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Purpose: To report a series of cases demonstrating the resolution of Acanthamoeba keratitis (AK) with adjunctive use of oral miltefosine.Methods: Retrospective case series.Results: The first case was a 27-year-old female who presented with severe pain and photophobia. The diagnosis of AK was made with confocal microscopy, which revealed a significant burden of stromal cysts. After approximately 2 weeks of adjunctive oral miltefosine therapy, there was a severe inflammatory response within the cornea followed by quick resolution of the AK. The second case was a 31-year-old male in whom the diagnosis of AK was confirmed by culture and polymerase chain reaction. Adjunctive oral miltefosine was started 3 months after presentation, leading to a quick resolution.Conclusions: Oral miltefosine may have cysticidal properties and should be considered as adjunctive therapy for the treatment of AK, particularly in cases with a significant burden of cysts or in cases recalcitrant to other treatments. [ABSTRACT FROM AUTHOR]

Drug dependence has long been thought to have a genetic component. Research seeking to identify the genetic basis of addiction has gone through important transitions over its history, in part based upon the emergence of new technologies, but also as the result of changing perspectives. Early research approaches were largely dictated by available technology, with technological advancements having highly transformative effects on genetic research, but the limitations of technology also affected modes of thinking about the genetic causes of disease. This review explores these transitions in thinking about the genetic causes of addiction in terms of the "streetlight effect," which is a type of observational bias whereby people search for something only where it is easiest to search. In this way, the genes that were initially studied in the field of addiction genetics were chosen because they were the most "obvious," and formed current understanding of the biological mechanisms underlying the actions of drugs of abuse and drug dependence. The problem with this emphasis is that prior to the genomic era the vast majority of genes and proteins had yet to be identified, much less studied. This review considers how these initial choices, as well as subsequent choices that were also driven by technological limitations, shaped the study of the genetic basis of drug dependence. While genome-wide approaches overcame the initial biases regarding which genes to choose to study inherent in candidate gene studies and other approaches, genome-wide approaches necessitated other assumptions. These included additive genetic causation and limited allelic heterogeneity, which both appear to be incorrect. Thus, the next stage of advancement in this field must overcome these shortcomings through approaches that allow the examination of complex interactive effects, both gene × gene and gene × environment interactions. Techniques for these sorts of studies have recently been developed and represent the next step in our understanding of the genetic basis of drug dependence. [ABSTRACT FROM AUTHOR]

Purpose: To capture UK societal health utility values for high-risk metastatic hormone-sensitive prostate cancer (mHSPC) and the disutility associated with treatment-related adverse events (AEs) to inform future cost-utility analyses.Methods: A literature review, and patient and clinical expert interviews informed the development of health states characterising mHSPC symptoms and the impact of treatment-related AEs on health-related quality of life (HRQL). Three base health states were developed describing a typical patient with high-risk mHSPC: receiving androgen deprivation therapy (ADT) [Base State 1]; receiving docetaxel plus ADT [Base State 2]; completed docetaxel and still receiving ADT whose disease has not yet progressed [Base State 3]. Six additional health states described treatment-related AEs. The health states were validated with experts and piloted with general public participants. Health state utilities were obtained using the time trade-off (TTO) method with 200 members of the UK general population. A generalised estimating equation (GEE) model was used to estimate disutility weights.Results: Mean TTO scores for Base State 1 to 3 were 0.71 (SD = 0.26), 0.64 (SD = 0.27), and 0.68 (SD = 0.26), respectively, indicating that receiving docetaxel plus ADT was most impactful on HRQL. The GEE model indicated when compared to Base State 2 that the nausea and vomiting AE had the most impact on HRQL (- 0.21), while alopecia was least burdensome (- 0.04).Conclusions: The study highlights the differences in utility between base health states and the significant impact of treatment-related AEs on the HRQL of patients with mHSPC. These findings underline the importance of accounting for impaired HRQL when assessing treatments for mHSPC. [ABSTRACT FROM AUTHOR]

The article focuses on vaccination which can be proved helpful for patients with systemic lupus erythematosus (SLE) and thereby help in reduction of morbidity and mortality associated with serious infections. It mentions information on use of measles, mumps and rubella (MMR) vaccine, human papilloma virus (HPV) vaccine, and Shingles vaccine, for vaccination of SLE. It presents information on use of immunosuppressant therapy in SLE patients.

Glaucoma is a well-known complication after corneal transplantation surgery. Traditional corneal transplantation surgery, specifically penetrating keratoplasty, has been slowly replaced by the advent of new corneal transplantation procedures: primarily lamellar keratoplasties. There has also been an emergence of keratoprosthesis implants for eyes that are high risk of failure with penetrating keratoplasty. Consequently, there are different rates of glaucoma, pathogenesis, and potential treatment in the form of medical, laser, or surgical therapy. [ABSTRACT FROM AUTHOR]

Smokers have substantial individual differences in quit success in response to current treatments for nicotine dependence. This observation may suggest that different underlying motivations for continued tobacco use across individuals and nicotine cessation may require different treatments in different individuals. Although most animal models of nicotine dependence emphasize the positive reinforcing effects of nicotine as the major motivational force behind nicotine use, smokers generally report that other consequences of nicotine use, including the ability of nicotine to alleviate negative affective states or cognitive impairments, as reasons for continued smoking. These states could result from nicotine withdrawal, but also may be associated with premorbid differences in affective and/or cognitive function. Effects of nicotine on cognition and affect may alleviate these impairments regardless of their premorbid or postmorbid origin (e.g., before or after the development of nicotine dependence). The ability of nicotine to alleviate these symptoms would thus negatively reinforce behavior, and thus maintain subsequent nicotine use, contributing to the initiation of smoking, the progression to dependence and relapse during quit attempts. The human and animal studies reviewed here support the idea that self-medication for pre-morbid and withdrawal-induced impairments may be more important factors in nicotine addiction and relapse than has been previously appreciated in preclinical research into nicotine dependence. Given the diverse beneficial effects of nicotine under these conditions, individuals might smoke for quite different reasons. This review suggests that inter-individual differences in the diverse effects of nicotine associated with self-medication and negative reinforcement are an important consideration in studies attempting to understand the causes of nicotine addiction, as well as in the development of effective, individualized nicotine cessation treatments. [ABSTRACT FROM AUTHOR]

