bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison between the Role of the Neuronal and Inducible Nitric Oxide Synthase in Methamphetamine‐induced Neurotoxicity and Sensitization
Authors: ITZHAK YOSSEF , MARTIN JULIO L. , ALI SYED F. 
Published: July 2010

AbstractThe involvement of the neuronal and inducible nitric oxide synthase (nNOS and iNOS, respectively) in methamphetamine (METH)‐induced dopaminergic neurotoxicity and behavioral sensitization was investigated. To determine METH‐induced neurotoxicity, mice deficient in the nNOS and iNOS genes, nNOS(‐/‐) and iNOS(‐/‐) mice, and wild‐type controls received either saline or METH (5 mg/kg × 3). After 72 h the level of striatal dopaminergic markers were measured. Administration of METH to nNOS(‐/‐) mice had no significant effect on the level of striatal dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), or dopamine transporter (DAT) binding sites. However, METH caused 25‐40% depletion of dopaminergic markers in iNOS(‐/‐) mice and 63‐69% depletion in the wild‐type mice. METH‐induced locomotor activity was measured following the administration of a low dose (1 mg/kg) on day 1. Subsequently animals received the high dose of METH (5 mg/kg × 3). On day 4, after a 68‐72 h drug free period, animals were challenged with 1 mg/kg METH, and locomotor activity was recorded. The intensity of METH‐induced locomotion in nNOS(‐/‐) mice on day 1 and 4 was similar, suggesting that locomotor sensitization did not develop. However, the intensity of METH‐induced locomotion in the iNOS(‐/‐) and wild‐type mice on day 4 was doubled compared to day 1, suggesting the development of sensitization. The present findings indicate that nNOS(‐/‐) mice are more resistant to METH‐induced neurotoxicity and behavioral sensitization than iNOS(‐/‐) mice. These results suggest a major role for nNOS rather than iNOS in the effects of METH.
Serotonin Transporters, Serotonin Release, and the Mechanism of Fenfluramine Neurotoxicity
Authors: BAUMANN MICHAEL H. , AYESTAS MARIO A. , DERSCH CHRISTINA M. , PARTILLA JOHN S. , ROTHMAN RICHARD B. 
Published: July 2010

AbstractAdministration ofd,l‐fenfluramine (FEN), or the more active isomerd‐fenfluramine (dFEN), causes long‐term depletion of forebrain serotonin (5‐HT) in animals. The mechanism underlying FEN‐induced 5‐HT depletion is not known, but appears to involve 5‐HT transporters (SERTs) in the brain. Some investigators have postulated that 5‐HT release evoked by FEN is responsible for the deleterious effects of the drug. In the present work, we sought to examine the relationship between drug‐induced 5‐HT release and long‐term 5‐HT depletion. The acute 5‐HT‐releasing effects of dFEN and the non‐amphetamine 5‐HT agonist 1‐(m‐chlorophenyl)piperazine (mCPP) were evaluated usingin vivomicrodialysis in rat nucleus accumbens. The ability of dFEN and mCPP to interact with SERTs was assessed usingin vitroassays for [3H]‐transmitter uptake and release in rat forebrain synaptosomes. Drugs were subsequently tested for potential long‐lasting effects on brain tissue 5‐HT after repeated dosing (2.7 or 8.1 mg/kg, ip × 4). dFEN and mCPP were essentially equipotent in their ability to stimulate acute 5‐HT releasein vivoandin vitro. Both drugs produced very selective effects on 5‐HT with minimal effects on dopamine. Interestingly, when dFEN or mCPP was administered repeatedly, only dFEN caused long‐term 5‐HT depletion in the forebrain at 2 weeks later. These data suggest that acute 5‐HT release per se does not mediate the long‐term 5‐HT depletion associated with dFEN. We hypothesize that dFEN and other amphetamine‐type releasers gain entrance into 5‐HT neurons via interaction with SERTs. Once internalized in nerve terminals, drugs accumulate to high concentrations, causing damage to cells. The relevance of this hypothesis for explaining clinical side effects of FEN and dFEN, such as cardiac valvulopathy and primary pulmonary hypertension, warrants further study.
Correlation between 5‐HT Content and Uptake Site Density following (S)‐MDMA and Dexfenfluramine‐induced Depletion, and with Neuroprotection by the Glycine Site‐specific NMDA Antagonist ACEA 1021
Authors: RUSSELL B. R. , LAVERTY R. 
Published: July 2010

