Serotonergic Regulation of Somatosensory Cortical Development: Lessons from Genetic Mouse ModelsLuo X.a · Persico A.M.b · Lauder J.M.a
aDepartment of Cell and Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, N.C., USA; bLaboratory of Molecular Psychiatry and Neurogenetics, University ‘Campus Bio-Medico’, Rome, Italy
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Monoaminergic neurotransmitter systems appear early during embryogenesis, suggesting that they could play important roles in brain development. Accumulated evidence indicates that serotonin (5-hydroxytryptamine, 5-HT) regulates neural as well as nonneural development, including early aspects of embryonic development, differentiation of neuronal progenitors, and morphogenesis of the craniofacial region, heart and limb. Recent studies using monoamine oxidase-A (MAO-A), 5-HT transporter, vesicular monoamine transporter-2 (VMAT2) and 5-HT1B receptor single, double and triple knockout mice have provided evidence that the serotonergic system plays important roles in barrel field formation in the developing somatosensory cortex. Here we review evidence from these genetic mouse models and, based on the accumulated evidence, propose a testable model for future studies of mechanisms underlying serotonergic regulation of cortical development.
© 2003 S. Karger AG, Basel
- Abdel-Majid RM, Leong WL, Schalkwyk LC, Smallman DS, Wong ST, Storm DR, Fine A, Dobson MJ, Guernsey DL, Neumann PE (1998): Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nat Genet 19:289–291.
- Agmon A, Yang LT, Jones EG, O’Dowd DK (1995): Topological precision in the thalamic projection to neonatal mouse barrel cortex. J Neurosci 15:549–561.
- Agmon A, Yang LT, O’Dowd DK, Jones EG (1993): Organized growth of thalamocortical axons from the deep tier of terminations into layer IV of developing mouse barrel cortex. J Neurosci 13:5365–5382.
- Alvarez C, Vitalis T, Fon EA, Hanoun N, Hamon M, Seif I, Edwards R, Gaspar P, Cases O (2002): Effects of genetic depletion of monoamines on somatosensory cortical development. Neuroscience 115:753–764.
- Barnes NM, Sharp T (1999): A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152.
- Bastmeyer M, O’Leary DD (1996): Dynamics of target recognition by interstitial axon branching along developing cortical axons. J Neurosci 16:1450–1459.
- Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mossner R, Westphal H, Lesch KP (1998): Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (‘Ecstasy’) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655.
Bennett-Clarke CA, Chiaia NL, Rhoades RW (1996): Thalamocortical afferents in rat transiently express high-affinity serotonin uptake sites. Brain Res 733:301–306.
- Bennett-Clarke CA, Leslie MJ, Chiaia NL, Rhoades RW (1993): Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons. Proc Natl Acad Sci USA 90:153–157.
- Bennett-Clarke CA, Leslie MJ, Lane RD, Rhoades RW (1994): Effect of serotonin depletion on vibrissa-related patterns of thalamic afferents in the rat’s somatosensory cortex. J Neurosci 14:7594–7607.
- Bennett-Clarke CA, Mooney RD, Chiaia NL, Rhoades RW (1991): Serotonin immunoreactive neurons are present in the superficial layers of the hamster’s, but not the rat’s, superior colliculus. Exp Brain Res 85:587–597.
- Berg KA, Clarke WP (2001): Regulation of 5-HT1A and 5-HT1B receptor systems by phospholipid signaling cascades. Brain Res Bull 56:471–477.
- Blue ME, Erzurumlu RS, Jhaveri S (1991): A comparison of pattern formation by thalamocortical and serotonergic afferents in the rat barrel field cortex. Cereb Cortex 1:380–389.
- Burnet H, Bevengut M, Chakri F, Bou-Flores C, Coulon P, Gaytan S, Pasaro R, Hilaire G (2001): Altered respiratory activity and respiratory regulations in adult monoamine oxidase A-deficient mice. J Neurosci 21:5212–5221.
- Buznikov GA, Lambert HW, Lauder JM (2001): Serotonin and serotonin-like substances as regulators of early embryogenesis and morphogenesis. Cell Tissue Res 305:177–186.
- Buznikov GA, Shmukler YB, Lauder JM (1996): From oocyte to neuron: Do neurotransmitters function in the same way throughout development? Cell Mol Neurobiol 16:537–559.
- Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Muller U, Aguet M, Babinet C, Shih JC, et al (1995): Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766.
- Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT (1999): Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 45:287–295.
- Colas JF, Choi DS, Launay JM, Maroteaux L (1997): Evolutionary conservation of the 5-HT2B receptors. Ann NY Acad Sci 812:149–153.