Purpose: To compare long-term outcomes of simultaneous accelerated corneal crosslinking (CXL) with intrastromal corneal ring segments (CXL-ICRS) with simultaneous accelerated CXL with topography-guided photorefractive keratectomy (CXL-TG-PRK) in progressive keratoconus (KC). Setting: Kensington Eye Institute and Bochner Eye Institute, Toronto, Canada. Design: Prospective nonrandomized interventional study. Methods: The change in visual and topographical outcomes of CXLICRS and CXL-TG-PRK 4 to 5 years postoperatively were compared using linear regression models adjusted for preoperative corrected distance visual acuity (CDVA) and maximum keratometry (Kmax). Results: 57 eyes of 43 patients with progressive KC who underwent simultaneous accelerated (9 mW/cm2, 10 minutes) CXLICRS (n = 32) and CXL-TG-PRK (n = 25) were included. Mean follow-up duration was 51.28 (9.58) and 54.57 (5.81) months for the CXL-ICRS and CXL-TG-PRK groups, respectively. Initial mean Kmax was higher in the CXL-ICRS group compared with the CXL-TG-PRK group (60.68 ± 6.81 diopters [D] vs 57.15 ± 4.19 D, P = .02). At the last follow-up, change (improvement) in logMAR uncorrected distance visual acuity (UDVA) compared with that preoperatively was significant with CXL-ICRS (-0.31 ± 0.27, P < .001, which is equivalent to approximately 3 lines) and not significant with CXL-TG-PRK (-0.06 ± 0.42, P = .43). The logMAR CDVA improved significantly with CXL-ICRS (-0.22 ± 0.20, P < .001), but not with CXL-TG-PRK (-0.05 ± 0.22, P = .25). Adjusting for baseline Kmax and CDVA, the improvement in UDVA was significantly greater with CXL-ICRS than with CXL-TG-PRK (-0.27, 95% CI, 0.06-0.47, P = .01). Improvement in CDVA was not significantly different. Conclusions: In this cohort of progressive KC with long-term follow-up, UDVA showed more improvement with accelerated CXL-ICRS than with CXL-TG-PRK. [ABSTRACT FROM AUTHOR]

Abstract: Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS. [Copyright &y& Elsevier]

Metoprine increases the content of histamine in brain by inhibiting histamine N -methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect. • Pretreatment with metoprine attenuates METH-induced hyperlocomotion. • Metoprine pretreatment itself induced hyperlocomotion. • Activation of histamine neurotransmission might exert metoprine effects. [ABSTRACT FROM AUTHOR]

Chronic tobacco exposure can alter the endocannabinoid (eCB) system, consequently leading to an anxiety state. In this study, we investigated the effects of waterpipe tobacco smoke (WTS) on cannabinoid receptor 1 and 2 (CBR1 and CBR2) gene and protein expression in mesocorticolimbic brain regions. Using elevated plus maze (EPM) and open field (OF) tests, the effects of WTS exposure on withdrawal-induced anxiety-like behavior were examined. The effect of ceftriaxone (CEF), a β-lactam known to upregulate glutamate transporter 1 (GLT-1), on anxiety and the expression of cannabinoid receptors was also determined. Male Sprague-Dawley rats were randomly assigned to four groups: 1) the Control group was exposed only to standard room air; 2) the WTS group was exposed to tobacco smoke and treated with saline vehicle; 3) the WTS-CEF group was exposed to WTS and treated with ceftriaxone; and 4) the CEF group was exposed only to standard room air and treated with ceftriaxone. Rats were exposed to WTS (or room air) for two hours per day, five days per week for a period of four weeks. Behavioral tests (EPM and OF) were conducted weekly during acute withdrawal, 24 h following WTS exposure. Rats were given either saline or ceftriaxone (200 mg/kg i.p.) for five days during Week 4, 30 min prior to WTS exposure. Withdrawal-induced anxiety was induced by WTS exposure but was reduced by ceftriaxone treatment. WTS exposure decreased CBR1 mRNA and protein expression in the NAc and VTA, but not PFC, and ceftriaxone treatment attenuated these effects. WTS exposure did not change CBR2 mRNA expression in the NAc, VTA, or PFC. These findings demonstrate that WTS exposure dysregulated the endocannabinoid system and increased anxiety-like behavior, and these effects were reversed by ceftriaxone treatment, which suggest the involvement of glutamate transporter 1 in these effects. • WTS withdrawal-induced anxiety was induced by WTS exposure. • WTS exposure decreased relative mRNA and protein CB1R expression in NAc and VTA. • WTS exposure did not change the relative mRNA CB2R expression in the brain. • Ceftriaxone treatment attenuated withdrawal-induced anxiety. • Ceftriaxone treatment attenuated the decrease in CB1R level. [ABSTRACT FROM AUTHOR]

