[en] Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
McEwen B. S., Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators. European Journal of Pharmacology 2008 583 2-3 174 185 2-s2.0-40849133755 10.1016/j.ejphar.2007.11.071
DeCarolis N. A., Eisch A. J., Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 2010 58 6 884 893 2-s2.0-77649338801 10.1016/j.neuropharm.2009.12.013
Lucassen P. J., Meerlo P., Naylor A. S., van Dam A. M., Dayer A. G., Fuchs E., Oomen C. A., Czéh B., Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. European Neuropsychopharmacology 2010 20 1 1 17 2-s2.0-71549167579 10.1016/j.euroneuro.2009.08.003
Santarelli L., Saxe M., Gross C., Surget A., Battaglia F., Dulawa S., Weisstaub N., Lee J., Duman R., Arancio O., Belzung C., Hen R., Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003 301 5634 805 809 2-s2.0-0042528720 10.1126/science.1083328 (Pubitemid 36962615)
Dranovsky A., Hen R., Hippocampal neurogenesis: regulation by stress and antidepressants. Biological Psychiatry 2006 59 12 1136 1143 2-s2.0-33745214865 10.1016/j.biopsych.2006.03.082
Mateus-Pinheiro A., Pinto L., Bessa J. M., Morais M., Alves N. D., Monteiro S., Patrício P., Almeida O. F., Sousa N., Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Translational Psychiatry 2013 3 article e210 10.1038/tp.2012.141
Banasr M., Hery M., Brezun J. M., Daszuta A., Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus. European Journal of Neuroscience 2001 14 9 1417 1424 2-s2.0-0035783450 10.1046/j.0953-816X.2001.01763.x (Pubitemid 35463709)
Brezun J. M., Daszuta A., Serotonin may stimulate granule cell proliferation in the adult hippocampus, as observed in rats grafted with foetal raphe neurons. European Journal of Neuroscience 2000 12 1 391 396 2-s2.0-0033980604 10.1046/j.1460-9568.2000.00932.x (Pubitemid 30068446)
Brezun J. M., Daszuta A., Serotonin depletion in the adult rat produces differential changes in highly polysialylated form of neural cell adhesion molecule and tenascin-C immunoreactivity. Journal of Neuroscience Research 1999 55 1 54 70 (Pubitemid 29014411)
Brezun J. M., Daszuta A., Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 1999 89 4 999 1002 2-s2.0-0033051299 10.1016/S0306-4522(98)00693-9 (Pubitemid 29074620)
Varrault A., Bockaert J., Waeber C., Activation of 5-HT(1A) receptors expressed in NIH-3T3 cells induces focus formation and potentiates EGF effect on DNA synthesis. Molecular Biology of the Cell 1992 3 9 961 969 2-s2.0-0027010262 (Pubitemid 23079768)
Malberg J. E., Eisch A. J., Nestler E. J., Duman R. S., Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Journal of Neuroscience 2000 20 24 9104 9110 2-s2.0-0034671366 (Pubitemid 32042912)
Banasr M., Hery M., Printemps R., Daszuta A., Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 2004 29 3 450 460 2-s2.0-1642331289 10.1038/sj.npp.1300320 (Pubitemid 38365922)
Gould E., Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 1999 21 supplement 2 46S 51S 2-s2.0-0032819263 10.1016/S0893-133X(99)00045-7 (Pubitemid 29396470)
Wainwright S. R., Galea L. A., The neural plasticity theory of depression: assessing the roles of adult neurogenesis and PSA-NCAM within the hippocampus. Neural Plasticity 2013 2013 14 805497 10.1155/2013/805497
Bessa J. M., Ferreira D., Melo I., Marques F., Cerqueira J. J., Palha J. A., Almeida O. F. X., Sousa N., The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Molecular Psychiatry 2009 14 8 764 773 2-s2.0-67349216843 10.1038/mp.2008.119
Pawluski J. L., Brummelte S., Barha C. K., Crozier T. M., Galea L. A. M., Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging. Frontiers in Neuroendocrinology 2009 30 3 343 357 2-s2.0-67651210695 10.1016/j.yfrne.2009.03.007
Steiner M., Dunn E., Born L., Hormones and mood: from menarche to menopause and beyond. Journal of Affective Disorders 2003 74 1 67 83 2-s2.0-0037341824 10.1016/S0165-0327(02)00432-9 (Pubitemid 36324478)
Weissman M. M., Olfson M., Depression in women: implications for health care research. Science 1995 269 5225 799 801 2-s2.0-0029099186