Abstract3,4‐Methylenedioxymethamphetamine (MDMA) and fenfluramine are amphetamine analogues that both cause long‐term depletion of serotonin (5‐HT) and 5‐HT uptake sites in brain tissue. Depletion caused by these amphetamines is commonly measured by labeling 5‐HT uptake sites using3H‐paroxetine combined with autoradiography or, alternatively measuring the concentration of 5‐HT in tissue using high‐performance liquid chromatography (HPLC). A close correlation between the 5‐HT concentration measured in micropunch samples and the density of3H‐paroxetine‐labeled 5‐HT uptake sites measured in corresponding 20 μm coronal slices was determined (R2= 0.92). These methods combined demonstrated that the glycine‐site specific NMDA antagonist ACEA 1021 (4 × 30 mg/kg, i.p., 2 hourly) given 30 minutes before (S)‐MDMA (4 × 10 mg/kg, i.p., 2 hourly) was able to prevent the depletion of both 5‐HT content and uptake site density but unable to prevent the depletion of 5‐HT content and uptake site density caused dexfenfluramine (4 × 15 mg/kg, i.p., 2 hourly).
Immunomodulating Activity of MDMA
Authors: PACIFICI R. , ZUCCARO P. , FARRÉ M. , PICHINI S. , DI CARLO S. , ROSET P. N. , LÓPEZ C. HERNADEZ , ORTUÑO J. , SEGURA J. , CAMÍ J. , DE LA TORRE R. 
Published: July 2010

AbstractMDMA (3,4‐methylenedioxymethamphetamine) use can cause neurochemical, behavioral and endocrine alterations, similar to those produced by exposure to acute stress, suggesting its potential as a “chemical stressor.” It is known that stressful stimuli can produce a depression of immune function and an alteration in immune cells distribution.In vitroexposure to MDMA resulted in a modulation of several immune functional parameters such as T‐cell regulatory function, cytotoxic T‐lymphocyte activity, natural killer cell activity and macrophage function.Administration of MDMA in rats produced a rapid and sustained suppression of induced lymphocytes proliferation and a significant decrease in circulating lymphocytes. These alterations in rat immune function were accompanied by a significant rapid increase in plasma corticosterone concentrations. It was postulated that the result of altered induced proliferation response of lymphocytes could have been due to a combined effect of direct action of MDMA on lymphocytes and to the activation of the hypothalamic pituitary adrenal axis (HPA axis) and/or the sympathetic nervous system (SNS) via central mechanisms.In humans, acute MDMA treatment produced a time‐dependent immune dysfunction associated with MDMA plasma concentrations. Although total leukocyte count remained unchanged, there was a decrease in CD4+T‐cells and functional responsiveness of lymphocytes to mitogenic stimulation, while percentage of natural killer cells significantly increased. A rise of cortisol plasma concentrations similar to that observed in the rat model supported the hypothesis of MDMA‐induced release of corticotrophin‐releasing factor from the median eminence of the hypothalamus and subsequent HPA axis and SNS activation. The present findings indicate that MDMA ingestion may represent a potential health hazard for an increased risk of immune system‐related diseases.
Protein Phosphorylation Cascades Associated with Methamphetamine‐induced Glial Activation
Authors: HEBERT MELEIK A. , O'CALLAGHAN JAMES P. 
Published: July 2010

