Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats

  • Ambalika Sarkar
    Department of Biomedical Sciences, Program in Neuroscience, College of Medicine, Florida State University, Tallahassee, Florida
    Search for articles by this author
  • Mohamed Kabbaj
    Address correspondence to Mohamed Kabbaj, Ph.D., Department of Biomedical Sciences, Program in Neuroscience, Florida State University, 1115 West Call Street, Tallahassee, FL 32306.
    Department of Biomedical Sciences, Program in Neuroscience, College of Medicine, Florida State University, Tallahassee, Florida
    Search for articles by this author



      The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats.


      We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine density was also examined in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle.


      Male rats showed anhedonia and depression-like behavior after 8 weeks of IS, concomitant with decreases in spine density and levels of synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 weeks of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline observed in synaptic proteins and spine density in IS and in diestrus female rats could not be reversed by ketamine. Spine density was higher in female rats during proestrus than in diestrus.


      Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 and medial prefrontal cortex spine density in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kessler R.C.
        Epidemiology of women and depression.
        J Affect Disord. 2003; 74: 5-13
        • Holden C.
        Sex and the suffering brain.
        Science (New York, NY). 2005; 308: 1574
        • Kajantie E.
        • Phillips D.I.
        The effects of sex and hormonal status on the physiological response to acute psychosocial stress.
        Psychoneuroendocrinology. 2006; 31: 151-178
        • Chaplin T.M.
        • Hong K.
        • Bergquist K.
        • Sinha R.
        Gender differences in response to emotional stress: An assessment across subjective, behavioral, and physiological domains and relations to alcohol craving.
        Alcohol Clin Exp Res. 2008; 32: 1242-1250
        • Kornstein S.G.
        • Schatzberg A.F.
        • Thase M.E.
        • Yonkers K.A.
        • McCullough J.P.
        • Keitner G.I.
        • et al.
        Gender differences in treatment response to sertraline versus imipramine in chronic depression.
        Am J Psychiatry. 2000; 157: 1445-1452
        • Young E.A.
        • Kornstein S.G.
        • Marcus S.M.
        • Harvey A.T.
        • Warden D.
        • Wisniewski S.R.
        • et al.
        Sex differences in response to citalopram: A STAR∗ D report.
        J Psychiatr Res. 2009; 43: 503-511
        • Thase M.E.
        • Frank E.
        • Kornstein S.G.
        • Yonkers K.A.
        Gender differences in response to treatments of depression.
        in: Frank E. Gender and Its Effects on Psychopathology. American Psychiatric Association Press, Washington, DC2000: 103-129
        • Frank J.B.
        • Weihs K.
        • Minerva E.
        • Lieberman D.Z.
        Women’s mental health in primary care: Depression, anxiety, somatization, eating disorders, and substance abuse.
        Med Clin North Am. 1998; 82: 359-389
        • Marcus S.M.
        • Kerber K.B.
        • Rush A.J.
        • Wisniewski S.R.
        • Nierenberg A.
        • Balasubramani G.K.
        • et al.
        Sex differences in depression symptoms in treatment-seeking adults: Confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study.
        Compr Psychiatry. 2008; 49: 238-246
        • Kokras N.
        • Dalla C.
        Sex differences in animal models of psychiatric disorders.
        Br J Pharmacol. 2014; 171: 4595-4619
        • Cosgrove K.P.
        • Mazure C.M.
        • Staley J.K.
        Evolving knowledge of sex differences in brain structure, function, and chemistry.
        Biol Psychiatry. 2007; 62: 847-855
        • McCarthy M.M.