Green A. D., Galea L. A. M., Adult hippocampal cell proliferation is suppressed with estrogen withdrawal after a hormone-simulated pregnancy. Hormones and Behavior 2008 54 1 203 211 2-s2.0-43949102024 10.1016/j.yhbeh.2008. 02.023
Hodes G. E., Yang L., van Kooy J., Santollo J., Shors T. J., Prozac during puberty: distinctive effects on neurogenesis as a function of age and sex. Neuroscience 2009 163 2 609 617 2-s2.0-69249214017 10.1016/j.neuroscience. 2009.06.057
Pawluski J. L., Charlier T. D., Fillet M., Houbart V., Crispin H. T., Steinbusch H. W., van den Hove D. L., Chronic fluoxetine treatment and maternal adversity differentially alter neurobehavioral outcomes in the rat dam. Behavioural Brain Research 2012 228 1 159 168 2-s2.0-84155191110 10.1016/j.bbr.2011.11.043
Hajszan T., MacLusky N. J., Leranth C., Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus. European Journal of Neuroscience 2005 21 5 1299 1303 2-s2.0-17144385440 10.1111/j.1460-9568.2005.03968.x (Pubitemid 40516628)
Brown A. P., Dinger N., Levine B. S., Stress produced by gavage administration in the rat. Contemporary Topics in Laboratory Animal Science 2000 39 1 17 21 2-s2.0-0033761032
Meijer M. K., Spruijt B. M., van Zutphen L. F. M., Baumans V., Effect of restraint and injection methods on heart rate and body temperature in mice. Laboratory Animals 2006 40 4 382 391 2-s2.0-33750095436 10.1258/ 002367706778476370 (Pubitemid 44594483)
Huang G.-J., Herbert J., Stimulation of neurogenesis in the hippocampus of the adult rat by fluoxetine requires rhythmic change in corticosterone. Biological Psychiatry 2006 59 7 619 624 2-s2.0-33644823580 10.1016/j.biopsych. 2005.09.016 (Pubitemid 43357956)
Caccia S., Cappi M., Fracasso C., Garattini S., Influence of dose and route of administration on the kinetics of fluoxetine and its metabolite norfluoxetine in the rat. Psychopharmacology 1990 100 4 509 514 2-s2.0-0025268525 (Pubitemid 20102360)
Yang D., Kim K. H., Phimister A., Bachstetter A. D., Ward T. R., Stackman R. W., Mervis R. F., Wisniewski A. B., Klein S. L., Kodavanti P. R. S., Anderson K. A., Wayman G., Pessah I. N., Lein P. J., Developmental exposure to polychlorinated biphenyls interferes with experience-dependent dendritic plasticity and ryanodine receptor expression in weanling rats. Environmental Health Perspectives 2009 117 3 426 435 2-s2.0-64049093248 10.1289/ehp.11771
Powers B. E., Widholm J. J., Lasky R. E., Schantz S. L., Auditory deficits in rats exposed to an environmental PCB mixture during development. Toxicological Sciences 2006 89 2 415 422 2-s2.0-31144435951 10.1093/toxsci/ kfj051 (Pubitemid 43125999)
AlAhmed S., Herbert J., Strain differences in proliferation of progenitor cells in the dentate gyrus of the adult rat and the response to fluoxetine are dependent on corticosterone. Neuroscience 2008 157 3 677 682 2-s2.0-56049125925 10.1016/j.neuroscience.2008.08.072
Porsolt R. D., Anton G., Blavet N., Jalfre M., Behavioural despair in rats: a new model sensitive to antidepressant treatments. European Journal of Pharmacology 1978 47 4 379 391 2-s2.0-0018268297
Xu J., Kirigiti M. A., Grove K. L., Smith M. S., Regulation of food intake and gonadotropin-releasing hormone/luteinizing hormone during lactation: role of insulin and leptin. Endocrinology 2009 150 9 4231 4240 2-s2.0-69249141504 10.1210/en.2009-0190
Knaepen L., Rayen I., Charlier T. D., Fillet M., Houbart V., van Kleef M., Steinbusch H. W., Patijn J., Tibboel D., Joosten E. A., Pawluski J. L., Developmental fluoxetine exposure normalizes the long-term effects of maternal stress on post-operative pain in Sprague-Dawley rat offspring. PLoS ONE 2013 8 2 e57608 10.1371/journal.pone.0057608
Houbart V., Servais A. C., Charlier T. D., Pawluski J. L., Abts F., Fillet M., A validated microfluidics-based LC-chip-MS/MS method for the quantitation of fluoxetine and norfluoxetine in rat serum. Electrophoresis 2012 33 22 3370 3379 10.1002/elps.201200168
Pawluski J. L., van den Hove D. L. A., Rayen I., Prickaerts J., Steinbusch H. W. M., Stress and the pregnant female: impact on hippocampal cell proliferation, but not affective-like behaviors. Hormones and Behavior 2011 59 4 572 580 2-s2.0-79954792477 10.1016/j.yhbeh.2011.02.012
