Abstract
Reactivity of the nociceptive system, psychoemotional behavior and cognitive abilities in female and male rats born to mothers that were exposed to chronic injection of fluoxetine, a serotonin reuptake inhibitor, on days 9–20 of pregnancy were studied in a battery of behavioral tests during the prepubertal period. It was found that chronic injection of physiological saline to pregnant females evoked enhanced nociceptive responses in their offspring of both sexes while fluoxetine injection neutralized the effects of such an invasive intervention, demonstrating thereby the antinociceptive effect of this agent. Negative effects of maternal fluoxetine included a weight loss in the neonate offspring of both sexes and 25-day-old males, as well as the increased anxiety level in females only as detected in the elevated plus maze test. Fluoxetine had no effect on the level of depressive-like behavior in the forced swim test in rats of both sexes. The positive prenatal effect of fluoxetine manifested itself in males as an improved spatial learning ability in the Morris water maze; the anti-nociceptive effect of chronic fluoxetine injection, as compared to the pro-nociceptive effect of chronic saline injection, can also be considered as a positive effect of fluoxetine. Sex differences in the prenatal effect of fluoxetine were revealed in the anxiety level with more anxiety behavior in females.
Similar content being viewed by others
References
Vitale, S.G., Laganà, A.S., Muscatello, M.R., La Rosa, V.L., Currò, V., Pandolfo, G., Zoccali, R.A., and Bruno, A., Psychopharmacotherary in pregnancy and breastfeeding, Obstet. Gynecol. Surv., 2016, vol. 71, no. 12, pp. 721–733.
Hendrick, V., Stowe, Z.N., Altshuler, L.L., Hwang, S., Lee, E., and Haynes, D., Placental passage of antidepressant medications, Am. J. Psychiatry, 2003, vol. 160, pp. 993–996.
Gemmel, M., Rayen, I., Lotus, T., van Donkelaar, E., Steinbusch, H.W., De Lacalle, S., Kokras, N., Dalla, C., and Pawluski, J.L., Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning, Dev. Psychobiol., 2016, vol. 58, no. 3, pp. 315–327.
Gaspar, P., Cases, O., and Maroteaux, L., The developmental role of serotonin: news from mouse molecular genetics, Nat. Rev. Neurosci., 2003, vol. 4, pp. 1002–1012.
Misri, S., Reebye, P., Kendrick, K., Carter, D., Ryan, D., Grunau, R.E., and Oberlander, T.F., Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications, Am. J. Psychiatry, 2006, vol. 163, no. 6, pp. 1026–1032.
Oberlander, T.F., Grunau, R.E., Fitzgerald, C., Ellwood, A.L., Misri, S., Rurak, D., and Riggs, K.W., Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response, Pediatr. Res., 2002, vol. 51, no. 4, pp. 443–453.
Oberlander, T.F., Papsdorf, M., Brain, U.M., Misri, S., Ross, C., and Grunau, R.E., Prenatal effects of seletive serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age, Arch. Pediatr. Adolesc. Med., 2010, vol. 164, no. 5, pp. 444–451.
Podrebarac, A.K., Duerden, E.G., Chau, V., Grunau, R.E., Synnes, A., Oberlander, T.F., and Miller, S.P., Antenal exposure to antidepressants is associated with altered brain development in very preterm-born neonates, Neurosci., 2017, vol. 342, pp. 251–262.
Kaihola, H., Yaldir, F.G., Hreinsson, J., Hörnaeus, K., Bergquist, J., Olivier, J.D.A., Akerud, H., and Sundström-Poromaa, I., Effects of fluoxetine on human embryo development, Front. Cell Neurosci., 2016, vol. 10, 160. Doi: 10.3389/fincel. 2016.00160.
Pawluski, J.L., Rayen, I., Niessen, N.A., Kristensen, S., Van Donkelaar, E.L., Balthazart, J., Steinbusch, H.W., and Charlier, T.D., Developmental fluoxetine exposure differentially alters central and peripheral measures of the HPA system in adolescent male and female offspring, Neurosci., 2012, vol. 220, pp. 131–141.
Boulle, F., Pawluski, J.L., Homberg, J.R., Machiels, B., Kroeze, Y., Kumar, N., Steinbusch, H.W.M., Kenis, G., and van den Hove, D.L.A., Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring, Horm. Behav., 2016, vol. 80, pp. 47–57.
Avitsur, R., Increased symptoms of illness following prenatal stress: Can it be prevented by fluoxetine? Behav. Brain Res., 2017a, vol. 317, pp. 62–70.
Avitsur, R., Prenatal fluoxetine modifies the behavioral and hormonal responses to stress in male mice: role for glucocorticoid insensitivity, Behav. Pharmacol., 2017b, vol. 28, no. 5, pp. 345–355.
Kiryanova, V., McAllister, B.B., and Dyck, R.H., Long-term outcomes of developmental exposure to fluoxetine: A review of the animal literature, Dev. Neurosci., 2013, vol. 35, no. 6, pp. 437–449.
Hammerslag, L.R. and Gulley, J.M., Sex differences in behavior and neural development and their role in adolescent vulnerability to substance use, Behav. Brain Res., 2016, vol. 298, pt. A, pp. 15–26.
Zohar, I., Dosoretz-Abittan, L., Shoham, S., and Weinstock, M., Sex dependent reduction by prenatal stress of the expression of 5HT1A receptors in the prefrontal cortex and CRF type 2 receptors in the raphe nucleus in rats: reversal by citalopram, Psychopharmacol., 2015, vol. 232, no. 9, pp. 1643–1653.
Yohn, C.N., Gerques, M.M., and Samuels, B.A., The role of 5-HT receptors in depression, Mol. Brain, 2017, vol. 10, no. 1 (28). Doi: 10.1186/s13041-017-0306-y.
