Perinatal exposure to fluoxetine increases anxiety- and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression
Restricted accessResearch articleFirst published online February, 2019
Perinatal exposure to fluoxetine increases anxiety- and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression
With approximately 10% of pregnant women prescribed antidepressant drugs for the treatment of depressive disorders, there is growing concern regarding the potential long-term effects of this exposure on offspring. Research is needed in clinically relevant models to determine the effects on offspring behaviour and associated neurobiological systems.
Aim:
The aim of this study was to determine the effects of maternal fluoxetine treatment on anxiety-like and depressive-like behaviours in adolescent offspring as well as associated glutamatergic markers, using a clinically relevant rodent model of depression.
Methods:
Wistar-Kyoto (model of innate depression) and Sprague-Dawley rats were treated with fluoxetine (10 mg/kg) from gestational day 0 to postnatal day 14. Male offspring underwent behavioural testing (open field, elevated plus maze, forced swim test) at adolescence followed by quantitative immuno-detection of glutamatergic markers in the prefrontal cortex and ventral hippocampus.
Results:
Perinatal fluoxetine exposure exacerbated the anxiety-like and depressive-like phenotype in Wistar-Kyoto offspring and induced an anxiety-like and depressive-like phenotype in Sprague-Dawley offspring. Wistar-Kyoto offspring showed reductions in NMDA receptor NR1, NR2A and NR2B subunits, as well as post-synaptic density 95 (PSD-95) and metabotropic glutamate receptor subtype 1 (mGluR1) in the prefrontal cortex; perinatal fluoxetine exposure further reduced NR1, NR2A, PSD-95 and mGluR1 expression in Wistar-Kyoto as well as Sprague-Dawley offspring. In the ventral hippocampus perinatal fluoxetine exposure reduced PSD-95 and increased metabotropic glutamate receptor subtype 5 (mGluR5) and Homer1b/c in both Sprague-Dawley and Wistar-Kyoto strains.
Conclusion:
These findings suggest that maternal fluoxetine treatment exacerbates effects of underlying maternal depression on offspring behaviour, which may be mediated through alterations in the glutamatergic system. Further research investigating how to minimise these effects, whilst ensuring optimal treatment for mothers, is essential to move the field forward.
AbeHHidakaNKawagoeCet al. (2007) Prenatal psychological stress causes higher emotionality, depression-like behavior, and elevated activity in the hypothalamo-pituitary-adrenal axis. Neurosci Res59: 145–151.
2.
AhmadiyehNSlone-WilcoxonJLTakahashiJSet al. (2004) Maternal behavior modulates X-linked inheritance of behavioral coping in the defensive burying test. Biol Psychiatry55: 1069–1074.
3.
AnsorgeMSMorelliEGingrichJA (2008) Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci Off J Soc Neurosci28: 199–207.
4.
AnsorgeMSZhouMLiraAet al. (2004) Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science306: 879–881.
5.
ArangoVUnderwoodMDBoldriniMet al. (2001) Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology25: 892–903.
6.
BairyKLMadhyasthaSAshokKPet al. (2006) Developmental and behavioral consequences of prenatal fluoxetine. Pharmacology79: 1–11.
7.
BansilPKuklinaEVMeikleSFet al. (2010) Maternal and fetal outcomes among women with depression. J Womens Health19: 329–334.
BonninAToriiMWangLet al. (2007) Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nat Neurosci10: 588–597.
10.
BoukhrisTSheehyOMottronLet al. (2016) Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatr170: 117–124.
11.
BoulleFPawluskiJLHombergJRet al. (2016a) Prenatal stress and early-life exposure to fluoxetine have enduring effects on anxiety and hippocampal BDNF gene expression in adult male offspring. Dev Psychobiol58: 427–438.
12.
BoulleFPawluskiJLHombergJRet al. (2016b) Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring. Horm Behav80: 47–57.
13.
BoyerP-ASkolnickPFossomLH (1998) Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. J Mol Neurosci10: 219–233.
14.
BrandlistuenREYstromEEberhard-GranMet al. (2015) Behavioural effects of fetal antidepressant exposure in a Norwegian cohort of discordant siblings. Int J Epidemiol44: 1397–1407.