Abstract: This review addresses the recent convergence of our long-standing knowledge of the regulation of behavioral phenotypes by developmental experience with recent advances in our understanding of mechanisms regulating gene expression. This review supports a particular perspective on the developmental regulation of behavioral phenotypes: That the role of common developmental experiences (e.g. maternal interactions, peer interactions, exposure to a complex environment, etc.) is to fit individuals to the circumstances of their lives within bounds determined by long-standing (evolutionary) mechanisms that have shaped responses to critical and fundamental types of experience via those aspects of gene structure that regulate gene expression. The phenotype of a given species is not absolute for a given genotype but rather variable within bounds that is determined by mechanisms regulated by experience (e.g. epigenetic mechanisms). This phenotypic variation is not necessarily random, or evenly distributed along a continuum of description or measurement, but often highly disjointed, producing distinct, even opposing, phenotypes. The potentiality for these varying phenotypes is itself the product of evolution, the potential for alternative phenotypes itself conveying evolutionary advantage. Examples of such phenotypic variation, resulting from environmental or experiential influences, have a long history of study in neurobiology, and a number of these will be discussed in this review: neurodevelopmental experiences that produce phenotypic variation in visual perception, cognitive function, and emotional behavior. Although other examples will be discussed, particular emphasis will be made on the role of social behavior on neurodevelopment and phenotypic determination. It will be argued that an important purpose of some aspects of social behavior is regulation of neurobehavioral phenotypes by experience via genetic regulatory mechanisms. [Copyright &y& Elsevier]

Humans differ in their ability to quit using addictive substances, including nicotine, the major psychoactive ingredient in tobacco. For tobacco smoking, a substantial body of evidence, largely derived from twin studies, indicates that approximately half of these individual differences in ability to quit are heritable genetic influences that likely overlap with those for other addictive substances. Both twin and molecular genetic studies support overlapping influences on nicotine addiction vulnerability and smoking cessation success, although there is little formal analysis of the twin data that support this important point. None of the current datasets provides clarity concerning which heritable factors might provide robust dimensions around which individuals differ in ability to quit smoking. One approach to this problem is to test mice with genetic variations in genes that contain human variants that alter quit success. This review considers which features of quit success should be included in a comprehensive approach to elucidate the genetics of quit success, and how those features may be modeled in mice. [ABSTRACT FROM AUTHOR]

Rationale: The neuropeptide neurotensin (NT), which has been implicated in the modulation of dopamine signaling, is expressed in a subset of dopamine neurons and antagonism of the NT receptor has been reported to reduce psychostimulant-induced behavior. Gene knockout (KO) of the neurotensin/neuromedin N precursor provides an approach to delineating possible roles of endogenous NT in psychostimulant-induced responses. Objectives: Involvement of NT in cocaine responses was examined by comparing acute and conditioned locomotor responses, conditioned place preference, and sensitization in wild-type (WT), heterozygous, and homozygous NT KO mice. Results: NT KO mice did not differ from their WT or heterozygous littermates in either baseline or acute cocaine-stimulated locomotor activity. The locomotor stimulant effects of cocaine were slightly prolonged in these mice under some, but not all, experimental conditions. The rewarding effects of cocaine as assessed in the conditioned place preference and conditioned locomotion paradigms were also similar between genotypes at all cocaine doses tested. Conclusions: These results suggest that endogenous NT is not involved in cocaine-mediated behaviors in most circumstances, but under some conditions, a slight prolongation of the effects of cocaine was observed in the absence of endogenous NT. [ABSTRACT FROM AUTHOR]

Abstract: Although cocaine is primarily known for its powerful hedonic effects, there is evidence that its affective experience has a notable aversive component that is less well understood. A variety of pharmacological and molecular approaches have implicated enhanced monoamine (MA) neurotransmission in the aversive effects of cocaine. Although numerous studies have yielded data supportive of the role of the monoamines (indirectly and directly), the specific system suggested to be involved differs across studies and paradigms (Freeman et al., 2005b; Grupp, 1997; Roberts and Fibiger, 1997). Monoamine transporter knockout mice have been useful in the study of many different aspects of cocaine effects relevant to human drug use and addiction, yet an assessment of the effects of deletion of the genes for the dopamine, norepinephrine and serotonin transporters (DAT, NET, and SERT, respectively) on cocaine''s aversive properties has yet to be performed (Uhl et al., 2002). In the current investigation, the strength of cocaine-induced aversions was compared among three groups of transgenic mice with deletions of the genes responsible for the production of one of the monoamine transporters. When compared to their respective WT controls, dopamine transporter deletion slightly attenuated cocaine-induced aversion while deletion of SERT or NET resulted in a more significant delay in the onset and strength of cocaine-induced taste aversions. The data lead us to conclude that the action of cocaine to inhibit NET contributes most substantially to its aversive effects, with some involvement of SERT and minimal contribution of DAT. [Copyright &y& Elsevier]

Abstract: Despite the impact of cocaine''s aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine''s aversive effects using conditioned taste aversion (CTA) learning [ Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955;122:157–158.]. Specifically, Experiment 1 assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined, the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine''s aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin. [Copyright &y& Elsevier]

There has been much interest in the relative importance of dopamine and serotonin transporters in the abuse-related-effects of cocaine. We tested the hypotheses that mice lacking the dopamine transporter (DAT-/-), the serotonin transporter (SERT-/-), or both (DAT-/-SERT-/-) exhibit decreased reinforcing effects of cocaine. We also assessed whether observed effects on self-administration are specific to cocaine or if operant behavior maintained by food or a direct dopamine agonist are similarly affected. We used a broad range of experimental conditions that included acquisition without previous training, behavior established with food training and subsequent testing with food, cocaine or a direct dopamine agonist as reinforcers, fixed ratio and progressive ratio schedules of reinforcement, and a reversal procedure. Wild-type mice readily acquired cocaine self-administration and showed dose-response curves characteristic of the schedule of reinforcement that was used. While some DAT-/- mice appeared to acquire cocaine self-administration transiently, almost all DAT-/- mice failed to self-administer cocaine reliably. Food-maintained behaviors were not decreased by the DAT mutation, and IV self-administration of a direct dopamine agonist was robust in the DAT-/- mice. In contrast to those mice, cocaine's reinforcing effects were not diminished in SERT-/- mice under any of the conditions tested, except for impaired initial acquisition of both food- and cocaine-maintained behavior. These findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine. [ABSTRACT FROM AUTHOR]

