Elsevier

Neurobiology of Disease

Volume 100, April 2017, Pages 1-8
Neurobiology of Disease

Ketamine accelerates fear extinction via mTORC1 signaling

https://doi.org/10.1016/j.nbd.2016.12.026Get rights and content

Highlights

  • Glutamatergic signaling plays an important role in the formation of traumatic memories and in the onset of PTSD .

  • Ketamine accelerates extinction learning in a model of fear conditioning.

  • mTORC1 signaling and AMPA receptor signaling are required for ketamine’s effect on extinction learning.

  • Inhibition of mTORC1 signaling blocks ketamine’s effect on extinction learning.

Abstract

Impaired fear extinction contributes to the persistence of post-traumatic stress disorder (PTSD), and can be utilized for the study of novel therapeutic agents. Glutamate plays an important role in the formation of traumatic memories, and in the pathophysiology and treatment of PTSD, highlighting several possible drug targets. Recent clinical studies demonstrate that infusion of ketamine, a glutamate NMDA receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients. In the present study, we examine the mechanisms underlying the actions of ketamine in a rodent model of fear conditioning, extinction, and renewal. Rats received ketamine or saline 24 h after fear conditioning and were then subjected to extinction-training on each of the following three days. Ketamine administration enhanced extinction on the second day of training (i.e., reduced freezing behavior to cue) and produced a long-lasting reduction in freezing on exposure to cue plus context 8 days later. Additionally, ketamine and extinction exposure increased levels of mTORC1 in the medial prefrontal cortex (mPFC), a region involved in the acquisition and retrieval of extinction, and infusion of the selective mTORC1 inhibitor rapamycin into the mPFC blocked the effects of ketamine on extinction. Ketamine plus extinction also increased cFos in the mPFC and administration of a glutamate-AMPA receptor antagonist blocked the effects of ketamine. These results support the hypothesis that ketamine produces long-lasting mTORC1/protein synthesis and activity dependent effects on neuronal circuits that enhance the expression of extinction and could represent a novel approach for the treatment of PTSD.

Introduction

Post-traumatic stress disorder (PTSD) is a chronic and debilitating disorder with a life-time prevalence of 7.8% in the general population and higher in trauma-exposed groups (Kessler et al., 2008). PTSD is typically characterized as persistent re-experiencing of memories, avoidance of cues or situations that are reminiscent of the traumatic event, emotional numbing, and hyperarousal. PTSD symptoms, particularly those related to re-experiencing the traumatic event, may fall within the fear-conditioning paradigm of neurobiology. Alterations in fear conditioning and extinction learning are thought to play a role in the onset and maintenance of PTSD (Milad et al., 2007, Pitman et al., 2012).

Significant progress has been made in understanding the neurobiological basis of fear (Johansen et al., 2011, Kessler et al., 2008). Pavlovian fear conditioning is believed to take place at the convergence of neural circuits linking the amygdala, hippocampus and medial prefrontal cortex (mPFC) (Knapska et al., 2012, Milad et al., 2007, Pitman et al., 2012, Sierra-Mercado et al., 2011). Fear conditioning and extinction represent basic forms of associative learning that are highly conserved across species (Johnson et al., 2012). Trauma-exposed patients suffering from PTSD experience deficits in the extinction of learned fear associations when compared to those who do not develop PTSD (Holmes and Singewald, 2013, Lommen et al., 2013, Parsons and Ressler, 2013). Therefore, animal models involving fear conditioning and extinction learning in rodents represent an ideal paradigm for preclinical assessments of PTSD and for identifying novel pharmacotherapies.

Antidepressants, particularly selective serotonin reuptake inhibitors, can reduce PTSD symptoms in humans (Zhang and Davidson, 2007) and fear in rodents (Karpova et al., 2011) when combined with extinction therapy. During extinction, repeated exposure to a cue previously associated with a fear-provoking event results in the gradual formation of a new memory that is thought to suppress fear expression by establishing an inhibitory memory (Orsini and Maren, 2012). However, currently available antidepressants have several limitations, including slow onset of action (weeks to months) and low rates of efficacy, with only a subset of patients showing complete remission of PTSD symptoms (Ursano et al., 2004). These factors underscore the urgent need to develop new pharmacotherapies that enhance extinction and can provide a more persistent and rapid reduction in PTSD symptoms.