15.
BrandonNJMcKayR (2015) The cellular target of antidepressants. Nat Neurosci18: 1537–1538.
16.
BrowneCALuckiI (2013) Antidepressant effects of ketamine: Mechanisms underlying fast-acting novel antidepressants. Front Pharmacol4: 161.
17.
Cabrera-VeraTMBattagliaG (1998) Prenatal exposure to fluoxetine (Prozac) produces site-specific and age-dependent alterations in brain serotonin transporters in rat progeny: Evidence from autoradiographic studies. J Pharmacol Exp Ther286: 1474–1481.
18.
CalvoNCecchiMKabbajMet al. (2011) Differential effects of social defeat in rats with high and low locomotor response to novelty. Neuroscience183: 81–89.
19.
CapelloCFBourkeCHRitchieJCet al. (2011) Serotonin transporter occupancy in rats exposed to serotonin reuptake inhibitors in utero or via breast milk. J Pharmacol Exp Ther339: 275–285.
20.
CastagnéVMoserPRouxSet al. (2011) Rodent models of depression: Forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci, 55: 8.10A.1-8.10A.14.
21.
ClementsCCCastroVMBlumenthalSRet al. (2015) Prenatal antidepressant exposure is associated with risk for attention deficit-hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry20: 727–734.
22.
CommonsKGCholaniansABBabbJAet al. (2017) The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci8: 955–960.
23.
CooperWOWillyMEPontSJet al. (2007) Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol196: 544.e1–544.e5.
24.
CroenLAGretherJKYoshidaCKet al. (2011) Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry68: 1104–1112.
25.
CurleyJPChampagneFA (2016) Influence of maternal care on the developing brain: Mechanisms, temporal dynamics and sensitive periods. Front Neuroendocrinol40: 52–66.
26.
DavalosDBYadonCATregellasHC. (2012) Untreated prenatal maternal depression and the potential risks to offspring: A review. Arch Womens Ment Health15: 1–14.
27.
DeaveTHeronJEvansJet al. (2008) The impact of maternal depression in pregnancy on early child development. Int J Obstet Gynaecol115: 1043–1051.
28.
DeschwandenAKarolewiczBFeyissaAMet al. (2011) Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. Am J Psychiatry168: 727–734.
29.
du BoisTMHuangX-FDengC (2008) Perinatal administration of PCP alters adult behaviour in female Sprague–Dawley rats. Behav Brain Res188: 416–419.
30.
DulawaSCHolickKAGundersenBet al. (2004) Effects of chronic fluoxetine in animal models in anxiety and depression. Neuropsychopharmacology29: 1321–1330.
31.
DusiNBarlatiSVitaAet al. (2015) Brain structural effects of antidepressant treatment in major depression. Curr Neuropharmacol13: 458–465.
32.
EdgarJMPriceDJ (2001) Radial migration in the cerebral cortex is enhanced by signals from thalamus. Eur J Neurosci13: 1745–1754.
33.
FanselowMSDongH-W (2010) Are the dorsal and ventral hippocampus functionally distinct structures?Neuron65: 7–19.
34.
FeyissaAMChandranAStockmeierCAet al. (2009) Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry33: 70–75.
FigueroaR (2010) Use of antidepressants during pregnancy and risk of attention-deficit/hyperactivity disorder in the offspring. J Dev Behav Pediatr31: 641–648.
37.
FoldiCJEylesDWMcGrathJJet al. (2011) The effects of breeding protocol in C57BL/6J mice on adult offspring behaviour. PLoS One6: e18152.
38.
GemmelMKokrasNDallaCet al. (2018) Perinatal fluoxetine prevents the effect of pre-gestational maternal stress on 5-HT in the PFC, but maternal stress has enduring effects on mPFC synaptic structure in offspring. Neuropharmacology128: 168–180.
39.
GidayaNBLeeBKBurstynIet al. (2014) In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. J Autism Dev Disord44: 2558–2567.
40.
GloverMEPughPCJacksonNLet al. (2015) Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats. Neuroscience284: 775–797.