In 2013, President Obama launched what has been optimistically described as the “decade of the brain”. The launch of this effort comes on the back of widespread acknowledgement that more is required to aid those suffering from mental health disorders. Specifically, a greater understanding of the neural circuitry related to behaviors specific to mental health disorders is needed. The field of research that relates the circuitry of the brain to specific aspects of behavior is referred to as behavioral neuroscience. The International Behavioral Neuroscience Society (IBNS) was founded in 1992 specifically to meet on an annual basis and present the latest research findings in this field, and to gather together the international research community to discuss issues important for the development and progress of this scientific discipline. This special issue includes reviews of topics of emerging interest and advancing knowledge in behavioral neuroscience, based on symposia presented at the 2014 IBNS meeting. Topics discussed at the annual IBNS meeting ranged from investigations of the neural mechanisms underlying bipolar disorder, schizophrenia, depression, traumatic brain injury, and risk-taking behavior, to behavioral consequences of obesity and immune dysfunction. Novel treatment areas are covered such as the use of deep brain stimulation, as well as investigation of the behavioral impacts of nicotine withdrawal and how this research will influence the development of nicotine cessation treatments. Hence, this special issue covers a wide-range of topics in behavioral neuroscience offering an insight into the challenges faced by researchers in this decade of the brain. [ABSTRACT FROM AUTHOR]

The μ-opioid receptor (OPRM1) is expressed in brain regions implicated in reward and locomotor processes. Reduced reward, not only from opiates, but also from several other abused substances has been observed in mice with lifelong deletions of the OPRM1 gene. To further define the roles of μ-opioid receptors in psychostimulant actions, cocaine psychomotor stimulant and rewarding effects were examined in wild-type (WT), heterozygous and homozygous μ-opioid receptor knockout mice. While μ-opioid receptor knockout did not affect basal locomotion, locomotor stimulant effects of cocaine were enhanced in a within-subjects dose–response experiment. However, further study revealed that in mice injected with 20 mg/kg for the first time, there was no difference in the locomotor-stimulating effects of cocaine between knockout and wild-type mice. In a sensitization study (modeled after the conditions in the dose–response experiment) although not observed in WT mice, OPRM1−/− mice did exhibit cocaine sensitization. By stark contrast, and similar to the effects of other rewarding drugs in OPRM1 KO mice, cocaine reward, as assessed by conditioned place preference, was reduced in both homozygous and heterozygous OPRM1 KO mice. The present results confirm a central role of the μ-opioid receptor in drug reward but opposing effects on locomotor sensitization. The reduced cocaine reward identified in heterozygous μ-opioid receptor knockout mice supports the possibility that humans with fewer available μ-opioid receptors might experience less cocaine reward. [Copyright &y& Elsevier]

Brain-derived neurotrophic factor (BDNF) affects the development of brain neurotransmitter systems, including dopamine and serotonin systems that are important for cocaine's rewarding and locomotor stimulatory properties. Human genomic markers within or near the BDNF locus have been linked to or associated with substance abuse. Post-mortem human brain specimens reveal individual differences in the levels of BDNF mRNA and in mRNA splicing patterns. To assess the effects of lifelong alterations in the levels of BDNF expression on a measure of psychostimulant reward, we have compared locomotor stimulant and rewarding effects of cocaine in heterozygous BDNF knockout mice with effects in their wild-type littermates. Heterozygous BDNF knockout mice displayed less locomotion during habituation and less locomotion after cocaine injections. Cocaine-conditioned place preferences were reduced in the BDNF heterozygotes. These mice displayed no significant difference from saline control values at a dose of 10 mg/kg s.c. cocaine, although they exhibited cocaine-induced preference at a 20 mg/kg dose. These data confirm important roles for BDNF in psychostimulant actions, presumably via neurotrophic effects on dopamine and serotonin systems. Furthermore, these data support suggestions that differences in human BDNF expression may underlie associations between markers near the human BDNF gene locus and drug addiction. [ABSTRACT FROM AUTHOR]

Homozygous µ-opioid receptor (MOR) knockout (KO) mice developed on a chimeric C57B6/129SV background lack morphine-induced antinociception, locomotion and reward. Therefore it appears that MOR largely mediates these morphine actions. However, one factor that could affect the extent of knockout deficits in morphine-induced behavior is the genetic background against which the gene deletion is expressed. To examine the effect of genetic background chimeric C57B6/129SV MOR knockout mice from the 15th generation of those developed in our laboratory were backcrossed for 10 successive generations with C57BL/6 mice, a strain which is more sensitive to many of the properties of morphine, to produce congenic MOR (conMOR) KO mice. Heterozygote conMOR KO mice display attenuated morphine locomotion and reduced morphine analgesia compared to wild-type mice. Homozygote conMOR KO mice display baseline hyperalgesia, no morphine place preference, no morphine analgesia and no morphine locomotion. These results are not qualitatively different from those observed in the MOR KO strain with a chimeric C57B6/129SV background, and suggest that although the strain has separate influences on these functions, it does not substantially interact with deletion of the µ opiate receptor gene. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that monoaminergic systems, especially dopaminergic and serotoninergic systems, modulate ethanol consumption. Humans display significant differences in expression of the vesicular and plasma membrane monoamine transporters important for monoaminergic functions, including the vesicular monoamine transporter (VMAT2, SLC18A2) and dopamine transporter (DAT, SLC6A3). In addition, many ethanol effects differ by sex in both humans and animal models. Therefore, ethanol consumption and preference were compared in male and female wild-type mice, and knockout (KO) mice with deletions of genes for DAT and VMAT2. Voluntary ethanol (2-32% v/v) and water consumption were compared in two-bottle preference tests in wild-type (+/+) vs heterozygous VMAT2 KO mice (+/-) and in wild-type (+/+) vs heterozygous (+/-) or homozygous (-/-) DAT KO mice. Deletions of either the DAT or VMAT2 genes increased ethanol consumption in male KO mice, although these effects were highly dependent on ethanol concentration, while female DAT KO mice had higher ethanol preferences. Thus, lifetime reductions in the expression of either DAT or VMAT2 increase ethanol consumption, dependent on sex. [ABSTRACT FROM AUTHOR]

