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Stress is a potent etiological factor in the onset of major depressive disorder and posttraumatic stress disorder (PTSD). Therefore, significant efforts have been made to identify factors that produce resilience to the outcomes of a later stressor, in hopes of preventing untoward clinical outcomes. The NMDA receptor antagonist ketamine has recently emerged as a prophylactic capable of preventing neurochemical and behavioral outcomes of a future stressor. Despite promising results of preclinical studies performed in male rats, the effects of proactive ketamine in female rats remains unknown. This is alarming given that stress-related disorders affect females at nearly twice the rate of males. Here we explore the prophylactic effects of ketamine on stress-induced anxiety-like behavior and the neural circuit-level processes that mediate these effects in female rats. Ketamine given one week prior to an uncontrollable stressor (inescapable tailshock; IS) reduced typical stress-induced activation of the serotonergic (5-HT) dorsal raphe nucleus (DRN) and eliminated DRN-dependent juvenile social exploration (JSE) deficits 24 h after the stressor. Proactive ketamine altered prelimbic cortex (PL) neural ensembles so that a later experience with IS now activated these cells, which it ordinarily would not. Ketamine acutely activated a PL to DRN (PL-DRN) circuit and inhibition of this circuit with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) at the time of IS one week later prevented stress prophylaxis, suggesting that persistent changes in PL-DRN circuit activity are responsible, at least in part, for mediating long-term effects associated with ketamine.

Significance Statement

Stress-related disorders affect females at twice the rate of males, and so identifying factors capable of producing resilience in females is critically important. Recent efforts to identify neural mechanisms underlying the prophylactic effects of ketamine on the behavioral and neural impact of a later stressor have focused solely on male rodents. Here we show that ketamine administered to female rats one week before an uncontrollable stressor prevents stress-induced anxiety-like behavioral effects. The mechanisms by which ketamine exerts prophylactic effects were explored, and ketamine was found to activate an inhibitory prelimbic cortex (PL)-dorsal raphe nucleus (DRN) circuit and that this circuit activation is required for the stress-buffering effects of ketamine. These data provide a basis for prophylactic use of ketamine in females.


Stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), affect females at nearly twice the rate of males (Kessler et al., 2005Steiner et al., 2005) and are among the leading causes of disability worldwide (Kessler et al., 1995; Mathers et al., 2008). Only one third of patients prescribed conventional pharmacotherapies achieve full remission, underscoring the need for more effective therapeutic modalities. (Gaynes et al., 2009). Recently, it has been shown that a single subanesthetic dose (0.5 mg/kg, i.v.) of the nonselective NMDA receptor antagonist ketamine produces rapid and enduring therapeutic effects in individuals with treatment-resistant depression, anxiety, and PTSD (Berman et al., 2000Zarate et al., 2006Glue et al., 2017; Price et al., 2009; Feder et al., 2014). Accordingly, a growing body of research has been dedicated to identifying the underlying neurobiological mechanisms by which ketamine produces its effects.

Because of its clinical effectiveness, laboratory work has focused on two paradigms. In one, a single subanesthetic dose (10 mg/kg, i.p.) of ketamine is delivered at various time points before behavioral tests that are thought to reflect depressive or anxiety-related behavior. For example, ketamine delivered minutes to hours before behavioral testing prevents typical behavioral changes measured during the forced swim test (Garcia et al., 2008), tail suspension test (da Silva et al., 2010), novelty suppressed feeding test (NSF; Fuchikami et al., 2015) and the open-field test (Thelen et al., 2016). In the second, ketamine is given after exposure to a stressor to determine whether it would reverse stress effects on behavior. Ketamine delivered shortly after (0–24 h) exposure to a chronic unpredictable stressor reverses the effects of the stressor on NSF and sucrose preference (Li et al., 2011). Surprisingly, nearly all of the preclinical studies designed to identify the mechanistic actions of ketamine have focused on male rats. Indeed, a small number of studies have demonstrated differential sensitivity and responsivity of females and males to the direct and restorative effects of ketamine (Carrier and Kabbaj, 2013; Frnasceschelli et al., 2015; Zanos et al., 2016).

There has been a great deal of recent interest in factors that can lead to resilience in the face of adversity (for review, see Baratta et al., 2013), and interestingly, 3 recent reports indicate that single dose of ketamine can blunt the impact of stressors occurring as much as two weeks later (Amat et al., 2016Brachman et al., 2016McGowan et al., 2017). Unfortunately, none of these reports employed female subjects. Thus, we chose to explore the proactive effects of ketamine in female rats, as well as the underlying neural circuit-level processes that mediate such effects. We sought to determine whether ketamine delivered one week before an uncontrollable stressor (inescapable tailshock; IS) is sufficient to prevent anxiety-like behavior measured during juvenile social exploration (JSE) 24 h later, in a manner similar to that observed in male rats (Amat et al., 2016). IS-induced behavioral changes are mediated in part by activation of serotonergic (5-HT) neurons within the dorsal raphe nucleus (DRN; Maier and Watkins, 2005). Specifically, IS activates 5-HT neurons in the mid to caudal DRN (Grahn et al., 1999) leading to 5-HT release in projection regions that are proximal mediators of stress-induced behavioral changes, such as the basolateral amygdala (BLA; Amat et al., 1998Christianson et al., 2010Dolzani et al., 2016). Indeed, blockade of 5-HT2C receptors in the BLA eliminates the reduction in JSE produced by prior IS (Christianson et al., 2010). Therefore, we examined the effect of ketamine on IS-induced Fos activation in DRN 5-HT neurons to determine whether ketamine mitigates IS-induced DRN activation (Amat et al., 2016). Plastic changes in the prelimbic region (PL) of the medial prefrontal cortex (mPFC), a potent regulator of DRN activity (for review, see Maier and Watkins, 2010), are critical for the stress-buffering effects of ketamine (Li et al., 2010Lepack et al., 2016; for review, see Duman and Krystal, 2016). Thus, we explored whether ketamine alters PL neural ensembles so that later IS now activates the same ensembles. Finally, we examined whether ketamine directly activates the PL-DRN pathway, and if so, whether PL-DRN pathway activation is critical for the protective effects of ketamine at the time of later IS.

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