        • Arnold A.P.
        • Ball G.F.
        • Blaustein J.D.
        • De Vries G.J.
        Sex differences in the brain: The not so inconvenient truth.
        J Neurosci. 2012; 32: 2241-2247
        • Hodes G.E.
        Sex, stress, and epigenetics: Regulation of behavior in animal models of mood disorders.
        Biol Sex Differ. 2013; 4: 1
        • Kirsch I.
        • Moore T.J.
        • Scoboria A.
        • Nicholls S.S.
        The emperor’s new drugs: An analysis of antidepressant medication data submitted to the US Food and Drug Administration.
        Prev Treat. 2002; 5: 23a
        • Lader M.
        Limitations of current medical treatments for depression: Disturbed circadian rhythms as a possible therapeutic target.
        Eur Neuropsychopharmacol. 2007; 17: 743-755
        • Berman R.M.
        • Cappiello A.
        • Anand A.
        • Oren D.A.
        • Heninger G.R.
        • Charney D.S.
        • et al.
        Antidepressant effects of ketamine in depressed patients.
        Biol Psychiatry. 2000; 47: 351-354
        • Covvey J.R.
        • Crawford A.N.
        • Lowe D.K.
        Intravenous ketamine for treatment-resistant major depressive disorder.
        Ann Pharmacother. 2012; 46: 117-123
        • Zarate C.A.
        • Singh J.B.
        • Carlson P.J.
        • Brutsche N.E.
        • Ameli R.
        • Luckenbaugh D.A.
        • et al.
        A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
        Arch Gen Psychiatry. 2006; 63: 856-864
        • Diazgranados N.
        • Ibrahim L.
        • Brutsche N.E.
        • Newberg A.
        • Kronstein P.
        • Khalife S.
        • et al.
        A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.
        Arch Gen Psychiatry. 2010; 67: 793-802
        • Niciu M.J.
        • Luckenbaugh D.A.
        • Ionescu D.F.
        • Richards E.M.
        • Voort J.L.V.
        • Ballard E.D.
        • et al.
        Ketamine’s antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder.
        Int J Neuropsychopharmacol 18. 2015; : pyu039
        • Carrier N.
        • Kabbaj M.
        Sex differences in the antidepressant-like effects of ketamine.
        Neuropharmacology. 2013; 70: 27-34
        • Franceschelli A.
        • Sens J.
        • Herchick S.
        • Thelen C.
        • Pitychoutis P.M.
        Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and “depressed” mice exposed to chronic mild stress.
        Neuroscience. 2015; 290: 49-60
        • Wallace D.L.
        • Han M.-H.
        • Graham D.L.
        • Green T.A.
        • Vialou V.
        • Iniguez S.D.
        • et al.
        CREB regulation of nucleus accumbens excitability mediates social isolation–induced behavioral deficits.
        Nat Neurosci. 2009; 12: 200-209
        • Carrier N.
        • Kabbaj M.
        Testosterone and imipramine have antidepressant effects in socially isolated male but not female rats.
        Horm Behav. 2012; 61: 678-685
        • Li N.
        • Liu R.-J.
        • Dwyer J.M.
        • Banasr M.
        • Lee B.
        • Son H.
        • et al.
        Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.
        Biol Psychiatry. 2011; 69: 754-761
        • Autry A.E.
        • Adachi M.
        • Nosyreva E.
        • Na E.S.
        • Los M.F.
        • Cheng P.-F.
        • et al.
        NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
        Nature. 2011; 475: 91-95
        • Duclot F.
        • Hollis F.
        • Darcy M.J.
        • Kabbaj M.
        Individual differences in novelty-seeking behavior in rats as a model for psychosocial stress-related mood disorders.
        Physiol Behav. 2011; 104: 296-305
        • Carrier N.
        • Kabbaj M.
        Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate gyrus mediates the antidepressant effects of testosterone.
        Biol Psychiatry. 2012; 71: 642-651
        • Hollis F.
        • Wang H.
        • Dietz D.
        • Gunjan A.
        • Kabbaj M.