Describes the action of cocaine in blocking the uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET). Cocaine reward/reinforcement linked to actions at DAT; Details of the molecular basis of cocaine reward.

Background Alcohol is a major abused drug worldwide that contributes substantially to health and social problems. These problems result from acute alcohol overuse as well as chronic use, leading to alcohol use disorder (AUD). A major goal of this field is to establish a treatment for alcohol abuse and dependence in patients with AUD. The central molecular mechanisms of acute alcohol actions have been extensively investigated in rodent models. Aims One of the central mechanisms that may be involved is glycogen synthase kinase-3β (GSK-3β) activity, a key enzyme involved in glycogen metabolism but which has crucial roles in numerous cellular processes. Although the exact mechanisms leading from acute alcohol actions to these chronic changes in GSK-3β function are not yet clear, GSK-3β nonetheless constitutes a potential therapeutic target for AUD by reducing its function using GSK-3β inhibitors. This review is focused on the correlation between GSK-3β activity and the degree of alcohol consumption. Methods Research articles regarding investigation of effect of GSK-3β on alcohol consumption in rodents were searched on PubMed, Embase, and Scopus databases using keywords "glycogen synthase kinase," "alcohol (or ethanol)," "intake (or consumption)," and evaluated by changes in ratios of pGSK-3βSer9/pGSK-3β. Results In animal experiments, GSK-3β activity decreases in the brain under forced and voluntary alcohol consumption while GSK-3β activity increases under alcohol-seeking behavior. Conclusions Several pieces of evidence suggest that alterations in GSK-3β function are important mediators of chronic ethanol actions, including those related to alcohol dependence and the adverse effects of chronic ethanol exposure. [ABSTRACT FROM AUTHOR]

Abstract Voluntary ethanol (EtOH) consumption is increased by isolation-rearing in several rat strains. The following experiments examined the effects of isolation-rearing on basal and ethanol-stimulated behavior in Fawn Hooded rats, an alcohol-preferring rat strain, compared to Wistar rats. Locomotor activity and anxiety were examined under both conditions. Basal locomotor activity was higher in isolated subjects of both strains in low light conditions, but under bright light conditions, this difference was only observed in Wistar rats. Locomotor stimulant effects of EtOH were only observed in isolation-reared rats. In the elevated plus maze, Fawn Hooded rats were more anxious than Wistar rats under low light conditions, but under bright light conditions, Wistar socials were less anxious than all of the other groups. Administration of 1.5 mg/kg EtOH produced an anxiolytic response in the elevated plus maze under bright light conditions in Fawn Hooded rats, but to a lesser degree Wistar rats, particularly Wistar isolates. In conclusion, although both strain and isolation-rearing had effects on locomotion and anxiety as well as the stimulatory and anxiolytic effects of EtOH, these effects appeared to be independent. [ABSTRACT FROM AUTHOR]

Abstract These experiments examined the hypothesis that isolation-rearing and strain influence hedonic mechanisms. In experiment 1, voluntary consumption of ethanol and water was monitored in the home cage of Fawn Hooded (FH) and Wistar rats. FH rats were found to consume more ethanol at low concentrations than Wistar rats, independent of rearing condition, and isolation-reared rats were found to consume more of high ethanol concentrations, independent of strain. In experiment 2, isolation-reared rats were found to consume more sucrose, independent of concentration, than socially reared rats. In experiment 3, Fawn Hooded rats were found to be more sensitive to low concentration solutions of saccharin, and to consume less of the high concentration solutions, while isolation-rearing was found to enhance consumption of high concentrations. Thus, hedonic processes are independently modulated by strain and rearing conditions, although the effects of isolation-rearing appear to be exacerbated in Fawn Hooded rats. [ABSTRACT FROM AUTHOR]

This article focuses on the new eosinophilic syndrome. Peripheral and tissue eosinophilia are associated with a group of idiopathic inflammatory syndromes. The description of a new eosinophilic syndrome in this issue of the journal prompts a reappraisal of the role of eosinophils in this heterogeneous group of disorders. The association of asthma, eosinophilia, vasculitis and extravascular granulomata was described in 1951 as allergic angiitis. Cardiac and cutaneous involvement is common. In the acute phase, vessel walls exhibit fibrinoid necrosis with an inflammatory eosinophilic infiltrate.

