Ketamine accelerates fear extinction via mTORC1 signaling
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.
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