AbstractReactive gliosis is the most prominent response to diverse forms of central nervous system (CNS) injury. The signaling events that mediate this characteristic response to neural injury are under intense investigation. Several studies have demonstrated the activation of phosphoproteins within the mitogen‐activated protein kinase (MAPK) and Janus kinase (JAK) pathways following neural insult. These signaling pathways may be involved or responsible for the glial response following injury, by virtue of their ability to phosphorylate and dynamically regulate the activity of various transcription factors. This study sought to delineate,in vivo, the relative contribution of MAPK‐ and JAK‐signaling components to reactive gliosis as measured by induction of glial‐fibrillary acidic protein (GFAP), following chemical‐induced neural damage. At time points (6, 24, and 48 h) following methamphetamine (METH, 10 mg/kg × 4, s.c.) administration, female C57BL/6J mice were sacrificed by focused microwave irradiation, a technique that preserves steady‐state phosphorylation. Striatal (target) and nontarget (hippocampus) homogenates were assayed for METH‐induced changes in markers of dopamine (DA) neuron integrity as well as differences in the levels of activated phosphoproteins. GFAP upregulation occurred as early as 6 h, reaching a threefold induction 48 h following METH exposure. Neurotoxicant‐induced reductions in striatal levels of DA and tyrosine hydroxylase (TH) paralleled the temporal profile of GFAP induction. Blots of striatal homogenates, probed with phosphorylation‐state specific antibodies, demonstrated significant changes in activated forms of extracellular‐regulated kinase 1/2 (ERK 1/2),c‐junN‐terminal kinase/stress‐activated protein kinase (JNK/SAPK), MAPK/ERK kinase (MEK1/2), 70‐kDa ribosomal S6 kinase (p70 S6), cAMP responsive element binding protein (CREB), and signal transducer and activator of transcription 3 (STAT3). MAPK‐related phosphoproteins exhibited an activation profile that peaked at 6 h, remained significantly increased at 24, and fell to baseline levels 48 h following neurotoxicant treatment. The ribosomal S6 kinase was enhanced over 60% for all time points examined. Immunoreactivity profiles for the transcription factors CREB and STAT3 indicated maximal increases in phosphorylation occurring at 24 h, and measuring greater than 2‐ or 17‐fold, respectively. Specific signaling events were found to occur with a time course suggestive of their involvement in the gliotic response. The toxicant‐induced activation of these growth‐associated signaling cascades suggests that these pathways could be obligatory for the triggering and/or persistence of reactive gliosis and may therefore serve as potential targets for modulation of glial response to neural damage.
Effect of Acute and Chronic Administration of Methamphetamine on Calcium‐Calmodulin Dependent Protein Kinase II Activity in the Rat Brain
Authors: AKIYAMA KAZUFUMI , SUEMARU JUNKO 
Published: July 2010

AbstractSeveral lines of evidence have implicated Ca2+/calmodulin (CaM)‐dependent protein kinase II (CaM‐kinase II), a multifunctional protein kinase, in the regulation of signal transduction after chronic administration of psycho‐stimulants. CaM‐Kinase II activities were decreased in discrete brain regions after a single methamphetamine (METH) injection to rats. Pretreatment with either SCH 23390 (a dopamine D1 receptor antagonist) or MK‐801 (anN‐methyl‐D‐aspartate receptor antagonist) prevented the acute METH‐induced decrease in CaM‐kinase II activity in the parietal cortex, nucleus accumbens, and substantia nigra/ventral tegmental area (SN/VTA). Striatal CaM‐kinase II activity was significantly lower than that of the chronic saline‐treated controls after a one‐week, but not a four‐week, abstinence from chronic administration of METH. A METH challenge after a four‐week abstinence period decreased CaM‐kinase II activity in rats chronically injected with METH to a greater extent than in rats chronically injected with saline. Western blot analysis revealed that protein amount of CaM‐kinase II was not altered after a single METH injection or after chronic METH injections, as compared with saline‐treated controls. However, amounts of phosphorylated (Thr286) CaM‐kinase II in the parietal cortex, striatum, and SN/VTA were significantly decreased at 3 h after an acute METH injection compared with saline‐treated controls. It is suggested that dephosphorylation of CaM‐kinase II may contribute to the decreased enzyme activities induced by acute METH administration, and that chronic treatment with METH leads to an enhanced capacity of METH to decrease CaM‐kinase II activity after an extended withdrawal period.
Calpain Upregulation in Spinal Cords of Mice with 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinson's Disease
Authors: RAY SWAPAN K. , WILFORD GLORIA G. , ALI SYED F. , BANIK NAREN L. 
Published: July 2010