Chemical injuries involving the eye account for 11.5%-22.1% of ocular trauma. Serious ocular chemical injuries are characterized by corneal opacification (Figure 1A), ischemia to the margin of the cornea (Figure 1B, black arrow) and extensive conjunctival involvement (Figure 1C). Graph: Figure 1: A) Slit-lamp examination using fluorescein stain of a left eye after sulfuric acid injury from an automobile battery explosion, showing extensive epithelial damage of the entire cornea and corneal opacification. [Extracted from the article]

• WTS exposure for four weeks caused withdrawal-induced anxiety behavior. • Ceftriaxone reduces waterpipe tobacco smoke withdrawal-induced anxiety. • WTS exposure increased the relative mRNA levels for NFĸB, TNF-α and BDNF. • WTS exposure reduced the relative mRNA levels for Nrf2, GLT-1 and xCT. • Ceftriaxone attenuated the dysregulation in the relative mRNA levels. Tobacco exposure has been linked to neuroinflammation and adaptive/maladaptive changes in neurotransmitter systems, including in glutamatergic systems. We examined the effects of waterpipe tobacco smoke (WTS) on inflammatory mediators and astroglial glutamate transporters in mesocorticolimbic brain regions including the prefrontal cortex (PFC), nucleus accumbens (NAc) and ventral tegmental area (VTA). The behavioral consequences of WTS exposure on withdrawal-induced anxiety-like behavior were assessed using elevated plus maze (EPM) and open field (OF) tests. Male Sprague-Dawley rats were randomly assigned to 3 experimental groups: a control group exposed only to standard room air, a WTS exposed group treated with saline vehicle, and a WTS exposed group treated with ceftriaxone. WTS exposure was performed for 2 h/day, 5 days/week, for 4 weeks. Behavioral tests (EPM and OF) were conducted weekly 24 h after WTS exposure, during acute withdrawal. During week 4, rats were given either saline or ceftriaxone (200 mg/kg i.p.) 30 min before WTS exposure. WTS increased withdrawal-induced anxiety, and ceftriaxone attenuated this effect. WTS exposure increased the relative mRNA levels for nuclear factor ĸB (NFĸB), tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor (BDNF) in the PFC, NAc and VTA, and ceftriaxone treatment reversed these effects. In addition, WTS decreased the relative mRNA of nuclear factor erythroid 2 related factor 2 (Nrf2), glutamate transporter 1 (GLT-1) and cystine-glutamate transporter (xCT) in PFC, NAc and VTA, and ceftriaxone treatment normalized their expression. WTS caused neuroinflammation, alteration in relative mRNA glutamate transport expression, and increased anxiety-like behavior, and these effects were attenuated by ceftriaxone treatment. [ABSTRACT FROM AUTHOR]

We investigated morphine-induced Straub's tail reaction (STR) in mice pretreated with or without glycogen synthase kinase-3 (GSK-3) inhibitors (SB216763 and AR-A014418) by using a newly modified, infrared beam sensor-based automated apparatus. Mice treated with a single injection of morphine (30 mg/kg, i.p.) showed a significant STR with a plateau level at a time point of 20 min after morphine challenge. Pretreatment of mice with SB216763 (5 mg/kg, s.c.) or AR-A014418 (3 mg/kg, i.p.) significantly inhibited morphine-induced STR and attenuated the duration of STR in a dose-dependent fashion. In the striatum and the nucleus accumbens, expression of pGSK-3βTyr216 but not GSK3β or pGSK-3βSer9 was largely but not significantly reduced after treatment with SB216763 (5 mg/kg, s.c.) in combination with/without morphine, indicating that the inhibitory effect of GSK-3 inhibitors on morphine-induced STR and hyperlocomotion might not depend on the direct blockade of GSK-3β function. In constipated mice after morphine challenge (30 mg/kg), the effect of GSK-3 inhibitors on gastrointestinal transit was examined to reveal whether the action of GSK-3 inhibitors on morphine effects was central and/or peripheral. Pretreatment with SB216763 (5 mg/kg) did not block constipation in morphine-injected mice. The mechanism of action seems to be central but not peripheral, although the underlying subcellular mechanism of GSK-3 inhibitors is not clear. Our measurement system is a useful tool for investigating the excitatory effects of morphine in experimental animals. [ABSTRACT FROM AUTHOR]

To report a rare case of fungal keratitis and endophthalmitis due to Coniochaeta hoffmannii. Case report. A 71-year-old immunocompetent male sustained a corneal laceration, traumatic cataract, and retinal detachment due to penetrating injury from a nail pulled from a wooden deck. The patient's postoperative course was complicated by infectious keratitis. Fungal cultures, DNA sequencing and analysis of the internal transcribed spacer sequence confirmed Coniochaeta hoffmannii. Topical and oral voriconazole treatments were initiated; however, due to impending perforation, a therapeutic corneal transplant was required. One year later, the patient developed a new corneal infiltrate at the graft-host junction: Corneal scrapings were culture positive for Coniochaeta hoffmannii. This was treated with topical and intrastromal voriconazole along with oral itraconazole 200 mg once daily for 8 months. Coniochaeta hoffmannii may cause recalcitrant keratitis and endophthalmitis, which required longstanding antifungal treatment. [ABSTRACT FROM AUTHOR]

A single administration with morphine (30 mg/kg, i.p.) induced long-lasting hyperlocomotion in male ICR mice. Pretreatment of mice with a benzoquinolizine derivative tetrabenazine (TBZ; a reversible vesicular monoamine transporter-2 inhibitor) (1 mg/kg, i.p.) for 30 min significantly attenuated the hyperlocomotion induced by morphine, as compared with vehicle (saline)-pretreated mice. No significant change in locomotion was observed in mice pretreated with TBZ (1 mg/kg) alone. Mice treated with TBZ (1 mg/kg) showed an increase in immobility time in a tail suspension test, as compared with saline-treated mice. Pretreatment with TBZ (1 mg/kg) had no effect on morphine (1–30 mg/kg)-induced antinociception. TBZ at a dose of 1 mg/kg inhibited dopamine turnover (the ratio of 3,4-dihydroxyphenylacetic acid/dopamine) and 5-hydroxytryptamine turnover (the ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine) in the cerebral cortex of mice challenged with morphine, as compared with saline-pretreated mice challenged with morphine. No stereotypic behavior was observed in mice treated with morphine (30 mg/kg) in combination with TBZ (1 mg/kg), so the reduction in observed locomotion did not result from induction of stereotypical behavior. Moreover, TBZ (1 and 2 mg/kg) pretreatment had no effect on stereotyped behaviors observed in mice challenged with 10 mg/kg methamphetamine. These data support the potential antagonistic actions of TBZ on some opiate actions, and encourage further exploration of potential effects on morphine reinforcement. [ABSTRACT FROM AUTHOR]

