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By V. Dan. The Catholic University of America.

However buy discount coumadin 2 mg online, motivational measures of ab- effects qualitatively similar to or different from that of the stinence have proven to be more sensitive measures of drug training drug discount coumadin 5mg on-line. Dose 1 versus Operant Drug Self-Administration dose 2 and drug 1 versus drug 2 versus saline discriminations also can be employed. Details can be found in the following Drug self-administration can be conducted under condi- references (13,29,46,72). Although it is clear that animals will self-administer drugs in the absence of with- drawal, some evidence suggests that physical dependence can increase the reinforcing efficacy of a drug. Monkeys made physically dependent on morphine show increases in their progressive-ratio performance compared to animals that do not exhibit withdrawal symptomology (101). Also, baboons in a discrete-trials choice procedure for food and heroin showed significant behavioral plasticity when al- lowed periodic access to heroin or food (20). In the with- drawal state, one would hypothesize that the animals would be much less likely to respond for food, even if the cost of heroin in terms of response requirements was dramatically increased. Thus, the reinforcing value of drugs may change depending on the presence or absence of a withdrawal state. The neurobiological basis for such a change is only begin- ning to be investigated, but much evidence has been gener- ated to show that drug withdrawal can produce an aversive or negative motivational state that is manifested by changes in a number of behavioral measures including response dis- ruption, increased drug intake, changes in reward thresh- olds, and place aversions. Recent studies with alcohol have shown that rats with a history of self-administration of alcohol will self-administer alcohol during withdrawal in sufficient quantities to prevent withdrawal symptoms and maintain blood alcohol levels above 100 mg% (75). To assess the relationship of with- drawal severity, blood alcohol levels, and alcohol self-admin- istration in dependent and nondependent rats, rats were trained to lever press for 10% alcohol versus water using the saccharin fadeout procedure and subjected to induction of dependence on alcohol (75). Dependent animals allowed to respond for alcohol during a second 12-hour test period showed sustained alcohol intake that maintained blood alco- FIGURE 97. Operant responding for alcohol across a 12-hour hol levels above 100 mg% throughout the 12-hour period, test period by air-exposed and alcohol vapor-exposed rats (top). Animals not allowed access to alcohol during severity (bottom) obtained during test 2 (while rats were allowed access to alcohol in the operant boxes) and test 3 (while in home withdrawal on a third test showed a precipitous drop in cages) are shown. One blood alcohol levels and a dramatic increase in withdrawal group of animals was assigned to 2 weeks of alcohol exposure scores (75) (Fig. These results show that rats will in alcohol vapor chambers. Rats then were tested in the operant boxes with access maintain and sustain lever pressing for alcohol during de- to 10% alcohol and water across two 12-hour periods separated pendence if the animals have a history of lever pressing for by 4 days of vapor exposure. A third and final withdrawal phase alcohol to the point of suppressing alcohol withdrawal and was included after another 4 days of vapor exposure; however, animals were kept in their home cages and not allowed to re- maintaining blood alcohol levels. Blood was collected for blood alcohol determi- nations, and observational withdrawal signs were rated during tests 2 and 3 at 0, 8, and 12 hours post withdrawal. Data are Responding for Non-Drug Reinforcers expressed as means SEM. Taken with permission from Roberts AJ, Cole M, Koob GF. Intra-amygdala muscimol decreases operant Several operant schedules have been used to characterize ethanol self-administration in dependent rats. Alcohol Clin Exp the response-disruptive effects of drug withdrawal (37,84). However, response disruption can be caused by any number of variables from motor problems to malaise and decreases in appetite, and thus other measures must be used to rule out nonspecific effects (see the following). Chapter 97: Recent Advances in Animal Models of Drug Addiction 1387 Conditioned Place Aversion 30). Examples of a more specific aspect of withdrawal are animals that have been trained to discriminate pentylenete- The conditioned place preference paradigm can also be used trazol, an anxiogenic-like substance, from saline in alcohol-, to characterize the conditioned aversive effects of drug with- diazepam-, and opiate-dependent animals. Rodents are exposed to one environment while drawal, generalization to the pentylenetetrazol cue has undergoing withdrawal and to another in the absence of a suggested an anxiogenic-like component to the withdrawal withdrawal state. During tests of conditioning, animals are syndrome (14,21). To date, this procedure has been used almost exclusively to study withdrawal from opiate drugs. Ethological Measures Administration of opioid receptor antagonists to animals Animals models of withdrawal that illustrate aversive stimu- rendered physically dependent on morphine via implanta- lus effects can be extended to observational measures, some tion of morphine pellets or repeated injections of an opiate of which may be common to withdrawal from many differ- produces dose-related conditioned place aversions, an effect ent drugs of abuse. Increased anxiety-like responses are ob- that can be observed after only a single conditioning session served following abstinence from cocaine, opiates, benzodi- with the antagonist (27,34). In contrast, the administration azepines, and alcohol (9,25,79,81,85). Measures used to of the same doses of antagonist to opiate-naive animals fails assess anxiety-like responses during include validated animal to produce a conditioned response. Interestingly, the mini- models of anxiety such as the elevated plus-maze, light-dark mum effective dose of an antagonist that produces condi- test, defensive withdrawal, and defensive burying. Although place conditioning typically Reinforcing Effects of Drugs has been used to characterize antagonist-precipitated with- drawal, more recent work indicates its utility for studies of The advantages and disadvantages of models used to evalu- spontaneous withdrawal (10).