41.
GloverV (2014) Maternal depression, anxiety and stress during pregnancy and child outcome; what needs to be done. Best Pract Res Clin Obstet Gynaecol28: 25–35.
42.
HarringtonRALeeL-CCrumRMet al. (2014) Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay. Pediatrics2013–3406.
43.
HashimotoKSawaAIyoM (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry Depress62: 1310–1316.
44.
HeikkinenTEkbladULaineK (2002) Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta. Int J Obstet Gynaecol109: 1003–1008.
45.
HendrickVStoweZNAltshulerLLet al. (2001) Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk. Biol Psychiatry50: 775–782.
46.
HermesGLiNDumanCet al. (2011) Post-weaning chronic social isolation produces profound behavioral dysregulation with decreases in prefrontal cortex synaptic-associated protein expression in female rats. Physiol Behav104: 354–359.
HutchisonSMMâsseLCPawluskiJLet al. (2018) Perinatal selective serotonin reuptake inhibitor (SSRI) effects on body weight at birth and beyond: A review of animal and human studies. Reprod Toxicol77: 109–121.
49.
HuybrechtsKFPalmstenKMogunHet al. (2013) National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry35: 265–271.
50.
IadarolaNDNiciuMJRichardsEMet al. (2015) Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: A perspective review. Ther Adv Chronic Dis6: 97–114.
51.
JamaACecchiMCalvoNet al. (2008) Inter-individual differences in novelty-seeking behavior in rats predict differential responses to desipramine in the forced swim test. Psychopharmacology (Berl.)198: 333–340.
52.
KarpovaNNLindholmJPruunsildPet al. (2009) Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure are restored by chronic fluoxetine treatment in adult mice. Eur Neuropsychopharmacol19: 97–108.
53.
KesslerR (2003) Epidemiology of women and depression. J Affect Disord74: 5–13.
54.
KimJRiggsKWMisriSet al. (2006) Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding. Br J Clin Pharmacol61: 155–163.
55.
KiryanovaVMcAllisterBBDyckRH (2013) Long-term outcomes of developmental exposure to fluoxetine: A review of the animal literature. Dev Neurosci35: 437–439.
56.
KiryanovaVMeunierSJVecchiarelliHAet al. (2016) Effects of maternal stress and perinatal fluoxetine exposure on behavioral outcomes of adult male offspring. Neuroscience320: 281–296.
57.
KoranLMCainJWDominguezRAet al. (1996) Are fluoxetine plasma levels related to outcome in obsessive-compulsive disorder?Am J Psychiatry153: 1450–1454.
58.
LakhanSECaroMHadzimichalisN (2013) NMDA receptor activity in neuropsychiatric disorders. Front Psychiatry4: 52.
59.
LamMWYoungCJMaburySA (2005) Aqueous photochemical reaction kinetics and transformations of fluoxetine. Environ Sci Technol39: 513–522.
60.
LavdasAABlueMELincolnJet al. (1997) Serotonin promotes the differentiation of glutamate neurons in organotypic slice cultures of the developing cerebral cortex. J Neurosci Off J Soc Neurosci17: 7872–7880.
López-FigueroaALNortonCSLópez-FigueroaMOet al. (2004) Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry55: 225–233.
63.
López-RubalcavaCLuckiI (2000) Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology22: 191–199.
64.
LumJSFernandezFMatosinNet al. (2016) Neurodevelopmental expression profile of dimeric and monomeric group 1 mGluRs: Relevance to schizophrenia pathogenesis and treatment. Sci Rep6: srep34391.
65.
LumJSMillardSJFrankEet al. (2018) Chronic adolescent CDPPB treatment alters short-term, but not long-term, glutamatergic receptor expression. Neurochem Res43: 1683–1691.
66.
MalmHBrownASGisslerMet al. (2016) Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: A National Register-Based Study. J Am Acad Child Adolesc Psychiatry55: 359–366.
67.
MaoLYangLTangQet al. (2005) The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons. J Neurosci Off J Soc Neurosci25: 2741–2752.
68.