The article discusses a research study on postoperative results, visual acuity and adverse events among patients after an I-CARE anterior-chamber phakic intraocular lens (IOL) implantation. Data on 29 eyes that received I-CARE phakic IOL from 2003 to 2006 were analyzed with 52 months as mean follow up average to measure visual acuity. Results showed that after 1 year, visual acuity was 0.63 while best-corrected visual acuity was 0.94 decimal and mean endothelial cell (EC) loss from 2% to 47%.

The article presents a study on the effectiveness of oral antiviral prophylaxis and its association with incidence, recurrence and outcomes of herpes simplex virus (HSV) eye disease in Olmsted County, Minnesota from January 1, 1976 to December 31, 2007. For the study, researchers utilized the Rochester Epidemiology Project (REP) medical records linkage program. They found that the yearly ocular HSV occurrence was about 11.8 per 100,000 individuals. They also found that oral antiviral prophylaxis reduced the risk of recurrence of various eye conditions.

The article discusses research being done on substance P-derived peptide and insulin-like growth factor-1-derived peptide. It references a study by N. Yamada et al, published in a 2008 issue of the "British Journal of Ophthalmology." The study examined the clinical efficacy of a combination eye drop of a substance P-derived peptide and an insulin-like growth factor-1-derived peptide for the treatment of corneal epithelial defects in patients with neurotrophic keratopathy. The eye drops used had no adverse side effects.

A single administration of mice with memantine (1-amino-3,5-dimethyladamantane), a glutamatergic N -methyl- d -aspartate (NMDA) receptor antagonist, induced stereotyped behaviors in dose- and time-dependent manners. The predominant behavioral component of the stereotypy was a continuous, exaggerated sniffing which was accompanied by persistent locomotion. In contrast, a psychostimulant methamphetamine (METH) predominantly induced a stereotyped biting and other forms of intense stationary stereotypical behaviors. Memantine-induced stereotyped sniffing was attenuated by pretreatment with haloperidol, a dopamine D 2 receptor antagonist, in a dose-dependent manner. The memantine-induced stereotyped sniffing was also attenuated by pretreatment with betahistine (2-[2-(methylamino)ethyl]pyridine), an agent which increases histamine turnover and releases histamine in the brain. These observations suggest that memantine might induce stereotypies through neuronal mechanisms that are somewhat different from those of METH, but still overlap to a certain extent, since memantine-induced stereotypies can be attenuated by the mechanisms that also suppress METH-induced stereotypy. Importantly, these data suggests that the effects of memantine may be more limited to the ventral striatum including nucleus accumbens than those of METH, which is associated with dorsal striatal stimulation at high doses. In this respect memantine may also have pharmacological properties such as compartmentation ( i.e . brain distribution) and neuronal mechanisms different from those of other NMDA receptor antagonists, such as ketamine, which may have important implications for therapeutic uses of these drugs. [ABSTRACT FROM AUTHOR]

Introduction: Few studies have reported the physical complications among Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) survivors.Objective: The aim of this study was to comprehensively characterize the physical complications among SJS/TEN survivors and to learn about patients' perspectives of surviving SJS/TEN.Methods: SJS/TEN survivors older than 18 years of age were assessed by different methods: a medical interview; a questionnaire assessing patients' perspectives; thorough skin, oral mucous membrane, and ophthalmic examinations; and a retrospective assessment of medical records.Results: Our cohort consisted of 17 patients with a mean time of 51.6 ± 74.7 months (median 9, range 1-228) following SJS/TEN. The most common physical complications identified in the medical examination were post-inflammatory skin changes (77%), cutaneous scars (46%), dry eyes (44%), symblepharon, and chronic ocular surface inflammation (33% each). Novel physical sequelae included chronic fatigue (76%) and pruritus (53%). We also found a novel association between the number of mucous membranes affected in the acute phase of SJS/TEN and hair loss during the 6 months following hospital discharge; hair loss was reported in 88% of the group of patients who had three or more mucous membranes affected versus 29% of patients who had less than three mucous membranes involved (p = 0.0406). Following hospital discharge due to SJS/TEN, 59% of patients were followed by a dermatologist, although 88% had dermatological complications; 6% were followed by an ophthalmologist, even though 67% had ophthalmological complications; and 6% of female survivors were followed by a gynecologist, even though 27% had gynecological complications.Conclusion: Survivors of SJS/TEN suffer from severe physical complications impacting their health and lives that are mostly under recognized and not sufficiently treated by medical professionals. [ABSTRACT FROM AUTHOR]

A variety of genetic approaches, including twin studies, linkage studies, and candidate gene studies, has established a firm genetic basis for addiction. However, there has been difficulty identifying the precise genes that underlie addiction liability using these approaches. This situation became especially clear in genome-wide association studies (GWAS) of addiction. Moreover, the results of GWAS brought into clarity many of the shortcomings of those early genetic approaches. GWAS studies stripped away those preconceived notions, examining genes that would not previously have been considered in the study of addiction, consequently creating a shift in our understanding. Most importantly, those studies implicated a class of genes that had not previously been considered in the study of addiction genetics: cell adhesion molecules (CAMs). Considering the well-documented evidence supporting a role for various CAMs in synaptic plasticity, axonal growth, and regeneration, it is not surprising that allelic variation in CAM genes might also play a role in addiction liability. This review focuses on the role of various cell adhesion molecules in neuroplasticity that might contribute to addictive processes and emphasizes the importance of ongoing research on CAM genes that have been implicated in addiction by GWAS. [ABSTRACT FROM AUTHOR]