- Colas JF, Launay JM, Kellermann O, Rosay P, Maroteaux L (1995): Drosophila 5-HT2 serotonin receptor: Coexpression with fushi-tarazu during segmentation. Proc Natl Acad Sci USA 92:5441–5445.
Colas JF, Launay JM, Vonesch JL, Hickel P, Maroteaux L (1999): Serotonin synchronises convergent extension of ectoderm with morphogenetic gastrulation movements in Drosophila. Mech Dev 87:77–91.
- D’Amato RJ, Blue ME, Largent BL, Lynch DR, Ledbetter DJ, Molliver ME, Snyder SH (1987): Ontogeny of the serotonergic projection to rat neocortex: Transient expression of a dense innervation to primary sensory areas. Proc Natl Acad Sci USA 84:4322–4326.
Daws LC, Montanez S, Gould GG, Owens WA, Frazer A, Murphy DL (2001): Influence of genetic knockout (ko) of the serotonin transporter (5-htt) on kinetics of 5-ht clearance and 5-ht1b receptor regulation of 5-ht clearance in vivo. Soc Neurosci Abstr 27:2155.
- Dori I, Dinopoulos A, Blue ME, Parnavelas JG (1996): Regional differences in the ontogeny of the serotonergic projection to the cerebral cortex. Exp Neurol 138:1–14.
- Erzurumlu RS, Jhaveri S (1990): Thalamic axons confer a blueprint of the sensory periphery onto the developing rat somatosensory cortex. Brain Res Dev Brain Res 56:229–234.
- Erzurumlu RS, Kind PC (2001): Neural activity: Sculptor of ‘barrels’ in the neocortex. Trends Neurosci 24:589–595.
Fuchs JL (1995): Neurotransmitter receptors in developing barrel cortex: Cerebral cortex; in Jones EG, Diamond IT (eds): The Barrel Cortex of Rodents. New York, Plenum Press, vol 11, pp 375–409.
- Fujimiya M, Kimura H, Maeda T (1986): Postnatal development of serotonin nerve fibers in the somatosensory cortex of mice studied by immunohistochemistry. J Comp Neurol 246:191–201.
- Galter D, Unsicker K (2000): Sequential activation of the 5-HT1(A) serotonin receptor and TrkB induces the serotonergic neuronal phenotype. Mol Cell Neurosci 15:446–455.
- Gingrich JA, Hen R (2001): Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology (Berl) 155:1–10.
- Grimaldi B, Fillion G (2000): 5-HT-moduline controls serotonergic activity: Implication in neuroimmune reciprocal regulation mechanisms. Prog Neurobiol 60:1–12.
Hansson SR, Mezey E, Hoffman BJ (1999): Serotonin transporter messenger RNA expression in neural crest-derived structures and sensory pathways of the developing rat embryo. Neuroscience 89:243–265.
- Hellendall RP, Schambra U, Liu J, Breese GR, Millhorn DE, Lauder JM (1992): Detection of serotonin receptor transcripts in the developing nervous system. J Chem Neuroanat 5:299–310.
- Hohmann CF, Berger-Sweeney J (1998): Cholinergic regulation of cortical development and plasticity. Perspect Dev Neurobiol 5:401–425.
- Hoyer D, Hannon JP, Martin GR (2002): Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554.
Itami C, Mizuno K, Kohno T, Nakamura S (2000): Brain-derived neurotrophic factor requirement for activity-dependent maturation of glutamatergic synapse in developing mouse somatosensory cortex. Brain Res 857:141–150.
- Jahng JW, Houpt TA, Wessel TC, Chen K, Shih JC, Joh TH (1997): Localization of monoamine oxidase A and B mRNA in the rat brain by in situ hybridization. Synapse 25:30–36.
- Jhaveri S, Erzurumlu RS, Crossin K (1991): Barrel construction in rodent neocortex: Role of thalamic afferents versus extracellular matrix molecules. Proc Natl Acad Sci USA 88:4489–4493.
- Johns JM, Noonan LR, Zimmerman LI, McMillen BA, Means LW, Walker CH, Lubin DA, Meter KE, Nelson CJ, Pedersen CA, Mason GA, Lauder JM (1998): Chronic cocaine treatment alters social/aggressive behavior in Sprague-Dawley rat dams and in their prenatally exposed offspring. Ann NY Acad Sci 846:399–404.
- Killackey HP, Rhoades RW, Bennett-Clarke CA (1995): The formation of a cortical somatotopic map. Trends Neurosci 18:402–407.
- Lauder JM (1990): Ontogeny of the serotonergic system in the rat: Serotonin as a developmental signal. Ann NY Acad Sci 600:297–314.