Butkevich, I.P., Mikhailenko, V.A., Lavrova, Yu.A., and Ulanova, N.A., Repeated inflammation-related pain syndrome in neonatal male rats alters adaptive behavior during the adolescent period of development, Ross. Fiziol. Zh. im. I.M. Sechenova, 2014, vol. 100, no. 11, pp. 1241–1251.
Mikhailenko, V.A., Butkevich, I.P., and Astapova, M.K., Long-term effect of stress sxposures during the neonatal period of development on the nociceptive system and psychoemotional behavior, Ross. Fiziol. Zh. im. I.M. Sechenova, 2016, vol. 102, no. 5, pp. 540–559.
Zimmerman, M., Committee for research and ethical issues of the IASP, ethical standards for investigations of experimental pain in animals, Pain, 1983, vol. 16, vol. 109–110.
Velasquez, J.C., Goeden, N., and Bonnin, A., Placental serotonin: implications for the developmental effects of SSRIs and maternal depression, Front. Cell. Neurosci., 2013, vol. 7, p. 47.
Olivier, J.D.A., Akerud, H., Kaihola, H., Pawluski, J.L., Skalkidou, A., Högberg, U., and Sundström-Poromaa, I., The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring, Front. Cell. Neurosci., 2013, vol. 7, p. 73.
Butkevich, I.P., Mikhailenko, V.A., Vershinina, E.A., Khozhai, L.I., Grigorev, I., and Otellin, V.A., Reduced serotonin synthesis during early embryogeny changes effect of subsequent prenatal stress on persistent pain in the formalin test in adult male and female rats, Brain Res., 2005, vol. 1042, no. 2, pp. 144–159.
Leibowitz, S.F. and Alexander, J.T., Hypothalamic serotonin in control of eating behavior, meal size, and body weight, Biol. Psychiatry, 1998, vol. 44, pp. 851–864.
Vartazarmian, R., Malik, S., Baker, G.B., and Boksa, P., Long-term effects of fluoxetine or vehicle administration during pregnancy on behavioral outcomes in guinea pig offspring, Psychopharmacol., 2005, vol. 178, pp. 328–338.
Butkevich, I.P. and Vershinina, E.A., Effect of prenatal stress on tonic pain in rats, Bull. Exp. Biol. Med., 2001, vol. 131, no. 6, pp. 515–517.
Mahar, I., Bambico, F.R., and Mechawar, N., Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects, Neurosci. Biobehav. Rev., 2014, vol. 38, pp. 173–192.
Lanfumey, L., Mongeau, R., Cohen-Salmon, C., and Hamon, M., Corticosteroid-serotonin interactions in the neurobiological mechanisms of stress-related disorders, Neurosci. Biobehav. Rev., 2008, vol. 32, no. 6, pp. 1174–1184.
Cintra, A., Zoli, M., Rosen, L., Agnati, L., Okret, S., and Wikstrom, A.C., Mapping and computer assisted morphometry and microdensitometry of glucocorticoid receptor immunoreactive neurons and glial cells in the rat central nervous system, Neurosci., 1994, vol. 62, no. 3, pp. 843–897.
Kapoor, A., Petropoulos, S., and Matthews, S.G., Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids, Brain Res. Rev., 2008, vol. 57, pp. 586–595.
Knaepen, L., Rayen, I., Chartier, T.D., Fillet, M., Houbart, V., van Kleef, M., Steinbusch, H.W., Patijn, J., Tibboel, D., Joosten, E.A., and Pawluski, J.L., Developmental fluoxetine exposure normalizes the long-term effects of maternal stress on post-operative pain in Spraque-Dawley rat offspring, PloS One, 2013, vol. 8, no. 2. e57608. doi: 10.1371/journal.pone.0057608
Oberlander, T.F., Grunau, R.E, Fitzgerald, C., Papsdorf, M., Rurak, D., and Riggs, K.W., Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure, Pediatrics, 2005, vol. 115, pp. 411–425.
Patel, T.D. and Zhou, F.C., Ontogeny of 5-HT1A receptor expression in the developing hippocampus, Dev. Brain Res., 2005, vol. 157, pp. 42–57.
Arnold, A.P., The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues, Horm. Behav., 2009, vol. 55, pp. 570–578.
Weisz, J. and Ward, I.L., Plasma testosterone and progesterone titers of pregnant rats, their male and famale fetuses, and neonatal offspring, Endocrinol., 1980, vol. 106, pp. 306–316.
Grassi-Oliveira, R., Honeycutt, J.A., Holland, F.H., Ganguly, P., and Brenhouse, H.C., Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: impacts of sex, experience, and cytokines, Psychoneuroendocrinol., 2016, vol. 71, pp. 19–30.
Nelson, L.H. and Lenz, K.H., The immune system as a novel regulator of sex differences in brain and behavioral development, J. Neurosci. Res., 2017, vol. 95, pp. 447–461.
Lauder, J.M. and Grayson, D.R., In utero exposure to serotonergic drugs alters neonatal expression of 5-HT(1A) receptor transcripts: a quantitative RT-PCR study, Int. J. Dev. Neurosci., 2000, vol. 18, pp. 171–176.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © V.A. Mikhailenko, I.P. Butkevich, 2018, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2018, Vol. 54, No. 4, pp. 283–291.
Rights and permissions
About this article
Cite this article
Mikhailenko, V.A., Butkevich, I.P. Prenatal Effect of Fluoxetine on Nociceptive System Reactivity and Psychoemotional Behavior of Young Female and Male Rats. J Evol Biochem Phys 54, 322–331 (2018). https://doi.org/10.1134/S0022093018040099
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0022093018040099