Purpose To use patient-level microsimulation models to evaluate the comparative cost-effectiveness of early corneal cross-linking (CXL) and conventional management with penetrating keratoplasty (PKP) when indicated in managing keratoconus in Canada. Design Cost-utility analysis using individual-based, state–transition microsimulation models. Participants Simulated cohorts of 100 000 individuals with keratoconus who entered each treatment arm at 25 years of age. Fellow eyes were modeled separately. Simulated individuals lived up to a maximum of 110 years. Methods We developed 2 state–transition microsimulation models to reflect the natural history of keratoconus progression and the impact of conventional management with PKP versus CXL. We collected data from the published literature to inform model parameters. We used realistic parameters that maximized the potential costs and complications of CXL, while minimizing those associated with PKP. In each treatment arm, we allowed simulated individuals to move through health states in monthly cycles from diagnosis until death. Main Outcome Measures For each treatment strategy, we calculated the total cost and number of quality-adjusted life years (QALYs) gained. Costs were measured in Canadian dollars. Costs and QALYs were discounted at 5%, converting future costs and QALYs into present values. We used an incremental cost-effectiveness ratio (ICER = difference in lifetime costs/difference in lifetime health outcomes) to compare the cost-effectiveness of CXL versus conventional management with PKP. Results Lifetime costs and QALYs for CXL were estimated to be Can$5530 (Can$4512, discounted) and 50.12 QALYs (16.42 QALYs, discounted). Lifetime costs and QALYs for conventional management with PKP were Can$2675 (Can$1508, discounted) and 48.93 QALYs (16.09 QALYs, discounted). The discounted ICER comparing CXL to conventional management was Can$9090/QALY gained. Sensitivity analyses revealed that in general, parameter variations did not influence the cost-effectiveness of CXL. Conclusions CXL is cost-effective compared with conventional management with PKP in the treatment of keratoconus. Our ICER of Can$9090/QALY falls well below the range of Can$20 000 to Can$100 000/QALY and below US$50 000/QALY, thresholds generally used to evaluate the cost-effectiveness of health interventions in Canada and the United States. This study provides strong economic evidence for the cost-effectiveness of early CXL in keratoconus. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about paraneoplastic optic disc oedema and retinal periphlebitis associated with pineal germinoma.

BACKGROUND Risk of cardiovascular disease is increased in patients with rheumatoid arthritis (RA), although the reasons for this increase are not clear. Disease-modifying antirheumatic drugs (DMARDs) can affect cardiovascular disease risk in patients with RA by directly affecting atherosclerosis through inflammation or by influencing cardiovascular risk factors. OBJECTIVE The objective of this study was to investigate whether treatment with conventional DMARDs is associated with cardiovascular disease in patients with RA. DESIGN AND INTERVENTION This was a case-control study that included patients who fulfilled the American College of Rheumatology criteria for RA and who were receiving treatment with conventional DMARDs: sulfasalazine, hydroxychloroquine and methotrexate. Patients were separated into groups according to DMARD use: sulfa-salazine, hydroxychloroquine, methotrexate monotherapy, combination therapy with two or three of these drugs, or no past treatment with any of the studied DMARDs. Data analysis included comparisons between each DMARD treatment group and between patients with and without cardiovascular disease (defined as coronary, cerebral or peripheral arterial disease). Three correction models were used for the data analysis: data corrected for age, gender, smoking history and duration of RA; data corrected for hypertension, diabetes and hyper-cholesterolemia; and data corrected for presence of rheumatoid factor and radiographically visible joint erosions. The study period was defined as time from first diagnosis of RA until occurrence of the first cardiovascular event or the end of the follow-up period. OUTCOME MEASURES The primary outcome measure of this study was the occurrence of a cardiovascular event. RESULTS Data from a total of 613 patients with RA were included in this study. Overall, 72 patients developed cardiovascular disease during the study period, and 541 patients did not. Treatment with methotrexate, either alone or in combination with sulfasalazine or in combination with sulfasalazine and hydroxychloroquine, was associated with a significantly decreased risk of cardiovascular disease compared with no DMARD treatment; odds ratios were 0.16 (95% CI 0.04-0.66), 0.20 (95% CI 0.08-0.51) and 0.20 (95% CI 0.08-0.54), respectively. Risk reductions were significant regardless of correction for rheumatoid factor positivity and presence of joint erosions. Risk of cardiovascular disease was significantly decreased in patients in the methotrexate plus sulfasalazine group and the methotrexate, sulfasalazine and hydroxychloroquine combination group, after correcting for hypertension, diabetes and hyper- cholesterolemia. Risk of cardiovascular disease was increased in patients who tested positive for rheumatoid factor and who had joint erosions, with odds ratios of 2.04 (95% CI 1.02-4.07) and 2.36 (95% CI 0.92-6.08), respectively. A significantly lower risk of cardiovascular disease was associated with patients who received methotrexate compared with patients who had never used any of the study DMARDs. CONCLUSION The authors conclude that treatment with methotrexate could reduce the development of atherosclerosis, resulting in decreased risk of cardiovascular disease in patients with RA. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The Case for More U.S. Medical Students," by F. Mullan in the July 20, 2000 issue.

Rationale: The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish (Danio rerio) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches. Objectives: In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae. Methods: Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format. Results: METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems. Conclusions: These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances. [ABSTRACT FROM AUTHOR]