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BACKGROUND - The nematode Caenhorhabditis elegans offers great power for the identification and characterization of genes that regulate behavior. In support of this effort, analytical methods are required that provide dimensional analyses of subcomponents of behavior. Previously, we demonstrated that loss of the presynaptic dopamine (DA) transporter, dat-1, evokes DA-dependent Swimming-Induced Paralysis (Swip) (Mcdonald et al., 2007), a behavior compatible with forward genetic screens (Hardaway et al., 2012).
NEW METHOD - Here, we detail the development and implementation of SwimR, a set of tools that provide for an automated, kinetic analysis of C. elegans Swip. SwimR relies on open source programs that can be freely implemented and modified.
RESULTS - We show that SwimR can display time-dependent alterations of swimming behavior induced by drug-treatment, illustrating this capacity with the dat-1 blocker and tricyclic antidepressant imipramine (IMI). We demonstrate the capacity of SwimR to extract multiple kinetic parameters that are impractical to obtain in manual assays.
COMPARISON WITH EXISTING METHODS - Standard measurements of C. elegans swimming utilizes manual assessments of the number of animals exhibiting swimming versus paralysis. Our approach deconstructs the time course and rates of movement in an automated fashion, offering a significant increase in the information that can be obtained from swimming behavior.
CONCLUSIONS - The SwimR platform is a powerful tool for the deconstruction of worm thrashing behavior in the context of both genetic and pharmacological manipulations that can be used to segregate pathways that underlie nematode swimming mechanics.
Copyright © 2014 Elsevier B.V. All rights reserved.
OBJECTIVE - This is the fourth edition of diagnostic and treatment guidelines for complex regional pain syndrome (CRPS; aka reflex sympathetic dystrophy).
METHODS - Expert practitioners in each discipline traditionally utilized in the treatment of CRPS systematically reviewed the available and relevant literature; due to the paucity of levels 1 and 2 studies, less rigorous, preliminary research reports were included. The literature review was supplemented with knowledge gained from extensive empirical clinical experience, particularly in areas where high-quality evidence to guide therapy is lacking.
RESULTS - The research quality, clinical relevance, and "state of the art" of diagnostic criteria or treatment modalities are discussed, sometimes in considerable detail with an eye to the expert practitioner in each therapeutic area. Levels of evidence are mentioned when available, so that the practitioner can better assess and analyze the modality under discussion, and if desired, to personally consider the citations. Tables provide details on characteristics of studies in different subject domains described in the literature.
CONCLUSIONS - In the humanitarian spirit of making the most of all current thinking in the area, balanced by a careful case-by-case analysis of the risk/cost vs benefit analysis, the authors offer these "practical" guidelines.
Wiley Periodicals, Inc.
Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabelling for NET and co-localization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 d, 15 mg/kg.d), NET-immunoreactive (ir) axons were significantly less likely to co-localize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI- and vehicle-treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labelling. Our findings encourage consideration of possible post-translational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance.
Patients taking amitriptyline (AMT) have an increased risk of sudden cardiac death, yet the mechanism for AMT's proarrhythmic effects remains incompletely understood. Here, we hypothesize that AMT activates cardiac ryanodine channels (RyR2), causing premature Ca(2+) release from the sarcoplasmic reticulum (SR), a mechanism identified by genetic studies as a cause of ventricular arrhythmias and sudden cardiac death. To test this hypothesis, we measured the effect of AMT on RyR2 channels from mice and sheep and on intact mouse cardiomyocytes loaded with the Ca(2+) fluorescent indicator Fura-2 acetoxymethyl ester. AMT induced trains of long channel openings (bursts) with 60 to 90% of normal conductance in RyR2 channels incorporated in lipid bilayers. The [AMT], voltage, and open probability (P(o)) dependencies of burst frequency and duration indicated that AMT binds primarily to open RyR2 channels. AMT also activated RyR2 channels isolated from transgenic mice lacking cardiac calsequestrin. Reducing RyR2 P(o) by increasing cytoplasmic [Mg(2+)] significantly inhibited the AMT effect on RyR2 channels. Consistent with the single RyR2 channel data, AMT increased the rate of spontaneous Ca(2+) releases and decreased the SR Ca(2+) content in intact cardiomyocytes. Intracellular [AMT] were approximately 5-fold higher than extracellular [AMT], explaining AMT's higher potency in cardiomyocytes at clinically relevant concentrations (0.5-3 muM) compared with its effect in lipid bilayers (5-10 muM). Increasing extracellular [Mg(2+)] attenuated the effect of AMT in intact myocytes. We conclude that the heretofore unrecognized activation of RyR2 channels and increased SR Ca(2+) leak may contribute to AMT's proarrhythmic and cardiotoxic effects, which may be counteracted by interventions that reduce RyR2 channel open probability.
