Research reportRepeated ketamine treatment induces sex-specific behavioral and neurochemical effects in mice
Introduction
During the past decade, one of the most striking discoveries in the treatment of major depressive disorder (MDD) was the finding that infusion of a single sub-anesthetic dose of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine induces rapid and sustained antidepressant effects in treatment-resistant MDD patients and in rodents subjected to various antidepressant-predictive animal models, such as the forced swim test (FST) and the chronic mild stress (CMS) model of depression [1].
The intricate behavioral and neurobiological mechanisms underlying ketamine’s antidepressant actions appear to be brain region- and dose-dependent and have not yet been fully elucidated [1]. Compelling preclinical evidence indicates that ketamine’s antidepressant potential lies on its rapid synaptogenic effects in the medial prefrontal cortex (mPFC) and the hippocampus (HIPP), two brain regions that have been strongly implicated in the pathophysiology of MDD [2], [3]. Acute ketamine-induced NMDA antagonism in the brain accounts for the first step in the neurobiological cascade of events leading to regional alterations in the activity of brain’s neurotransmitter systems and synaptic protein synthesis, eventually resulting in synaptogenesis [1]. Specifically, it is currently believed that ketamine-induced alterations of glutamatergic tone in the HIPP and the PFC trigger neuroplasticity-related molecular cascades that in turn regulate the synthesis of synaptic proteins involved in synaptogenesis (e.g., synapsin-I) and in the pre-synaptic release machinery (e.g., syntaxin-I;SYX) [1], [3], [4]. Indeed, acute low-dose ketamine administration has been shown to rapidly increase synapsin-I protein levels and to decrease the accumulation of SYX-consisting SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes in synaptoneurosomal preparations from the HIPP and/or the PFC [3], [4]. Moreover, it has been reported that enhancement of central serotonergic activity also underlies the antidepressant-like effects of ketamine [3]. Specifically, activation of the dorsal raphe nucleus (DRN) and subsequent serotonin (5-hydroxytryptamine; 5-HT) release in the PFC and the HIPP [5], is possibly implicated in the sustained antidepressant-like effects of ketamine in the FST [6].
A battery of evidence indicates that behaviorally females are more sensitive to NMDA receptor antagonists such as dizocilpine (MK-801), phencyclidine and ketamine than males [7], [8], [9]. For instance, female rats have been reported to be more responsive to the motor-enhancing properties of MK-801 and to respond to lower doses of the drug that are not effective in their male counterparts [8]. Notably, in an early study it was also shown that female rats tend to sleep longer than males following administration of anesthetic doses of ketamine [10]. Interestingly, ketamine’s (40–80 mg/kg; s.c.) neurotoxic effects in the retrosplenial cortex have been found to be more severe in female rats [11]. Moreover, women have also been reported to experience more psychotropic effects (i.e., emergence hallucinations) than men upon ketamine anesthesia [12], [13]. Despite the fact that women experience MDD at roughly twice the rate of men [14], [15], [16], research regarding the neurobiological antidepressant-relevant effects of ketamine has focused almost exclusively on the male sex. Recent preclinical data from our group and others show that female rodents are more sensitive and/or reactive to the rapid and the sustained antidepressant-like effects of acute ketamine treatment, as assessed in antidepressant-predictive behavioral tasks, such as the FST and the CMS model of depression [17], [18]. Most importantly, we recently reported that acute ketamine administration affects the levels of excitatory amino acid neurotransmitters (EAAs; glutamate and aspartate) and serotonergic activity in the HIPP and the PFC of stress-naïve mice in a sex- and brain region-dependent manner [18]. Indeed, both these brain regions have been strongly implicated in sex-related neurobehavioral responses to stress and antidepressant treatments [19], [20], [21], [22], [23], [24], [25].
Strikingly, the clinical antidepressant-like effects of ketamine are transient and can only be sustained by repeated drug treatment [26]. However, our knowledge regarding the frequency and the dose on which repeated ketamine administration stops being beneficial and becomes harmful is limited [1]. Following our recent demonstration that female mice are more sensitive to the antidepressant-like effects of a single dose of ketamine in the FST [18], we hypothesized that the female sex may also be at greater risk for developing adverse drug reactions (ADRs) upon repeated ketamine treatment.