Abstract1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a heroin analogue, is a neurotoxin that undergoesin vivooxidation by monoamine oxidase‐B (MAO‐B) to 1‐methyl‐4‐phenylpyridinium ion (MPP+) which preferentially exerts its toxic effects on the dopaminergic neurons of the substantia nigra in brain. Spinal interneuronal pathways are also likely to be affected in the course of MPP+neurotoxicity. The primary effect of MPP+is mediated by irreversible inhibition of mitochondrial complex I, releasing free radicals. MPP+may also activateN‐methyl‐d‐aspartate (NMDA) receptors, increasing the cytosolic concentration of free Ca2+. Intracellular free radicals indirectly and free Ca2+directly can activate Ca2+‐dependent proteases such as calpain. We investigated involvement of calpain in spinal cord degeneration due to neurotoxin by subjecting male C57BL/6N mice (17 months old) to MPTP administration (12.5 mg/kg for 0.5 h; 25 mg/kg for 0.25 h; and 50 mg/kg for 0.25, 0.5, 1, 2, and 24 h). RT‐PCR and Western blot analysis were performed using the thoracic segment of spinal cords from control and MPTP‐administered mice. The administration of MPTP caused calpain upregulation at the mRNA and protein levels to various extents, compared to control mice. Calpain activity was measured by 68 kDa neurofilament protein (NFP) degradation, which was increased in MPTP‐induced PD mice. These results suggest that calpain may play a role in spinal cord degeneration in mice with MPTP‐induced PD.
The Effects of DCG‐IV and L‐CCG‐1 upon Phencyclidine (PCP)‐induced Locomotion and Behavioral Changes in Mice
Authors: TOMITA NAOKI , MURATA MASAMI , WATANABE HIROMI , ICHIKAWA TOMIO , WASHIYAMA KAZUO , KUMANISHI TOSHIRO , TAKAHASHI YASUO 
Published: July 2010

AbstractThe behavioral changes of mice induced by acute and repeated ip injection of phencyclidine (PCP) were observed by measuring locomotor activity and stereotyped behavior. Then, the effects of metabotropic glutamate receptor (mGluR) agonists, DCG‐IV and L‐CCG‐1, on the above behavioral changes induced by PCP were found. The effects of DCG‐IV were very strong and completely depressed the PCP‐induced hyperlocomotion. The effects of L‐CCG‐1 were not so strong. Repeated injection of PCP for 20 days into mice induced lower locomotor activity than that in acutely injected mice. These behavioral changes may be related with the negative symptoms of schizophrenia. In order to examine some molecular mechanisms of PCP‐induced behavioral changes, Northern blot analysis of total RNA from prefrontal cortical tissues of mice treated with PCP, DCG‐IV, and L‐CCG‐1 was carried out.
Noribogaine (12‐Hydroxyibogamine): A Biologically Active Metabolite of the Antiaddictive Drug Ibogaine
Authors: BAUMANN M. H. , PABLO J. P. , ALI S. F. , ROTHMAN R. B. , MASH D. C. 
Published: July 2010

AbstractIbogaine (IBO) is a plant‐derived alkaloid that is being evaluated as a possible medication for substance use disorders. When administered peripherally to monkeys and humans, IBO is rapidly converted to ano‐demethylated metabolite, 12‐hydroxyibogamine (NORIBO). We have found in rats that peak blood levels of NORIBO can exceed those of the parent compound, and NORIBO persists in the bloodstream for at least 24 h. Surprisingly few studies have examined thein vivobiological activity of NORIBO. In the present series of experiments, we compared the effects of intravenous (iv) administration of IBO and NORIBO (1 and 10 mg/kg) on unconditioned behaviors, circulating stress hormones, and extracellular levels of dopamine (DA) and serotonin (5‐HT) in the nucleus accumbens of male rats. IBO caused dose‐related increases in tremors and forepaw treading, whereas NORIBO did not. Both IBO and NORIBO produced significant elevations in plasma corticosterone and prolactin, but IBO was more potent as a stimulator of corticosterone secretion. Neither drug affected extracellular DA levels in the nucleus accumbens. However, both IBO and NORIBO increased extracellular 5‐HT levels, and NORIBO was more potent in this regard. The present data demonstrate that NORIBO is biologically active and undoubtedly contributes to thein vivopharmacological profile of IBO in rats. Most importantly, NORIBO appears less likely to produce the adverse effects associated with IBO (i.e., tremors and stress‐axis activation), suggesting that the metabolite may be a safer alternative for medication development.
18‐Methoxycoronaridine (18‐MC) and Ibogaine: Comparison of Antiaddictive Efficacy, Toxicity, and Mechanisms of Action
Authors: GLICK STANLEY D. , MAISONNEUVE ISABELLE M. , SZUMLINSKI KAREN K. 
Published: July 2010

