Administration of the glutamate-modulating drug riluzole after stress reverses its delayed effects on the amygdala

Abstract

Extracellular glutamate levels are elevated across brain regions immediately after stress. Despite sharing common features in their genesis, the patterns of stress-induced plasticity that eventually take shape are strikingly different between these brain areas. While stress impairs structure and function in the hippocampus, it has the opposite effect on the amygdala. Riluzole, an FDA-approved drug known to modulate glutamate release and facilitate glutamate clearance, prevents stress-induced deficits in the hippocampus. But, whether the same drug is also effective in countering the opposite effects of stress in the amygdala remains unexplored. We addressed this question by using a rat model wherein even a single 2-hour acute immobilization stress causes a delayed build-up, 10 days later, in anxiety-like behavior, alongside stronger excitatory synaptic connectivity in the basolateral amygdala (BLA). This temporal profile - several days separating the acute stressor and its delayed impact - allowed us to test if these effects can be reversed by administering riluzole in the drinking water after acute stress. Post-stress riluzole not only prevented the delayed increase in anxiety-like behavior on the elevated plus-maze, but also reversed the increase in spine-density on BLA neurons 10 days later. Further, stress-induced increase in the frequency of miniature excitatory postsynaptic currents recorded in BLA slices, 10 days later, was reversed by the same post-stress riluzole administration. Together, these findings underscore the importance of therapeutic strategies, aimed at glutamate uptake and modulation, in correcting the delayed behavioral, physiological, and morphological effects of stress on the amygdala.