A controlled family history study of in reading-disabled twins cheap coumadin 1 mg online. Dyslexic children on attention-deficit hyperactivity disorder and learning disabili- have abnormal brain lactate response to reading-related language ties in Tourette syndrome subjects generic coumadin 5 mg mastercard. Evidence for a genetic nance imaging of early visual pathways in dyslexia. J Neurosci aetiology in reading disability of twins. A new gene related brain potentials elicited during phonological processing 612 Neuropsychopharmacology: The Fifth Generation of Progress differentiate subgroups of reading disabled adolescents. Is developmental dyslexia Proc Natl Acad Sci USA 1998;95:2636–2641. The visual deficit 31 magnetic resonance spectroscopy. NMR Biomed 1997;10: theory of developmental dyslexia. The planum temp- mechanisms in ADHD children with and without reading disa- orale: a systematic, quantitative review of its structural, func- bilities: a replication and extension. J Am Acad Child Adolesc tional and clinical significance. Brain Res Brain Res Rev 1999; Psychiatry 1997;36:1688–1697. Multiple neurotransmitters have been implicated in schizo- cially phencyclidine (PCP) and ketamine, can cause psy- phrenia. Dopamine is the neurotransmitter most often hy- chotic symptoms in normal humans (3,4), and worsen these pothesized to be associated with the pathophysiology of symptoms in persons with schizophrenia (5–7). First, dopaminergic agonists echolamine agonists, PCP can produce both the positive can cause or exacerbate psychotic symptoms. Second, the and negative (deficit) symptoms associated with this illness. For these reasons, a of the N-methyl-D-aspartate (NMDA) subtype of glutamate number of postmortem studies have focused on the dopami- receptor. Hence, this pharmacologic literature has been in- nergic system in schizophrenic brain. Although the results of terpreted as suggesting that schizophrenia may be associated these studies have generally been negative, the few positive with decreased NMDA-receptor activity (5,8). Schizophrenia is believed to be secondary to prior neuroleptic treatment. These studies have a neurodevelopmental component, and the NMDA of dopaminergic abnormalities in postmortem brain in receptor is critical in guiding axons to their targets in devel- schizophrenia have been recently reviewed (1,2). Further, NMDA receptors may be important in Given the lackof findings associated with the dopamine processes that lead to synaptic pruning seen in adolescence, system in the brain in schizophrenia, the elucidation of which has been hypothesized to be abnormal in schizophre- other potential neurotransmitter substrates of this illness has nia (10). Cognitive functioning depends on the plasticity been an area of recent investigation. Glutamatergic dysfunc- mediated in part by NMDA receptors, and schizophrenics tion has been hypothesized to occur in schizophrenia, and often have cognitive deficits (11). Finally, the reduction of this has been one of the most active areas of neurotransmit- gray matter in several brain regions seen in schizophrenia has been suggested to be the result of neurotoxicity mediated ter research in this illness during the past few years. A constellation of symptoms, chapter, the glutamate hypothesis of schizophrenia is re- findings, and hypotheses of schizophrenia can be parsimon- viewed, the complexity of the molecules associated with the iously explained by NMDA-receptor dysfunction. Thus, although NMDA-re- ceptor abnormalities have been hypothesized in schizophre- nia, apparent NMDA-receptor dysregulation could be asso- GLUTAMATE AND SCHIZOPHRENIA ciated with abnormalities of another receptor subtype that interacts with the NMDA receptor, which in turn results Several lines of evidence have implicated glutamatergic dys- in a breakdown of normal glutamatergic transmission in function in schizophrenia. Meador-Woodruff: Department of Psychiatry, University of Michigan, Ann Arbor, Michigan. Kleinman: Clinical Brain Disorders Branch, National Institutes The four classes of glutamate receptors are functionally and of Mental Health Neuroscience Center, Washington, DC. The iono- 718 Neuropsychopharmacology: The Fifth Generation of Progress FIGURE 52. Recent data suggest that glutamatergic transmission requires three cells: a presynaptic glu- tamate-releasing cell, a presynaptic glial cell that releases the endogenous agonist for the glycine co- agonist site (recently reported to be D-serine), and a postsynaptic neuron. The various glutamate