Abstract
Rationale
Alterations in the serotonergic transmission and activity of corticotropin-releasing factor (CRF) family may underlie anxiety and depressive disorders. These could be corrected by treatment with SSRIs.
Objectives
The objective of the current study is to determine whether the increased anxiety of prenatally stressed (PS) rats of both sexes is associated with changes in 5HT1A and CRF type 2 receptors (5HT1AR and CRFR2) in the prefrontal cortex (PFC)-dorsal raphe nuclei (DRN) axis, and how these are affected by chronic treatment with citalopram (10 mg/kg/day). We focussed on GABAergic cells that co-express parvalbumin and/or neuropeptide Y, and 5HT1AR in the medial prefrontal cortex (mPFC) and on cells that express 5HT, parvalbumin, 5HT1AR or CRFR2 in the DRN.
Results
Immunohistochemistry with fluorescent antibodies demonstrated sex differences in the expression of 5HT1AR and CRFR2 protein. Prenatal stress selectively reduced the expression of 5HT1AR on GABAergic cells in the mPFC in males and that of CRFR2 in the DRN of females. Citalopram treatment for 5 weeks abolished the increase in anxiety in both sexes, restored the intensity of expression of 5HT1AR in the mPFC in males and increased their expression in the mPFC and DRN in females. Citalopram reduced CRFR2 expression in control and PS males but increased it in PS females.
Conclusions
Male and female rats show differences in the expression of 5HT1AR and CRFR2 protein that are selectively reduced by prenatal stress. Reversal by citalopram of the changes in the expression of these receptors induced by prenatal stress support their role in the aetiology of anxiety.
Similar content being viewed by others
References
Albert PR, Vahid-Ansari F, Luckhart C (2014) Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression. Front Behav Neurosci 8:199
Alonso SJ, Arevalo R, Afonso D, Rodriguez M (1991) Effects of maternal stress during pregnancy on forced swimming test behavior of the offspring. Physiol Behav 50:511–517
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12
Azmitia EC, Segal M (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 179:641–667
Babb JA, Masini CV, Day HE, Campeau S (2013) Sex differences in activated corticotropin-releasing factor neurons within stress-related neurocircuitry and hypothalamic-pituitary-adrenocortical axis hormones following restraint in rats. Neuroscience 234:40–52
Baker S, Chebli M, Rees S, Lemarec N, Godbout R, Bielajew C (2008) Effects of gestational stress: 1. Evaluation of maternal and juvenile offspring behavior. Brain Res 1213:98–110
Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557
Biala YN, Bogoch Y, Bejar C, Linial M, Weinstock M (2011) Prenatal stress diminishes gender differences in behavior and in expression of hippocampal synaptic genes and proteins in rats. Hippocampus 21:1114–1125
Bledsoe AC, Oliver KM, Scholl JL, Forster GL (2011) Anxiety states induced by post-weaning social isolation are mediated by CRF receptors in the dorsal raphe nucleus. Brain Res Bull 85:117–122
Blier P, de Montigny C (1994) Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15:220–226
Bowers JM, Perez-Pouchoulen M, Edwards NS, McCarthy MM (2013) Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs order of maternal retrieval. J Neurosci 33:3276–3283
Celada P, Puig M, Amargos-Bosch M, Adell A, Artigas F (2004) The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci 29:252–265
Celada P, Puig MV, Artigas F (2013) Serotonin modulation of cortical neurons and networks. Front Integr Neurosci 7:25
Charil A, Laplante DP, Vaillancourt C, King S (2010) Prenatal stress and brain development. Brain Res Rev 65:56–79
Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, Abdi A, Baufreton J, Bienvenu TC, Herry C (2014) Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505:92–96
Daniels WM, Pietersen CY, Carstens ME, Daya S, Stein D (2000) Overcrowding induces anxiety and causes loss of serotonin 5HT-1a receptors in rats. Metab Brain Dis 15:287–295
Day HE, Greenwood BN, Hammack SE, Watkins LR, Fleshner M, Maier SF, Campeau S (2004) Differential expression of 5HT-1A, alpha 1b adrenergic, CRF-R1, and CRF-R2 receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. J Comp Neurol 474:364–378
Dilgen J, Tejeda HA, O’Donnell P (2013) Amygdala inputs drive feedforward inhibition in the medial prefrontal cortex. J Neurophysiol 110:221–229
Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C (2007) Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol 34:865–877
Drossopoulou G, Antoniou K, Kitraki E, Papathanasiou G, Papalexi E, Dalla C, Papadopoulou-Daifoti Z (2004) Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats. Neuroscience 126:849–857