- Lauder JM (1993): Neurotransmitters as growth regulatory signals: Role of receptors and second messengers. Trends Neurosci 16:233–240.
Lauder JM, Krebs H (1978): Serotonin as a differentiation signal in early neurogenesis. Int J Neurosci 1:15–30.
- Lauder JM, Liu JP, Grayson DR (2000): In utero exposure to serotonergic drugs alters neonatal expression of 5-HT1A receptor transcripts: A quantitative RT-PCR study. Int J Dev Neurosci 18:171–176.
Lauder JM, Moiseiwitsch J, Liu J, Wilkie MB (1994): Serotonin in development and pathophysiology; in Lou HC, Griesen G, Larsen JF (eds): Brain Lesions in the Newborn. Copenhagen, Munksgaard, vol 37, pp 60–72.
- Lebrand C, Cases O, Adelbrecht C, Doye A, Alvarez C, El Mestikawy S, Seif I, Gaspar P (1996): Transient uptake and storage of serotonin in developing thalamic neurons. Neuron 17:823–835.
- Lebrand C, Cases O, Wehrle R, Blakely RD, Edwards RH, Gaspar P (1998): Transient developmental expression of monoamine transporters in the rodent forebrain. J Comp Neurol 401:506–524.
- Leslie MJ, Bennett-Clarke CA, Rhoades RW (1992): Serotonin 1B receptors form a transient vibrissa-related pattern in the primary somatosensory cortex of the developing rat. Brain Res Dev Brain Res 69:143–148.
- Levallois C, Valence C, Baldet P, Privat A (1997): Morphological and morphometric analysis of serotonin-containing neurons in primary dissociated cultures of human rhombencephalon: A study of development. Brain Res Dev Brain Res 99:243–252.
- Levitt P (1982): Central monoamine neuron systems: Their organization in the developing and mature primate brain and the genetic regulation of their terminal fields. Adv Neurol 35:49–59.
Levitt P, Harvey JA, Friedman E, Simansky K, Murphy EH (1997): New evidence for neurotransmitter influences on brain development. Trends Neurosci 20:269–274.
- Lidov HG, Molliver ME (1982): An immunohistochemical study of serotonin neuron development in the rat: Ascending pathways and terminal fields. Brain Res Bull 8:389–430.
- Lotto B, Upton L, Price DJ, Gaspar P (1999): Serotonin receptor activation enhances neurite outgrowth of thalamic neurones in rodents. Neurosci Lett 269:87–90.
Lubin DA, Cannon JB, Black MC, Brown LE, Johns JM (2003): Effects of chronic cocaine on monoamine levels in discrete brain structures of lactating rat dams. Pharmacol Biochem Behav 74:449–454.
- Luque JM, Kwan SW, Abell CW, Da Prada M, Richards JG (1995): Cellular expression of mRNAs encoding monoamine oxidases A and B in the rat central nervous system. J Comp Neurol 363:665–680.
- Maier DL, Mani S, Donovan SL, Soppet D, Tessarollo L, McCasland JS, Meiri KF (1999): Disrupted cortical map and absence of cortical barrels in growth-associated protein (GAP)-43 knockout mice. Proc Natl Acad Sci USA 96:9397–9402.
Manivet P, Mouillet-Richard S, Callebert J, Nebigil CG, Maroteaux L, Hosoda S, Kellermann O, Launay JM (2000): PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor. J Biochem 275:9324–9331.
Mansour-Robaey S, Mechawar N, Radja F, Beaulieu C, Descarries L (1998): Quantified distribution of serotonin transporter and receptors during the postnatal development of the rat barrel field cortex. Brain Res Dev Brain Res 107:159–163.
Mathews TA, Fedele DE, Unger EL, Lesch KP, Murphy DL, Andrews AM (2000): Effects of serotonin transporter inactivation on extracellular 5-ht levels, in vivo microdialysis recovery and mdma-induced release of serotonin and dopamine in mouse striatum. Soc Neurosci Abstr 26:1666.
- Moiseiwitsch JR (2000): The role of serotonin and neurotransmitters during craniofacial development. Crit Rev Oral Biol Med 11:230–239.
Moiseiwitsch JRD, Lambert HW, Lauder JM (2001): Roles for serotonin in non-neural embryonic development in Kalverboer A, Gramsbergen A (eds): Brain and Behaviour in Human Development. Amsterdam, Kluwer, pp 139–152.
- Moiseiwitsch JR, Lauder JM (1995): Serotonin regulates mouse cranial neural crest migration. Proc Natl Acad Sci USA 92:7182–7186.