MarcusSMHeringhausenJE (2009) Depression in childbearing women: When depression complicates pregnancy. Prim Care Clin Off Pract36: 151–165.
69.
MartinowichKLuB (2007) Interaction between BDNF and serotonin: Role in mood disorders. Neuropsychopharmacology33: 73–83.
70.
MatosinNFrankEDengCet al. (2013) Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment. Schizophr Res146: 170–176.
71.
MattsonMP (2008) Glutamate and neurotrophic factors in neuronal plasticity and disease. Annals of the New York Academy of Sciences1144: 97–112.
72.
McIlwainKLMerriweatherMYYuva-PaylorLAet al. (2001) The use of behavioral test batteries: Effects of training history. Physiol Behav73: 705–717.
73.
MillardSJWeston-GreenKNewellKA (2017) The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders. Neurosci Biobehav Rev80: 743–765.
74.
MitchellAAGilboaSMWerlerMMet al.; National Birth Defects Prevention Study (2011) Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol205: 51.e1–8.
75.
MoghaddamBJavittD (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol37: 4–15.
76.
MohnARGainetdinovRRCaronMGet al. (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell98: 427–436.
77.
MolendijkMLde KloetER (2015) Immobility in the forced swim test is adaptive and does not reflect depression. Psychoneuroendocrinology62: 389–391.
78.
Morley-FletcherSMairesseJSoumierAet al. (2011) Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl.)217: 301.
79.
MusazziLTreccaniGMalleiAet al. (2013) The action of antidepressants on the glutamate system: Regulation of glutamate release and glutamate receptors. Biol Psychiatry73: 1180–1188.
80.
NamHClintonSMJacksonNLet al. (2014) Learned helplessness and social avoidance in the Wistar-Kyoto rat. Front Behav Neurosci8: 109.
81.
OberlanderTFGingrichJAAnsorgeMS (2009) Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: Molecular to clinical evidence. Clin Pharmacol Ther86: 672–677.
82.
OlivierJDAÅkerudHKaiholaHet al. (2013) The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring. Front Cell Neurosci7: 73.
83.
OlivierJDAVallèsAHeeschF vanet al. (2011) Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring. Psychopharmacology (Berl.)217: 419–432.
84.
PardonM-CGouldGGGarciaAet al. (2002) Stress reactivity of the brain noradrenergic system in three rat strains differing in their neuroendocrine and behavioral responses to stress: Implications for susceptibility to stress-related neuropsychiatric disorders. Neuroscience115: 229–242.
85.
PareWPTejani-ButtSM (1996) Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains. Integr Physiol Behav Sci31: 112.
86.
ParkSWLeeJGSeoMKet al. (2014) Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons. Int J Neuropsychopharmacol17: 1831–1846.
PaxinosGWatsonC (2007) The rat brain in stereotaxic coordinates. (6th Edition). San Diego: Academic Press.
89.
PaylorRSpencerCMYuva-PaylorLAet al. (2006) The use of behavioral test batteries, II: Effect of test interval. Physiol Behav87: 95–102.
90.
Pérez de la MoraMLara-GarcíaDJacobsenKXet al. (2006) Anxiolytic-like effects of the selective metabotropic glutamate receptor 5 antagonist MPEP after its intra-amygdaloid microinjection in three different non-conditioned rat models of anxiety. Eur J Neurosci23: 2749–2759.
91.
PrutLBelzungC (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur J Pharmacol463: 3–33.
92.
RamtekkarUPReiersenAMTodorovAAet al. (2010) Sex and age differences in attention-deficit/hyperactivity disorder symptoms and diagnoses: Implications for DSM-V and ICD-11. J Am Acad Child Adolesc Psychiatry49: 217–28.e1–3.
93.
RayenIvan den HoveDLPrickaertsJet al. (2011) Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence. PLoS One6: e24003.
94.
RedeiEPareWPAirdFet al. (1994) Strain differences in hypothalamic-pituitary-adrenal activity and stress ulcer. Am J Physiol Regul Integr Comp Physiol266: R353–R360.
95.