Abstract18‐MC, a novelibogaalkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18‐MC (40 mg/kg) decreases the intravenous self‐administration of morphine and cocaine and the oral self‐administration of ethanol and nicotine in rats; unlike ibogaine, 18‐MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18‐MC ameliorate opioid withdrawal signs. Both ibogaine and 18‐MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18‐MC block morphine‐induced and nicotine‐induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine‐induced increases in accumbal dopamine. Both ibogaine and 18‐MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18‐MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine‐induced locomotion in morphine‐experienced rats. Ibogaine produces whole body tremors and, at high doses (≥100 mg/kg), cerebellar damage; 18‐MC does not produce these effects. Ibogaine, but not 18‐MC, decreases heart rate at high doses. While 18‐MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18‐MC has much lower affinities than ibogaine for NMDA and sigma‐2 receptors, sodium channels, and the 5‐HT transporter. Both 18‐MC and ibogaine are sequestered in fat and, like ibogaine, 18‐MC probably has an active metabolite. The data suggest that 18‐MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine.
Application of Electrophysiological Method to Study Interactions between Ibogaine and Cocaine
Authors: BINIENDA ZBIGNIEW , BEAUDOIN MICHAEL A. , THORN BRETT T. , SADOVOVA NATALYA , SKINNER ROBERT D. , SLIKKER WILLIAM , ALI SYED F. 
Published: July 2010

AbstractThe psychoactive indole alkaloid, ibogaine (IBO), has been investigated for over a decade concerning its reported anti‐addictive properties for opioids as well as psychomotor stimulants. The mechanism for the anti‐addictive action of IBO is still unclear. IBO interactions with opioid, NMDA, nicotinic, adrenergic, and serotonergic receptor sites have been suggested. The involvement of the dopaminergic system in IBO action is well documented. Increased or decreased levels of dopamine (DA) in specific brain regions following IBO pretreatment have been seen concomitantly with increased or decreased motor activity after subsequent amphetamine or cocaine administration. In this report,in vivoelectrophysiological measures were monitored in awake adult male rats in order to investigate alterations of the electrocorticogram (ECoG) resulting from interactions between IBO and cocaine (COC). Rats were implanted bilaterally with bipolar ECoG electrodes. They were either injected with saline, COC alone (20 mg/kg, i.p.) or IBO (50 mg/kg, i.p.) and COC 1 hr later. The concentrations of DA, 5‐HT, and their metabolites DOPAC, HVA, and 5‐HIAA were assessed in the caudate nucleus in separate groups of saline‐, COC‐, and IBO/COC‐treated rats. An alpha1power increase was observed within 10 min after COC injection, which lasted for less than 20 min. A desynchronization over alpha2and both beta power bands was observed throughout the recording. In IBO/COC‐treated rats, a significant increase in delta, theta, and alpha1power occurred within 20 min after COC injection (p<0.05). This effect lasted for up to an hour. DA levels significantly increased after COC only and decreased after IBO administration. A further decrease in levels of DA was observed in IBO/COC‐treated rats. DA turnover increased significantly after IBO alone but was not observed after IBO/COC treatment. The alterations in ECoG and neurotransmitter levels suggest a decreased response to COC following IBO pretreatment.
Neonatal Methamphetamine in the Rat: Evidence for Gender‐specific Differences upon Tyrosine Hydroxylase Enzyme in the Dopaminergic Nigrostriatal System
Authors: GOMES‐DA‐SILVA JOANA , PÉREZ‐ROSADO ALBERTO , DE MIGUEL ROSARIO , FERNÁNDEZ‐RUIZ JAVIER , SILVA M. CAROLINA , TAVARES M. AMÉLIA 
Published: July 2010

AbstractMethamphetamine (Meth) neurotoxicity upon the mesencephalic dopaminergic systems was demonstrated in the adult, both in humans and in experimental models. In the rat, the development and maturation of the dopaminergic systems is accomplished during the first month of postnatal life, a period of particular vulnerability to environmental influences. In this study, the effect of Meth exposure during the first month of life was assessed in the nigrostriatal dopaminergic system of the rat. For this purpose, Wistar rat litters were culled to 8 pups, retaining preferentially 4 males and 4 females, which, in the day following birth (postnatal day 1, PND1), were randomly attributed to either the Meth or control group. Meth‐groups were administered 10 mg of (+)‐methamphetamine hydrochloride/kg body weight/day, subcutaneously, twice daily, from PND1 until PND29; control groups received isovolumetric doses of saline. Animals were sacrificed at PND30. Males exposed to Meth during the first month of life had increased tyrosine hydroxylase (TH) activity both in the caudate‐putamen and substantia nigra. Males also had increased nigral TH mRNA levels, as assessed by in situ hybridization. These effects did not exist in females. These results support the evidence that Meth exposure during the first month of life in the rat has a gender‐specific stimulatory effect upon the maturation of TH, the key enzyme for dopamine biosynthesis in the nigrostriatal dopaminergic system.