- Mossner R, Dringen R, Persico AM, Janetzky B, Okladnova O, Albert D, Gotz M, Benninghoff J, Schmitt A, Gerlach M, Riederer P, Lesch KP (2002): Increased hippocampal DNA oxidation in serotonin transporter deficient mice. J Neural Transm 109:557–565.
Nebigil C, Choi D-S, Launay J-M, Maroteaux L (1998): Mouse 5-HT2B receptors mediate serotonin embryonic functions. 4th IUPHAR Satellite Symposium on Serotonin, Abstracts, p 28.
- Nebigil CG, Launay JM, Hickel P, Tournois C, Maroteaux L (2000): 5-Hydroxytryptamine 2B receptor regulates cell-cycle progression: Cross-talk with tyrosine kinase pathways. Proc Natl Acad Sci USA 97:2591–2596.
Nebigil CG, Maroteaux L (2001): A novel role for serotonin in heart. Trends Cardiovasc Med 11:329–335.
- Nguyen L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G (2001): Neurotransmitters as early signals for central nervous system development. Cell Tissue Res 305:187–202.
- Northcutt RG, Kaas JH (1995): The emergence and evolution of mammalian neocortex. Trends Neurosci 18:373–379.
- O’Leary DDM, Nakagawa Y (2002): Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr Opin Neurobiol 12:14–25.
- Osterheld-Haas MC, Van der Loos H, Hornung JP (1994): Monoaminergic afferents to cortex modulate structural plasticity in the barrelfield of the mouse. Brain Res Dev Brain Res 77:189–202.
- Persico AM, Altamura C, Calia E, Puglisi-Allegra S, Ventura R, Lucchese F, Keller F (2000): Serotonin depletion and barrel cortex development: Impact of growth impairment vs. serotonin effects on thalamocortical endings. Cereb Cortex 10:181–191.
- Persico AM, Baldi A, Dell’Acqua ML, Moessner R, Murphy DL, Lesch KP, Keller F (2003): Reduced programmed cell death in brains of serotonin transporter knockout mice. Neuroreport 14:341–344.
- Persico AM, Mengual E, Moessner R, Hall SF, Revay RS, Sora I, Arellano J, DeFelipe J, Gimenez-Amaya JM, Conciatori M, Marino R, Baldi A, Cabib S, Pascucci T, Uhl GR, Murphy DL, Lesch KP, Keller F (2001): Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J Neurosci 21:6862–6873.
- Rakic P (1995): Radial versus tangential migration of neuronal clones in the developing cerebral cortex. Proc Natl Acad Sci USA 92:11323–11327.
- Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN (2001): Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 92:179–212.
Rebsam A, Seif I, Gaspar P (2002): Refinement of thalamocortical arbors and emergence of barrel domains in the primary somatosensory cortex: A study of normal and monoamine oxidase A knock-out mice. J Neurosci 22:8541–8552.
- Reh TA, Constantine-Paton M (1985): Eye-specific segregation requires neural activity in three-eyed Rana pipiens. J Neurosci 5:1132–1143.
- Rhoades RW, Bennett-Clarke CA, Shi MY, Mooney RD (1994a): Effects of 5-HT on thalamocortical synaptic transmission in the developing rat. J Neurophysiol 72:2438–2450.
- Rhoades RW, Chiaia NL, Bennett-Clarke CA, Janas GJ, Fisher CM (1994b): Alterations in brainstem and cortical organization of rats sustaining prenatal vibrissa follicle lesions. Somatosens Mot Res 11:1–17.
- Rhoades RW, Mooney RD, Chiaia NL, Bennett-Clarke CA (1990): Development and plasticity of the serotoninergic projection to the hamster’s superior colliculus. J Comp Neurol 299:151–166.
- Rodriguez MJ, Saura J, Billett EE, Finch CC, Mahy N (2001a): Cellular localization of monoamine oxidase A and B in human tissues outside of the central nervous system. Cell Tissue Res 304:215–220.
- Rodriguez MJ, Ursu G, Bernal F, Cusi V, Mahy N (2001b): Perinatal human hypoxia-ischemia vulnerability correlates with brain calcification. Neurobiol Dis 8:59–68.
Roerig B, Feller MB (2000): Neurotransmitters and gap junctions in developing neural circuits. Brain Res Dev Brain Res 32:86–114.
- Rorig B, Sutor B (1996): Serotonin regulates gap junction coupling in the developing rat somatosensory cortex. Eur J Neurosci 8:1685–1695.
