Abstract
Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation – a state in which recalled memories become susceptible to modification – we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory.
Highlights
Mitigation of persistent, intrusive, traumatic memories experienced by people with post-traumatic stress disorder (PTSD) remains a key therapeutic challenge [1]
Several chemical agents have been found to inhibit fear memory reconsolidation in animals [7] but do not translate well to humans, limiting their clinical use. They either are toxic, induce unwanted side effects, are slow acting such that brain drug concentrations peak outside of the reconsolidation window, or are slowly eliminated such that they interfere with later onset memory processes including extinction [8]
A recent human study documented that a single electroconvulsive therapy (ECT) treatment administered to unipolar depressed subjects immediately after emotional memory reactivation disrupted reconsolidation, confirming that reconsolidation occurs in humans and that it can be inhibited by a brief treatment [9]
Summary
Mitigation of persistent, intrusive, traumatic memories experienced by people with post-traumatic stress disorder (PTSD) remains a key therapeutic challenge [1] Behavioral treatments such as extinction training – administered alone or in combination with cognitive-enhancing drugs (e.g. d-cycloserine) – attempt to inhibit underlying traumatic memories by facilitating a new set of learning contingencies, but often achieve limited success [2]. Another learning and memory phenomenon known as reconsolidation, a process by which reactivated (retrieved) memories temporarily enter a labile state (the reconsolidation window), has been studied to determine whether drug or behavioral interventions can prevent a traumatic memory trace from being reincorporated back into the neural engram, inhibiting the memory [3,4,5,6]. There is a significant unmet need for a minimally invasive, safe and welltolerated treatment that can be used clinically to inhibit fear memory reconsolidation in people with PTSD
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