re- ceptors and transporters are differentially ex- pressed by these three distinct cell populations. The glutamate uptake transporter EAAT3 (excitatory amino acid transporter 3), which is not shown on this figure, appears to be expressed primarily on the cell body and dendrites. Three families of ionotropic glutamate receptors (N-methyl-D-aspartate, AMPA, and kainate) are known, each of which is composed of distinct subunits and has identifiable binding sites. The metabotropic receptors cluster into three groups, members of which share pharmacologic and structural features. Chapter 52: Neurochemistry of Schizophrenia: Glutamatergic Abnormalities 719 tropic glutamate receptors, AMPA ( -amino-3-hydroxy-5- dynorphin, and zinc have also been identified.

Hypersalivation (unknown with the FGAs) can be troublesome with clozapine (and rarely with some other atypicals buy generic coumadin 1mg on-line, such as olanzapine) generic 1mg coumadin amex. This is a formidable array of side-effects, but the antipsychotic benefits are substantial. Risperidone Risperidone is an effective antipsychotic. At high doses (8 mg and above) it loses some of its advantages over FGAs, insofar, as acute EPS readily appear. A major disadvantage is the elevation of prolactin levels. A preparation which dissolves in the mouth is available. Risperidone has an advantage over some other SGAs as an IMI depot (long-acting) preparation is available. This can be administered once per fortnight during the maintenance phase, somewhat reducing compliance problems. Paliperidone Paliperidone is the active metabolite of risperidone, which was released when the patent of the parent chemical was about to expire. There is less weight gain, but more EPS problems, and the elevation of prolactin remains problematic. The dosing strategy is simpler, a single daily dose is possible. Recently a paliperidone depot has become available which need only be repeated monthly (a great advantage over 2/52 injection). Olanzapine Olanzapine is an effective antipsychotic which has gained acceptance as a mood stabilizer (used in the prophylaxis of mood disorder; Tohen et al, 2005). It has a pharmacological action and side-effect profile similar to clozapine (except, it is not associated with blood dyscrasia). The most troublesome side-effects are weight gain and sedation. The risks of diabetes and hyperlipidemia need to be monitored. An occasional side-effect, which is seen more regularly with clozapine, is hypersalivation. Olanzapine does not elevate prolactin to a significant degree. The sedating/calming effect of olanzapine is useful in acute disturbance. Olanzapine has an advantage of over some other SGAs in being available in an IMI form for acute Pridmore S. A preparation which dissolves in the mouth is available. A long-acting depot form is available but because physiological response is variable, the patient must be observed for 3 hours following every injection (which is proving to be a disincentive). Quetiapine Quetiapine is an effective antipsychotic which has a receptor binding profile similar to clozapine, but with relatively lower affinity for all receptors. The side-effect profile is favourable, 75% of respondents denying any side-effects (Hellewell et al, 1999). Sedation and hypotension are reported, especially during the commencement phase. Weight gain, and the risk of diabetes and hyperlipidemia need to be considered. Quetiapine has little affinity for muscarinic receptors so that blurred vision and difficulty with micturition are rarely problems. The rate of EPS symptoms is similar to placebo and there is no significant elevation of prolactin. Amisulpride Amisulpride is a useful antipsychotic which has effects (potent antagonist) only at D2 and D3 receptors, and no effect on serotonin receptors. Thus, it could be considered an FGA, which was released in the age of the SGAs. At recommended doses it appears to be selective for limbic (rather than extra-pyramidal system) receptors (Xiberas et al, 2001). Unfortunately, when higher doses are required, EPS side-effects may become a problem. Amisulpride is less likely to cause weight gain than the other SGAs, but it produces robust elevation of prolactin levels, thus breast development and lactation in both men and women and amenorrhoea in women may be bothersome side effects (Leucht et al, 2013). Some guidelines list amisulpride as benign with respect to QTc prolongation and sudden death (Hasan et al, 2012). It has low sedation effects, and discontinuation rate, suggesting it is well tolerated.