Burton C. L., Chatterjee D., Chatterjee-Chakraborty M., Lovic V., Grella S. L., Steiner M., Fleming A. S., Prenatal restraint stress and motherless rearing disrupts expression of plasticity markers and stress-induced corticosterone release in adult female Sprague-Dawley rats. Brain Research 2007 1158 1 28 38 2-s2.0-34447558474 10.1016/j.brainres.2007.05.003 (Pubitemid 47068410)
Rayen I., van den Hove D. L., Prickaerts J., Steinbusch H. W., Pawluski J. L., Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence. PLoS ONE 2011 6 9 2-s2.0-80052381901 10.1371/journal.pone.0024003 e24003
Paxinos G., Watson C., The Rat Brain in Stereotaxic Coordinates 2004 5th Elsevier Academic Press
Larsen M. H., Hay-Schmidt A., Rønn L. C. B., Mikkelsen J. D., Temporal expression of brain-derived neurotrophic factor (BDNF) mRNA in the rat hippocampus after treatment with selective and mixed monoaminergic antidepressants. European Journal of Pharmacology 2008 578 2-3 114 122 2-s2.0-37349099023 10.1016/j.ejphar.2007.08.050 (Pubitemid 350309578)
Seo M. K., Lee C. H., Cho H. Y., Lee J. G., Lee B. J., Kim J. E., Seol W., Kim Y. H., Park S. W., Effects of antidepressant drugs on synaptic protein levels and dendritic outgrowth in hippocampal neuronal cultures. Neuropharmacology 2014 79 222 233 10.1016/j.neuropharm.2013.11.019
Begenisic T., Baroncelli L., Sansevero G., Milanese M., Bonifacino T., Bonanno G., Cioni G., Maffei L., Sale A., Fluoxetine in adulthood normalizes GABA release and rescues hippocampal synaptic plasticity and spatial memory in a mouse model of Down Syndrome. Neurobiology of Disease 2014 63 12 19 10.1016/j.nbd.2013.11.010
Hodes G. E., Hill-Smith T. E., Lucki I., Fluoxetine treatment induces dose dependent alterations in depression associated behavior and neural plasticity in female mice. Neuroscience Letters 2010 484 1 12 16 2-s2.0-79952484146 10.1016/j.neulet.2010.07.084
Dalla C., Pitychoutis P. M., Kokras N., Papadopoulou-Daifoti Z., Sex differences in animal models of depression and antidepressant response. Basic and Clinical Pharmacology and Toxicology 2010 106 3 226 233 2-s2.0-77149123942 10.1111/j.1742-7843.2009.00516.x
Woolley C. S., McEwen B. S., Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. Journal of Neuroscience 1994 14 12 7680 7687 2-s2.0-0027987251
Woolley C. S., McEwen B. S., Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. Journal of Neuroscience 1992 12 7 2549 2554 2-s2.0-0026627947
Woolley C. S., Gould E., Frankfurt M., McEwen B. S., Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. Journal of Neuroscience 1990 10 12 4035 4039 2-s2.0-0025617479
Gould E., Woolley C. S., Frankfurt M., McEwen B. S., Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. Journal of Neuroscience 1990 10 4 1286 1291 2-s2.0-0025411855
Jacome L. F., Gautreaux C., Inagaki T., Mohan G., Alves S., Lubbers L. S., Luine V., Estradiol and ER β agonists enhance recognition memory, and DPN, an ER β agonist, alters brain monoamines. Neurobiology of Learning and Memory 2010 94 4 488 498 2-s2.0-77958472758 10.1016/j.nlm.2010.08.016
Charoenphandhu J., Teerapornpuntakit J., Nuntapornsak A., Krishnamra N., Charoenphandhu N., Anxiety-like behaviors and expression of SERT and TPH in the dorsal raphé of estrogen- and fluoxetine-treated ovariectomized rats. Pharmacology Biochemistry and Behavior 2011 98 4 503 510 2-s2.0-79952994290 10.1016/j.pbb.2011.02.023
O'Leary O. F., Wu X., Castren E., Chronic fluoxetine treatment increases expression of synaptic proteins in the hippocampus of the ovariectomized rat: role of BDNF signalling. Psychoneuroendocrinology 2009 34 3 367 381 2-s2.0-59249099507 10.1016/j.psyneuen.2008.09.015
Heikkinen T., Ekblad U., Palo P., Laine K., Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation. Clinical Pharmacology and Therapeutics 2003 73 4 330 337 2-s2.0-0037384041 10.1016/S0009-9236(02) 17634-X (Pubitemid 36403593)
Corbett A., McGowin A., Sieber S., Flannery T., Sibbitt B., A method for reliable voluntary oral administration of a fixed dosage (mg/kg) of chronic daily medication to rats. Laboratory Animals 2012 46 4 318 324 10.1258/la.2012.012018