        The effects of repeated social defeat on long-term depressive-like behavior and short-term histone modifications in the hippocampus in male Sprague-Dawley rats.
        Psychopharmacology. 2010; 211: 69-77
        • Lucki I.
        The forced swimming test as a model for core and component behavioral effects of antidepressant drugs.
        Behav Pharmacol. 1997; 8: 523-532
        • Stefanik M.T.
        • Moussawi K.
        • Kupchik Y.M.
        • Smith K.C.
        • Miller R.L.
        • Huff M.L.
        • et al.
        Optogenetic inhibition of cocaine seeking in rats.
        Addict Biol. 2013; 18: 50-53
        • Li N.
        • Lee B.
        • Liu R.J.
        • Banasr M.
        • Dwyer J.M.
        • Iwata M.
        • et al.
        mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
        Science (New York, NY). 2010; 329: 959-964
        • Hall F.S.
        Social deprivation of neonatal, adolescent, and adult rats has distinct neurochemical and behavioral consequences.
        Crit Rev Neurobiol. 1998; 12: 129-162
        • Brenes J.C.
        • Rodríguez O.
        • Fornaguera J.
        Differential effect of environment enrichment and social isolation on depressive-like behavior, spontaneous activity and serotonin and norepinephrine concentration in prefrontal cortex and ventral striatum.
        Pharmacol Biochem Behav. 2008; 89: 85-93
        • Ferdman N.
        • Murmu R.
        • Bock J.
        • Braun K.
        • Leshem M.
        Weaning age, social isolation, and gender, interact to determine adult explorative and social behavior, and dendritic and spine morphology in prefrontal cortex of rats.
        Behav Brain Res. 2007; 180: 174-182
        • Hermes G.
        • Li N.
        • Duman C.
        • Duman R.
        Post-weaning chronic social isolation produces profound behavioral dysregulation with decreases in prefrontal cortex synaptic-associated protein expression in female rats.
        Physiol Behav. 2011; 104: 354-359
        • Silva-Gomez A.B.
        • Rojas D.
        • Juarez I.
        • Flores G.
        Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats.
        Brain Res. 2003; 983: 128-136
        • Leussis M.P.
        • Andersen S.L.
        Is adolescence a sensitive period for depression? Behavioral and neuroanatomical findings from a social stress model.
        Synapse. 2008; 62: 22-30
        • Haj-Mirzaian A.
        • Amiri S.
        • Kordjazy N.
        • Rahimi-Balaei M.
        • Haj-Mirzaian A.
        • Marzban H.
        • et al.
        Blockade of NMDA receptors reverses the depressant, but not anxiogenic effect of adolescence social isolation in mice.
        Eur J Pharmacol. 2015; 750: 160-166
        • Mileva G.R.
        • Bielajew C.
        Environmental manipulation affects depressive-like behaviours in female Wistar-Kyoto rats.
        Behav Brain Res. 2015; 293: 208-216
        • Than T.T.
        • Delay E.R.
        • Maier M.E.
        Sucrose threshold variation during the menstrual cycle.
        Physiol Behav. 1994; 56: 237-239
        • Green A.D.
        • Barr A.M.
        • Galea L.A.M.
        Role of estradiol withdrawal in ‘anhedonic’ sucrose consumption: A model of postpartum depression.
        Physiol Behav. 2009; 97: 259-265
        • Radley J.J.
        • Rocher A.B.
        • Miller M.
        • Janssen W.G.M.
        • Liston C.
        • Hof P.R.
        • et al.
        Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex.
        Cerebr Cortex. 2006; 16: 313-320
        • Michelsen K.A.
        • van den Hove D.L.
        • Schmitz C.
        • Segers O.
        • Prickaerts J.
        • Steinbusch H.W.
        Prenatal stress and subsequent exposure to chronic mild stress influence dendritic spine density and morphology in the rat medial prefrontal cortex.
        BMC Neurosci. 2007; 8: 107
        • Liu J.
        • Dietz K.
        • DeLoyht J.M.
        • Pedre X.
        • Kelkar D.
        • Kaur J.
        • et al.