- Salichon N, Gaspar P, Upton AL, Picaud S, Hanoun N, Hamon M, De Maeyer E, Murphy DL, Mossner R, Lesch KP, Hen R, Seif I (2001): Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-ht transporter knock-out mice. J Neurosci 21:884–896.
- Shih JC (1991): Molecular basis of human MAO A and B. Neuropsychopharmacology 4:1–7.
- Shih JC, Chen K, Ridd MJ (1999): Monoamine oxidase: From genes to behavior. Annu Rev Neurosci 22:197–217.
- Stojic AS, Lane RD, Killackey HP, Qadri BA, Rhoades RW (1998): Thalamocortical and intracortical projections to the forelimb-stump SI representation of rats that sustained neonatal forelimb removal. J Comp Neurol 401:187–204.
- Strolin Benedetti M, Dostert P, Tipton KF (1992): Developmental aspects of the monoamine-degrading enzyme monoamine oxidase. Dev Pharmacol Ther 18:191–200.
- Sundstrom E, Kolare S, Souverbie F, Samuelsson EB, Pschera H, Lunell NO, Seiger A (1993): Neurochemical differentiation of human bulbospinal monoaminergic neurons during the first trimester. Brain Res Dev Brain Res 75:1–12.
- Upton AL, Salichon N, Lebrand C, Ravary A, Blakely R, Seif I, Gaspar P (1999): Excess of serotonin (5-HT) alters the segregation of ispilateral and contralateral retinal projections in monoamine oxidase A knock-out mice: Possible role of 5-HT uptake in retinal ganglion cells during development. J Neurosci 19:7007–7024.
- Velez Pardo C, Jimenez del Rio M, Pinxteren J, De Potter W, Ebinger G, Vauquelin G (1995): Fe(2+)-mediated binding of serotonin and dopamine to skeletal muscle actin: Resemblance to serotonin binding proteins. Eur J Pharmacol 288:209–218.
- Verge D, Calas A (2000): Serotoninergic neurons and serotonin receptors: Gains from cytochemical approaches. J Chem Neuroanat 18:41–56.
- Vitalis T, Cases O, Callebert J, Launay JM, Price DJ, Seif I, Gaspar P (1998): Effects of monoamine oxidase a inhibition on barrel formation in the mouse somatosensory cortex: Determination of a sensitive developmental period. J Comp Neurol 393:169–184.
Vitalis T, Cases O, Gillies K, Hanoun N, Hamon M, Seif I, Gaspar P, Kind P, Price DJ (2002a): Interactions between TrkB signaling and serotonin excess in the developing murine somatosensory cortex: A role in tangential and radial organization of thalamocortical axons. J Neurosci 22:4987–5000.
Vitalis T, Fouquet C, Alvarez C, Seif I, Price D, Gaspar P, Cases O (2002b): Developmental expression of monoamine oxidases A and B in the central and peripheral nervous systems of the mouse. J Comp Neurol 442:331–347.
- Wallace H, Fox K (1999): The effect of vibrissa deprivation pattern on the form of plasticity induced in rat barrel cortex. Somatosens Mot Res 16:122–138.
- Wallace JA, Lauder JM (1983): Development of the serotonergic system in the rat embryo: An immunocytochemical study. Brain Res Bull 10:459–479.
- Wang YM, Gainetdinov RR, Fumagalli F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG (1997): Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19:1285–1296.
- Weiss ER, Maness P, Lauder JM (1998): Why do neurotransmitters act like growth factor? Perspect Dev Neurobiol 5:323–325.
- Whitaker-Azmitia PM (2001): Serotonin and brain development: Role in human developmental diseases. Brain Res Bull 56:479–485.
Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM (1996): Serotonin as a developmental signal. Behav Brain Res 73:19–29.
- Whitaker-Azmitia PM, Lauder JM, Shemmer A, Azmitia EC (1987): Postnatal changes in serotonin receptors following prenatal alterations in serotonin levels: Further evidence for functional fetal serotonin receptors. Brain Res 430:285–289.
- Woolsey TA, Van der Loos H (1970): The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res 17:205–242.
- Woolsey TA, Wann JR (1976): Areal changes in mouse cortical barrels following vibrissal damage at different postnatal ages. J Comp Neurol 170:53–66.
- Yavarone MS, Shuey DL, Tamir H, Sadler TW, Lauder JM (1993): Serotonin and cardiac morphogenesis in the mouse embryo. Teratology 47:573–584.
- Young-Davies CL, Bennett-Clarke CA, Lane RD, Rhoades RW (2000): Selective facilitation of the serotonin (1B) receptor causes disorganization of thalamic afferents and barrels in somatosensory cortex of rat. J Comp Neurol 425:130–138.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.