effect of agomelatine on survival was not reproduced by the 5-HT(2C) receptor antagonists or melatonin alone. However, it was blocked by a melatonin antagonist, S22153. These results show that agomelatine treatment facilitates all stages of neurogenesis and suggest that a joint effect of melatonin agonism and <em>5HT</em>(2C) antagonism may be involved in promotion by agomelatine of survival in the hippocampus.
Publication
Journal: Brain
February/22/1978
Abstract
Fifteen patients with a variety of myoclonic syndromes were studied clinically, pharmacologically, and physiologically. CSF tryptophan, 5HIAA, and HVA were also measured. Of these patients, 8 were improved to varying degrees by therapy with <em>5HT</em>P, tryptophan in combination with MAOI (but not tryptophan alone), and clonazepam. This group included 6 cases of post-anoxic myoclonus, one case of post-traumatic myoclonus and one undiagnosed case of non-progressive focal myoclonus and epilepsy. In this group low levels of CSF 5HIAA were found compared to non-responsive cases and controls. Two cases of dysynergia cerebellaris myoclonica, 2 cases of undiagnosed aetiology, 2 cases of essential myoclonus, and one case of palatal myoclonus failed to respond to drug therapy. However, even amongst the responsive group the improvement varied. The most dramatic responses were seen in those patients in whom physiological study suggested that myoclonus was mediated by brain-stem structures. Less dramatic responses were seen in patients in whom the myoclonus appeared to originate from cortical structures. The neurochemical basis of myoclonus responding to <em>5HT</em> precursors and clonazepam is discussed. It is suggested that such myoclonus arises from a relative hypoactivity of the <em>5HT</em> neuronal system which results in a release of abnormal responses to sensory stimuli which characterize this type of myoclonus.
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