Section snippets
Animals
C57BL/6J mice used in the present study were bred at the University of Dayton from a mouse colony originally obtained from the Jackson Laboratory (ME, USA). Adult (8–12 week-old) mice of both sexes were maintained on a 12 light:12 dark schedule (lights on at 8:00). Experimental procedures and animal husbandry were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23; revised 1996) and approved by the
Repeated ketamine treatment is beneficial for males but induces anxiety-like and depressive-like effects in females
Ketamine administration did not affect spontaneous locomotor activity in either sex (Fig. 1b,c). A repeated measures ANOVA regarding the time male and female mice spent in the center of the OFT arena revealed a significant effect of sex [F(1,51) = 8.699; p = 0.005] that was further investigated with follow-up repeated measures ANOVAs for each sex. This analysis in turn revealed that ketamine treatment affected the total time female mice spent exploring the center of the OFT arena, as indicated by a
Discussion
Herein, we report that repeated treatment with a low dose of ketamine (i.e., 10 mg/kg, once daily for 21 days) induced opposite behavioral effects in male and female mice. Ketamine treatment induced sustained antidepressant-like effects in male mice, as evidenced by the decreased immobility duration in the FST at 24 h post-administration (Fig. 2). However, the same treatment regimen induced sex-specific anxiety-like and depressive-like effects in female mice, as evidenced by the reduced time
Conclusions
Taken together, our findings indicate that repeated ketamine treatment induces opposite behavioral effects in male and female mice. Notably, our data suggest that sex-differentiated responsiveness to ketamine appears to become problematic when females are treated repeatedly with higher antidepressant-relevant doses of this drug. Thus, present findings have far-reaching implications for the use of ketamine in both experimental and clinical research settings.
Acknowledgements
C.T. was supported by the University of Dayton (UD) Graduate School and by the UD Office for Graduate Affairs through the Graduate Student Summer Fellowship (GSSF) Program. J.S. was supported by a Barry Goldwater Scholarship in Excellence and Education Award, by the UD Honors Program, and by a Lancaster-McDougall Award from the Department of Biology, University of Dayton. P.M.P. was supported by start-up funding from the University of Dayton, as well as by Research Council Seed Grants (RCSG)
References (44)
- et al.
Ketamine regulates the presynaptic release machinery in the hippocampus
J. Psychiatr. Res.
(2013) - et al.
Sex differences in NMDA receptor mediated responses in rats
Brain Res.
(1993) - et al.
The effects of magnesium deficiency of ketamine sleeping times in the rat
Br. J. Anaesth.
(1975) - et al.
A comparative evaluation of the neurotoxic properties of ketamine and nitrous oxide
Brain Res.
(2001) - et al.
Clinical studies of induction agents. XXXVI: ketamine
Br. J. Anaesth.
(1970) - et al.
Current status of ketamine anaesthesia
Lancet
(1971) - et al.
Gender differences in depression: findings from the STAR*D study
J. Affect. Disord.
(2005) - et al.
Sex differences in the antidepressant-like effects of ketamine
Neuropharmacology
(2013) - et al.
Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naive and depressed mice exposed to chronic mild stress
Neuroscience
(2015) - et al.
The prefrontal cortex and the integration of sensory, limbic and autonomic information
Prog. Brain Res.
(2000)
5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor mRNA modulation by antidepressant treatment in the chronic mild stress model of depression: sex differences exposed
Neuroscience
Individual differences in novelty-seeking predict differential responses to chronic antidepressant treatment through sex- and phenotype-dependent neurochemical signatures
Behav. Brain Res.
Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats
Neuroscience
Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats
Prog. Neuropsychopharmacol. Biol. Psychiatry
Effects of ketamine and N-methyl-d-aspartate on fluoxetine-induced antidepressant-related behavior using the forced swimming test
Neurosci. Lett.
Repeated ketamine exposure induces an enduring resilient phenotype in adolescent and adult rats
Biol. Psychiatry
An improved and rapid HPLC-EC method for the isocratic separation of amino acid neurotransmitters from brain tissue and microdialysis perfusates
Life Sci.
Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics
Annu. Rev. Med.
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Nature
mTOR-Dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists
Science
Raphe AMPA receptors and nicotinic acetylcholine receptors mediate ketamine-induced serotonin release in the rat prefrontal cortex
Int. J. Neuropsychopharmacol.
Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism
Psychopharmacology (Berl)
Cited by (56)
Sex-Dependent Attentional Impairments in a Subchronic Ketamine Mouse Model for Schizophrenia
2024, Biological Psychiatry Global Open ScienceS-ketamine exerts sex- and dose-dependent anti-compulsive-like effect as monotherapy or in augmentation to fluoxetine
2022, European Journal of PharmacologyCitation Excerpt :Ketamine is a non-competitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors (Anis et al., 1983) and, besides its original use as a general anaesthetic, it has been studied as a rapid antidepressant drug at sub-anaesthetic doses (Berman et al., 2000; Li et al., 2010; Maeng et al., 2008; Strasburger et al., 2017; Zarate et al., 2006; Zhou et al., 2014). Notwithstanding, previous data suggest a sex difference in the antidepressant response to this drug (Carrier and Kabbaj, 2013; Franceschelli et al., 2015; Thelen et al., 2016) related to the levels or presence/absence of female sex hormones (Carrier and Kabbaj, 2013; Dossat et al., 2018; Ho et al., 2018; Saland and Kabbaj, 2018). The anti-compulsive effect of ketamine has also been studied in clinical (Bandeira et al., 2022; Bloch et al., 2012; Rodriguez et al., 2011) and pre-clinical studies (Popik et al., 2017; Thompson et al., 2020).
Comprehensive metabolomic characterization of the hippocampus in a ketamine mouse model of schizophrenia
2022, Biochemical and Biophysical Research Communications