        Impaired adult myelination in the prefrontal cortex of socially isolated mice.
        Nat Neurosci. 2012; 15: 1621-1623
        • Chen J.-R.
        • Yan Y.-T.
        • Wang T.-J.
        • Chen L.-J.
        • Wang Y.-J.
        • Tseng G.-F.
        Gonadal hormones modulate the dendritic spine densities of primary cortical pyramidal neurons in adult female rat.
        Cerebr Cortex. 2009; 19: 2719-2727
        • Douma S.
        • Husband C.
        • O’Donnell M.
        • Barwin B.
        • Woodend A.
        Estrogen‐related mood disorders: Reproductive life cycle factors.
        Adv Nurs Sci. 2005; 28: 364-375
        • McEwen B.S.
        • Nasca C.
        • Gray J.D.
        Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex.
        Neuropsychopharmacology. 2016; 41: 3-23
        • Shors T.
        • Falduto J.
        • Leuner B.
        The opposite effects of stress on dendritic spines in male vs. female rats are NMDA receptor‐dependent.
        Eur J Neurosci. 2004; 19: 145-150
        • Murmu M.S.
        • Salomon S.
        • Biala Y.
        • Weinstock M.
        • Braun K.
        • Bock J.
        Changes of spine density and dendritic complexity in the prefrontal cortex in offspring of mothers exposed to stress during pregnancy.
        Eur J Neurosci. 2006; 24: 1477-1487
        • Shansky R.M.
        • Hamo C.
        • Hof P.R.
        • McEwen B.S.
        • Morrison J.H.
        Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific.
        Cerebr Cortex. 2009; 19: 2479-2484
        • Shansky R.M.
        • Hamo C.
        • Hof P.R.
        • Lou W.
        • McEwen B.S.
        • Morrison J.H.
        Estrogen promotes stress sensitivity in a prefrontal cortex–amygdala pathway.
        Cerebr Cortex. 2010; 20: 2560-2567
        • Wang Y.
        • Ma Y.
        • Hu J.
        • Cheng W.
        • Jiang H.
        • Zhang X.
        • et al.
        Prenatal chronic mild stress induces depression-like behavior and sex-specific changes in regional glutamate receptor expression patterns in adult rats.
        Neuroscience. 2015; 301: 363-374
        • Kang H.J.
        • Voleti B.
        • Hajszan T.
        • Rajkowska G.
        • Stockmeier C.A.
        • Licznerski P.
        • et al.
        Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.
        Nat Med. 2012; 18: 1413-1417
        • Jernigan C.S.
        • Goswami D.B.
        • Austin M.C.
        • Iyo A.H.
        • Chandran A.
        • Stockmeier C.A.
        • et al.
        The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder.
        Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 1774-1779
        • Aston C.
        • Jiang L.
        • Sokolov B.
        Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder.
        Mol Psychiatry. 2005; 10: 309-322
        • Gray A.
        • Hyde T.
        • Deep-Soboslay A.
        • Kleinman J.
        • Sodhi M.
        Sex differences in glutamate receptor gene expression in major depression and suicide.
        Mol Psychiatry. 2015; 20: 1057-1068
        • Maeng S.
        • Zarate Jr, C.A.
        • Du J.
        • Schloesser R.J.
        • McCammon J.
        • Chen G.
        • et al.
        Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.
        Biol Psychiatry. 2008; 63: 349-352

      Linked Article

      • Ketamine for Depression: An Update
        Biological PsychiatryVol. 80Issue 6
        • Preview
          A decade has now passed since research into the antidepressant effects of ketamine began in earnest, after the clinical trial reported by Zarate et al. in 2006 (1). In that proof-of-concept study, 18 medication-free patients with treatment-resistant major depressive disorder (TRD) showed a large reduction in core depressive symptoms within hours of receiving a single low-dose 0.5 mg/kg intravenous infusion of ketamine as measured by the 21-item Hamilton Depression Rating Scale compared with saline placebo.
        • Full-Text
        • PDF