It has been suggested that disturbances in endocannabinoid signaling contribute to the development of depressive illness; however, at present there is insufficient evidence to allow for a full understanding of this role. To further this understanding, we performed an analysis of the endocannabinoid system in an animal model of depression. Male rats exposed to chronic, unpredictable stress (CUS) for 21 days exhibited a reduction in sexual motivation, consistent with the hypothesis that CUS in rats induces depression-like symptoms. We determined the effects of CUS, with or without concurrent treatment with the antidepressant imipramine (10 mg/kg), on CP55940 binding to the cannabinoid CB(1) receptor; whole tissue endocannabinoid content; and fatty acid amide hydrolase (FAAH) activity in the prefrontal cortex, hippocampus, hypothalamus, amygdala, midbrain and ventral striatum. Exposure to CUS resulted in a significant increase in CB(1) receptor binding site density in the prefrontal cortex and a decrease in CB(1) receptor binding site density in the hippocampus, hypothalamus and ventral striatum. Except in the hippocampus, these CUS-induced alterations in CB(1) receptor binding site density were attenuated by concurrent antidepressant treatment. CUS alone produced a significant reduction in N-arachidonylethanolamine (anandamide) content in every brain region examined, which was not reversed by antidepressant treatment. These data suggest that the endocannabinoid system in cortical and subcortical structures is differentially altered in an animal model of depression and that the effects of CUS on CB(1) receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not.
Fibromyalgia syndrome (FMS) is a chronic multisymptom illness characterized by widespread pain and associated with neuropsychological symptoms including fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression. A discreet cause of FMS has not been identified. It is likely that multiple mechanisms give rise to symptom expression. Understanding specific etiologic factors and pathogenic mechanisms in individual patients will allow clinicians to determine treatments that are most effective for a given patient. Available evidence implicates the central nervous system as key in maintaining pain and other core symptoms of FMS. The approach to treatment of pain will typically address these central mechanisms. Nonpain symptoms may be treated by drugs affecting similar central neurochemicals. This paper will review the rationale for the different types of pharmaceutical treatments that may be useful for the treatment of FMS and issues regarding new drug development for this indication.
BACKGROUND - Tricyclic and other related cyclic antidepressants (TCAs), used frequently for the treatment of depression and several other indications, have cardiovascular effects that may increase the risk of sudden cardiac death. We thus sought to quantify the risk of sudden cardiac death among TCA users, according to dose, as well as among users of selective serotonin reuptake inhibitors (SSRIs).
METHODS - We conducted a retrospective cohort study in Tennessee Medicaid, from Jan 1, 1988, through Dec 31, 1993, which included large numbers of antidepressant users and computer files describing medication use and comorbidity. The cohort included 1,282,091 person-years of follow-up for persons aged 15 to 84 years who were not in a nursing home and were free of life-threatening noncardiac illness. This included 58,956 person-years for current use of TCAs alone, 6291 person-years for SSRIs only, and 96,220 person-years for former use.
RESULTS - The cohort included 1487 confirmed sudden cardiac deaths occurring in the community. When compared with nonusers of antidepressants, current users of TCAs had a dose-related increase in the risk of sudden cardiac death. Rate ratios increased from 0.97 (95% confidence interval [CI], 0.72-1.29) for doses lower than 100 mg (amitriptyline or its equivalent) to 2.53 (95% CI, 1.04-6.12) for doses of 300 mg or more (P =.03, test for dose-response). The rate ratio for SSRIs was 0.95 (95% CI, 0.42-2.15). There was no evidence that TCA doses lower than 100 mg increased the risk of sudden cardiac death in subgroups defined by pre-existing cardiovascular disease, female sex, age 65 years or older, or use of amitriptyline.