Signal Intensity of Tissue Elements and T1 and T2 Weighting APPENDIX A: STRUCTURAL MRI PULSE SPGR pulses lead to proton density-weighted images buy coumadin 2mg low price, be- SEQUENCES cause the small 'tilt' and short TR diminishes any T1 or T2 effects trusted 5 mg coumadin. In a proton density image produced by the SPGR Spin echo pulse sequences use at least two pulses. The first is sequence most commonly used in schizophrenia research, an initial excitation pulse (tilting the magnetization vector CSF appears dark, gray matter is gray, and white matter 770 Neuropsychopharmacology: The Fifth Generation of Progress has the most signal (is brightest). Metaanalysis, decision analysis, and cost-effectiveness produce proton density, T2- or T1-weighted images. Hippocampal vol- longer T1 relaxation time than white matter and thus shows ume reduction in schizophrenia as assessed by magnetic resonance a brighter signal with sequences allowing longer T1 relaxa- imaging: a meta-analytic study. Because the ability to capture relatively complete 433–440. MRI anatomy of T1 relaxation depends on longer TRs, longer TRs thus give schizophrenia. The neuropathology of schizophrenic diseases: histori- The tissue intensity in T2-weighted images depends on the cal aspects and present knowledge. Eur Arch Psychiatry Clin Neu- TE in spin echo sequences. CSF has longer T2 values than rosci 1999;249(Suppl 4):2–13. A critical review of the data and their interpretation. Brain 1999;122: weighted acquisitions with the long TE values commonly 593–624. Cell biology of the hippocampal formation in TR allows more time for T1 relaxation and produces more schizophrenia. Elevated neu- allows more time for T2 relaxation and produces more sig- ronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional stereologic counting nal from tissues with long T2 values. Temporal lobe sulco- gyral pattern anomalies in schizophrenia: an in vivo MR three- ACKNOWLEDGMENTS dimensional surface rendering study. An automated Supported in part by VA Medical Research Service, Depart- registration algorithm for measuring MRI subcortical brain struc- ment of Veterans Affairs Center for Clinical and Basic Neu- tures. Adapting multi-grid methods to the class 52807 (RWM). Parts of the introduction are adapted from of elliptic partial differential equation appearing in the estimation of displacement vector fields. In: Cantoni V, Creutzburg R, Levi- a previous review: McCarley RW, Wible C, Frumin M, et aldi S, et al, eds. Biol Psychiatry 1999;45: Berlin: Springer, 1989:266—274. Automatic identification of grey matter structures from MRI to improve the segmentation of white matter lesions. Proceedings of Medical Robotics and Com- puter Assisted Surgery (MRCAS), November, 1995;140–47. New York: New York: Churchill Livingstone, 1971 (German 23. Model based segmentation edition published in 1899). MRI: basic principles and applications, med Comput 1992;1808:10–23. J Comput Assist Tomogr 1993; white matter transverse relaxation time in schizophrenia. Voxel-based morphometry: the meth- Reson Imaging 1992;2:619–629. Mapping of grey matter image data quality using anisotropic diffusion filtering. Application of shape analysis of the temporal and prefrontal lobes of schizo- automated MRI volumetric measurement techniques to the ven- phrenic patients: a magnetic resonance image study. J Neuropsy- tricular system in schizophrenics and normals. A follow-up magnetic try in schizophrenia by high dimensional brain mapping. Proc resonance imaging study of schizophrenia: relationship of neuro- Natl Acad Sci USA 1998;95:11406–11411. MRI white matter Arch Gen Psychiatry 1998;55:145–152.