There is mounting evidence for a role of the excitatory neurotransmitter glutamate in stress responsiveness, the formation of traumatic memories, and the pathophysiology of PTSD, raising the possibility of identifying novel glutamatergic interventions for this disorder (Horn et al., 2016, Rasmussen, 2016, Riaza Bermudo-Soriano et al., 2012). Notably, recent clinical studies demonstrate that infusion of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients (Feder et al., 2014). Moreover, administration of ketamine immediately after witnessing a traumatic event has been shown to prevent the enhancement of passive avoidance learning in mice (Ito et al., 2015).

The rapid actions of ketamine in behavioral models of depression and antidepressant response have been linked to increased synapse number and function in the mPFC (Duman and Aghajanian, 2012, Li et al., 2010). These studies also demonstrate that ketamine increases the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway that regulates translation and synaptic protein synthesis (Duman and Aghajanian, 2012). Given the important role for neuroplasticity of the mPFC and its projections to amygdala in extinction learning we reasoned that the actions of ketamine in mPFC could also influence fear extinction (Orsini and Maren, 2012). The results of the current study show that ketamine improves extinction recall in adult rats and that this effect is mediated by activation of the mTORC1-dependent translation mechanisms in the mPFC.

Section snippets

Animals

Male Sprague-Dawley rats weighing between 175 and 250 g and between 7 and 9 weeks of age were used for all experiments. Rats were pair housed in rectangular polypropylene cages with laboratory bedding and kept under standard conditions with a 12-h light/dark cycle. Ambient temperature in the vivarium was maintained at 21 °C. Food and water were available ad libitum, throughout the duration of the experiment. Animal use and procedures were in accordance with the National Institutes of Health

Ketamine enhances fear extinction learning

Sprague-Dawley rats (200 g) were fear conditioned using 7 pairs of a neutral tone (conditioned stimulus, CS) that co-terminated with an aversive stimulus- footshock (0.6 mA) (unconditioned stimulus, US) (n = 16–19). Twenty-four hours after fear conditioning, the animals were administered ketamine (10 mg/kg, i.p.) or saline. This is the same ketamine dose that produces rapid antidepressant actions in rodent models(Li et al., 2010). It should be noted that the active form of ketamine is fully

Conclusion

The rapid-acting antidepressant effects of ketamine in rodent models and clinical trials have been well established (Berman et al., 2000, Li et al., 2010, Zarate et al., 2006), and recent studies demonstrate the efficacy of ketamine for the treatment of PTSD (Feder et al., 2014). Blockade of NMDA receptors by ketamine increases the number and function of synapses in the mPFC (Li et al., 2010), a region that also plays a critical role in the acquisition and retrieval of extinction (Knapska et

Funding and disclosure

This work is supported by NIMH R01MH93897 (RSD), the State of Connecticut, and Yale University. The authors list the following interests: R.S. Duman has consulted and/or received research support from Naurex, Lilly, Forest, Johnson & Johnson, Taisho, and Sunovion. The remaining authors, M.J. Girgenti, S. Ghosal, D. LoPresto, and J.R. Taylor have no competing financial interests.

References (49)

  • S. Maeng 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)
  • A.L. Mahan et al.

    Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder

    Trends Neurosci.

    (2012)
  • M.R. Milad et al.

    Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert

    Biol. Psychiatry

    (2007)
  • M.J. Millan

    The neurobiology and control of anxious states

    Prog. Neurobiol.

    (2003)
  • C.A. Orsini et al.

    Neural and cellular mechanisms of fear and extinction memory formation

    Neurosci. Biobehav. Rev.

    (2012)
  • K.G. Rasmussen

    Has psychiatry tamed the “ketamine tiger?” Considerations on its use for depression and anxiety

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2016)
  • C. Riaza Bermudo-Soriano et al.

    New perspectives in glutamate and anxiety

    Pharmacol. Biochem. Behav.

    (2012)
  • C.A. Zarate et al.

    Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression

    Biol. Psychiatry

    (2012)
  • A.E. Autry et al.

    NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

    Nature

    (2011)
  • R.S. Duman et al.

    Synaptic dysfunction in depression: potential therapeutic targets

    Science

    (2012)
  • A. Etkin et al.

    Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia

    Am. J. Psychiatry

    (2007)
  • A. Feder et al.

    Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder

    JAMA Psychiat.

    (2014)
  • M. Fuchikami et al.

    Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions

    Proc. Natl. Acad. Sci. U. S. A.

    (2015)
  • T.F. Giustino et al.

    The role of the medial prefrontal cortex in the conditioning and extinction of fear

    Front. Behav. Neurosci.

    (2015)
  • Cited by (95)

    View all citing articles on Scopus
    View full text