CONCLUSIONS - Our data suggest that SSRI antidepressants and TCAs in doses of less than 100 mg (amitriptyline equivalents) did not increase the risk of sudden cardiac death. However, higher doses of TCAs were associated with increased relative risk, which suggests that such doses should be used cautiously, particularly in patients with an elevated baseline risk of sudden death.
BACKGROUND - In nursing home residents, the use of tricyclic and other heterocyclic antidepressants is associated with an increased risk of falls. The newer selective serotonin-reuptake-inhibitor antidepressants are largely free of the side effects of the tricyclic agents thought to cause falls and so have been hypothesized to be safer for those at high risk for falls.
METHODS - We retrospectively identified an inception cohort of 2428 nursing home residents in Tennessee who were new users of tricyclic antidepressants (665 subjects), selective serotonin-reuptake inhibitors (612 subjects), or trazodone (304 subjects) or nonusers of antidepressants (847 subjects). We ascertained the number of falls during therapy and during a similar follow-up period for nonusers, then calculated the rate ratios for falls with adjustments for an extensive set of potential confounding factors.
RESULTS - The new users of each type of antidepressant had higher rates of falls than the nonusers, with adjusted rate ratios of 2.0 (95 percent confidence interval, 1.8 to 2.2) for tricyclic antidepressants, 1.8 (1.6 to 2.0) for selective serotonin-reuptake inhibitors, and 1.2 (1.0 to 1.4) for trazodone. The rate ratios increased with the daily dose for tricyclic antidepressants, reaching 2.4 (95 percent confidence interval, 2.1 to 2.8) for doses of 50 mg or more of amitriptyline or its equivalent, and for the serotonin-reuptake inhibitors, reaching 1.9 (1.7 to 2.2) for 20 mg or more of fluoxetine or its equivalent. The elevated rates of falls persisted through the first 180 days of therapy and beyond.
CONCLUSIONS - In this large study of nursing home residents, there was little difference in rates of falls between those treated with tricyclic antidepressants and those treated with selective serotonin-reuptake inhibitors. Hence, the preferential use of the newer antidepressants is unlikely to reduce the higher rate of falls among nursing home residents taking antidepressants.
When assayed in parallel using transfected mammalian cells, human and rat serotonin transporters (SERTs) exhibit consistent differences in potency for tricyclic antidepressants but not for 5-hydroxytryptamine, cocaine, or nontricyclic serotonin transporter-selective reuptake inhibitors. Previously, using chimeric proteins, we determined that domains or residues distal to transmembrane domain 11 (amino acid 531) dictate the increased sensitivity of human SERT to imipramine. Using an additional chimera and site-directed mutagenesis, we have determined that a single amino acid, F586, is responsible for increased sensitivity to imipramine, desipramine, and nortriptyline. Thus, mutation of wild-type rat SERT (V586) to the human SERT identity F586, but no other divergent amino acids between human and rat SERTs, selectively increased tricyclic antidepressant potency. A reciprocal reduction in potency was observed when human SERT F586 was converted to the cognate rat SERT residue (V586). Interactions with other SERT antagonists, including paroxetine and cocaine, as well as the SERT substrates 5-hydroxytryptamine and d-amphetamine were unaffected by interconversion of this residue. Phenylalanine conversion in the human norepinephrine transporter at the homologous position failed to alter tricyclic inhibition of catecholamine uptake, revealing a SERT-specific context for use of the aromatic side chain at this position. Additional constraints on aromaticity at rat SERT position 586 were revealed by conversion of rat SERT V586 to Y586, which failed to repllcate the effect of the F586 mutation. In addition, conversion to V586D, but not V586R, increased tricyclic potency to that of human SERT and additionally increased potency for cocaine but not paroxetine. These results implicate distal domains and a single residue in TMD 12 in the formation of high affinity SERT antagonist binding sites.