RittenhousePALópez-RubalcavaCStanwoodGDet al. (2002) Amplified behavioral and endocrine responses to forced swim stress in the Wistar–Kyoto rat. Psychoneuroendocrinology27: 303–318.
96.
Rodriguez-PorcelFGreenDKhatriNet al. (2011) Neonatal exposure of rats to antidepressants affects behavioral reactions to novelty and social interactions in a manner analogous to autistic spectrum disorders. Anat Rec Adv Integr Anat Evol Biol294: 1726–1735.
97.
RonaldAPennellCEWhitehouseAJO (2011) Prenatal maternal stress associated with ADHD and autistic traits in early childhood. Front Psychol1: 223.
98.
SahPFaberESLLopez De ArmentiaMet al. (2003) The amygdaloid complex: Anatomy and physiology. Physiol Rev83: 803–834.
99.
SchollJLRennerKJForsterGLet al. (2010) Central monoamine levels differ between rat strains used in studies of depressive behavior. Brain Res1355: 41–51.
100.
SempleBDBlomgrenKGimlinKet al. (2013) Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol106–107: 1–16.
101.
ShengM (2001) The postsynaptic NMDA-receptor—PSD-95 signaling complex in excitatory synapses of the brain. J Cell Sci114: 1251.
102.
ShengMKimE (2011) The postsynaptic organization of synapses. Cold Spring Harb Perspect Biol3: a005678–a005678.
103.
SlatteryDACryanJF (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc7: 1009–1014.
104.
SprowlesJLNHufgardJRGutierrezAet al. (2016) Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats. Int J Dev Neurosci54: 39–52.
105.
SunHGuanLZhuZet al. (2013a) Reduced levels of NR1 and NR2A with depression-like behavior in different brain regions in prenatally stressed juvenile offspring. PLoS One8: e81775.
106.
SunHJiaNGuanLet al. (2013b) Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring. Behav Brain Res257: 1–7.
107.
SwansonCJBuresMJohnsonMPet al. (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nature Reviews Drug Discovery4: 131–144.
108.
TatarczyńskaEKłodzińskaAChojnacka-WójcikEet al. (2001) Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol132: 1423–1430.
109.
TerbeckSAkkusFChestermanLPet al. (2015) The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: Combining preclinical evidence with human Positron Emission Tomography (PET) studies. Front Neurosci9.
110.
ThompsonMRLiKMClemensKJet al. (2004) Chronic fluoxetine treatment partly attenuates the long-term anxiety and depressive symptoms induced by MDMA (‘Ecstasy’) in rats. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol29: 694–704.
111.
TizabiYBhattiBHManayeKFet al. (2012) Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. Neuroscience213: 72–80.
112.
TrullasRSkolnickP (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol185: 1–10.
113.
TuJCXiaoBNaisbittSet al. (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron23: 583–592.
114.
TurnerKMBurneTHJ (2014) Comprehensive behavioural analysis of Long Evans and Sprague-Dawley rats reveals differential effects of housing conditions on tests relevant to neuropsychiatric disorders. PLoS One9: e93411.
115.
VanGuilderHDFarleyJAYanHet al. (2011) Hippocampal dysregulation of synaptic plasticity-associated proteins with age-related cognitive decline. Neurobiol Dis43: 201–212.
116.
VitalisTParnavelasJG (2003) The role of serotonin in early cortical development. Dev Neurosci25: 245–256.
117.
WalfAAFryeCA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc2: 322–328.
118.
WerlingDMGeschwindDH (2013) Sex differences in autism spectrum disorders. Curr Opin Neurol26: 146–153.
119.
WillCCAirdFRedeiEE (2003) Selectively bred Wistar-Kyoto rats: An animal model of depression and hyper-responsiveness to antidepressants. Mol Psychiatry8: 925–932.
120.
World Health Organization (2017) Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization.
121.
YuanHLowC-MMoodyOAet al. (2015) Ionotropic GABA and glutamate receptor mutations and human neurologic diseases. Mol Pharmacol88: 203.
122.
ZhangYZuXLuoWet al. (2012) Social isolation produces anxiety-like behaviors and changes PSD-95 levels in the forebrain. Neurosci Lett514: 27–30.
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