Fride E, Weinstock M (1988) Prenatal stress increases anxiety related behavior and alters cerebral lateralization of dopamine activity. Life Sci 42:1059–1065
Gerardin DC, Pereira OC, Kempinas WG, Florio JC, Moreira EG, Bernardi MM (2005) Sexual behavior, neuroendocrine, and neurochemical aspects in male rats exposed prenatally to stress. Physiol Behav 84:97–104
Goel N, Bale TL (2009) Examining the intersection of sex and stress in modelling neuropsychiatric disorders. J Neuroendocrinol 21:415–420
Goel N, Innala L, Viau V (2014) Sex differences in serotonin (5-HT) 1A receptor regulation of HPA axis and dorsal raphe responses to acute restraint. Psychoneuroendocrinology 40:232–241
Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416:396–400
Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, Parsons LH, Tecott LH (1998) Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A 95:15049–15054
Higgins GA, Jones BJ, Oakley NR (1992) Effect of 5-HT1A receptor agonists in two models of anxiety after dorsal raphe injection. Psychopharmacology (Berl) 106:261–267
Huttunen MO (1971) Persistent alteration of turnover of brain noradrenaline in the offspring of rats subjected to stress during pregnancy. Nature 230:53–55
Kirby LG, Rice KC, Valentino RJ (2000) Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology 22:148–162
Koprowska M, Krotewicz M, Romaniuk A, Strzelczuk M, Wieczorek M (2002) Fear behavior and regional brain monoamines distribution after R(+)-8-OHDPAT and R(+)-UH-301 injections into the dorsal raphe nucleus in rats. Acta Neurobiol Exp (Wars) 62:63–74
Kusserow H, Davies B, Hortnagl H, Voigt I, Stroh T, Bert B, Deng DR, Fink H, Veh RW, Theuring F (2004) Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors. Brain Res Mol Brain Res 129:104–116
Lanfumey L, Hamon M (2000) Central 5-HT(1A) receptors: regional distribution and functional characteristics. Nucl Med Biol 27:429–435
Llado-Pelfort L, Santana N, Ghisi V, Artigas F, Celada P (2012) 5-HT1A receptor agonists enhance pyramidal cell firing in prefrontal cortex through a preferential action on GABA interneurons. Cereb Cortex 22:1487–1497
Lukkes JL, Staub DR, Dietrich A, Truitt W, Neufeld-Cohen A, Chen A, Johnson PL, Shekhar A, Lowry CA (2011) Topographical distribution of corticotropin-releasing factor type 2 receptor-like immunoreactivity in the rat dorsal raphe nucleus: co-localization with tryptophan hydroxylase. Neuroscience 183:47–63
Martin EI, Ressler KJ, Binder E, Nemeroff CB (2009) The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Psychiatr Clin N Am 32:549–575
Marvan ML, Chavez-Chavez L, Santana S (1996) Clomipramine modifies fluctuations of forced swimming immobility in different phases of the rat estrous cycle. Arch Med Res 27:83–86
McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG, Murray EK, Nugent BM, Schwarz JM, Wilson ME (2009) The epigenetics of sex differences in the brain. J Neurosci 29:12815–12823
Meerlo P, Horvath KM, Luiten PG, Angelucci L, Catalani A, Koolhaas JM (2001) Increased maternal corticosterone levels in rats: effects on brain 5-HT1A receptors and behavioral coping with stress in adult offspring. Behav Neurosci 115:1111–1117
Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:83–244
Morley-Fletcher S, Darnaudery M, Mocaer E, Froger N, Lanfumey L, Laviola G, Casolini P, Zuena AR, Marzano L, Hamon M, Maccari S (2004) Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats. Neuropharmacology 47:841–847
Moses-Kolko EL, Price JC, Shah N, Berga S, Sereika SM, Fisher PM, Coleman R, Becker C, Mason NS, Loucks T, Meltzer CC (2011) Age, sex, and reproductive hormone effects on brain serotonin-1A and serotonin-2A receptor binding in a healthy population. Neuropsychopharmacology 36:2729–2740
Muller CP, Carey RJ, Huston JP, De Souza Silva MA (2007) Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors. Prog Neurobiol 81:133–178
Parks CL, Robinson PS, Sibille E, Shenk T, Toth M (1998) Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci U S A 95:10734–10739
Paxinos G, Watson C, Pennisi M, Topple A (1985) Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 13:139–143
Pernar L, Curtis AL, Vale WW, Rivier JE, Valentino RJ (2004) Selective activation of corticotropin-releasing factor-2 receptors on neurochemically identified neurons in the rat dorsal raphe nucleus reveals dual actions. J Neurosci 24:1305–1311
Peters DA (1988) Effects of maternal stress during different gestational periods on the serotonergic system in adult rat offspring. Pharmacol Biochem Behav 31:839–843
Picard M, Morisset S, Cloix JF, Bizot JC, Guerin M, Beneteau V, Guillaumet G, Hevor TK (2010) Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist. Neuroscience 169:1337–1346
Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391
Puig S (2005) Editorial. Eur J Radiol 53:1–2
Reul JM, Holsboer F (2002) Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2:23–33
Rodriguez N, Mayer N, Gauna HF (2007) Effects of prenatal stress on male offspring sexual maturity. Biocell 31:67–74
Salomon S, Bejar C, Schorer-Apelbaum D, Weinstock M (2011) Corticosterone mediates some but not other behavioural changes induced by prenatal stress in rats. J Neuroendocrinol 23:118–128
Schmidt MJ, Horvath S, Ebert P, Norris JL, Seeley EH, Brown J, Gellert L, Everheart M, Garbett KA, Grice TW, Caprioli RM, Mirnics K (2014) Modulation of behavioral networks by selective interneuronal inactivation. Mol Psychiatry 19:580–587
Schreiber R, De Vry J (1993) Neuronal circuits involved in the anxiolytic effects of the 5-HT1A receptor agonists 8-OH-DPAT ipsapirone and buspirone in the rat. Eur J Pharmacol 249:341–351
Shikanai H, Yoshida T, Konno K, Yamasaki M, Izumi T, Ohmura Y, Watanabe M, Yoshioka M (2012) Distinct neurochemical and functional properties of GAD67-containing 5-HT neurons in the rat dorsal raphe nucleus. J Neurosci 32:14415–14426
Shoham S, Bejar C, Kovalev E, Schorer-Apelbaum D, Weinstock M (2007) Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats. Neuropharmacology 52:836–843
Shoshani Y (2012) Effect of prenatal stress on brain development in the rat offspring. Ph.D thesis, The Hebrew University of Jerusalem
Silvagni A, Barros VG, Mura C, Antonelli MC, Carboni E (2008) Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: an ‘in vivo’ microdialysis study in adolescent and young adult rats. Eur J Neurosci 28:744–758
Solati J, Salari AA, Bakhtiari A (2011) 5HT(1A) and 5HT(1B) receptors of medial prefrontal cortex modulate anxiogenic-like behaviors in rats. Neurosci Lett 504:325–329
Staiti AM, Morgane PJ, Galler JR, Grivetti JY, Bass DC, Mokler DJ (2011) A microdialysis study of the medial prefrontal cortex of adolescent and adult rats. Neuropharmacology 61:544–549
Stamp JA, Semba K (1995) Extent of colocalization of serotonin and GABA in the neurons of the rat raphe nuclei. Brain Res 677:39–49
Takahashi LK, Ho SP, Livanov V, Graciani N, Arneric SP (2001) Antagonism of CRF(2) receptors produces anxiolytic behavior in animal models of anxiety. Brain Res 902:135–142
Temel Y, Blokland A, Lim LW (2012) Deactivation of the parvalbumin-positive interneurons in the hippocampus after fear-like behaviour following electrical stimulation of the dorsolateral periaqueductal gray of rats. Behav Brain Res 233:322–325
Van den Hove DL, Lauder JM, Scheepens A, Prickaerts J, Blanco CE, Steinbusch HW (2006) Prenatal stress in the rat alters 5-HT1A receptor binding in the ventral hippocampus. Brain Res 1090:29–34
Van den Hove DL, Kenis G, Brass A, Opstelten R, Rutten BP, Bruschettini M, Blanco CE, Lesch KP, Steinbusch HW, Prickaerts J (2013) Vulnerability versus resilience to prenatal stress in male and female rats; implications from gene expression profiles in the hippocampus and frontal cortex. Eur Neuropsychopharmacol 23:1226–1246
Van den Hove DL, Leibold NK, Strackx E, Martinez-Claros M, Lesch KP, Steinbusch HW, Schruers KR, Prickaerts J (2014) Prenatal stress and subsequent exposure to chronic mild stress in rats; interdependent effects on emotional behavior and the serotonergic system. Eur Neuropsychopharmacol 24:595–607
Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32:1073–1086
Weinstock M (2011) Sex-dependent changes induced by prenatal stress in cortical and hippocampal morphology and behaviour in rats: an update. Stress 14:604–613
Zhao Y, Valdez GR, Fekete EM, Rivier JE, Vale WW, Rice KC, Weiss F, Zorrilla EP (2007) Subtype-selective corticotropin-releasing factor receptor agonists exert contrasting, but not opposite, effects on anxiety-related behavior in rats. J Pharmacol Exp Ther 323:846–854
Zohar I, Weinstock M (2011) Differential effect of prenatal stress on the expression of corticotrophin-releasing hormone and its receptors in the hypothalamus and amygdala in male and female rats. J Neuroendocrinol 23:320–328
Acknowledgments
The authors gratefully acknowledge the assistance of Ms. Schorer-Apelbaum for statistical analysis and with preparation of the MS.
Conflict of interest
There is none to disclose.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zohar, I., Dosoretz-Abittan, L., Shoham, S. et al. 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. Psychopharmacology 232, 1643–1653 (2015). https://doi.org/10.1007/s00213-014-3803-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-014-3803-z