Behavioral Performance Characterization of the Putative Neuroinflammation Inhibitor 1-Methyl-Tryptophan Following Acute Traumatic Stress in Rats

Abstract

<b>Abstract ID 52631</b> <b>Poster Board 408</b> Of US Soldiers exposed to psychological trauma during deployment in current conflicts, 12-25% develop Post-Traumatic Stress Disorder, with greater numbers estimated for developing Acute Stress Reactions (ASR) or Acute Stress Disorder (ASD). At present there are no FDA-approved pharmacotherapies for the treatment of ASR or ASD, thus novel therapeutics are needed. One target of interest is a component of the kynurenine pathway of tryptophan metabolism, as increased expression of the pathway protein indoleamine-2,3-dioxygenase-1 (IDO-1) is found in the acute aftermath of traumatic stress exposure. The overall outcome of increased expression of IDO-1 and kynurenine metabolites is increased neuroinflammation, which also plays a role in stress-related disorders. 1-methyl-tryptophan (1MT) is a reported inhibitor of IDO-1 as well as a putative anti-inflammatory drug candidate. We sought to evaluate the efficacy of 1MT to prevent behavioral performance decrements using a rodent model of military-relevant complex traumatic stress (MRCTS). This preclinical model incorporates combat-relevant facets of traumatic stress events. Briefly, adult male and female Sprague-Dawley rats were exposed to MRCTS procedures (e.g., predator exposure, inescapable foot shock, &amp; underwater immersion) or left undisturbed in their home-cage. Rats were then administered 1MT (10 or 30 mg/kg, i.p.) or vehicle. At 24-h post-stress exposure, all rats were evaluated in a behavioral battery: elevated plus maze (EPM), open field (OF), and acoustic startle response (SR) tests. Data were analyzed in separate 2-way ANOVAs, based on <i>a priori</i> hypotheses. On the EPM, female rats traveled greater overall distance and distance on the open arms than males and stress exposure negatively impacted performance for both sexes (<i>p</i>s&lt;0.05). Significant (<i>p</i>&lt;0.05) main effects of various factors were observed for different EPM outcome measures and post-hoc analyses revealed a significant dose-dependent decrease in open arm distance in stress-exposed groups. Similarly, on the OF, females traveled significantly greater overall distance (<i>p</i>&lt;0.001) and distance in the center area (<i>p</i>&lt;0.01) than males. However, there was a lack of significant main effects of stress and 1MT treatment in most analyses. For SR, males significantly startled to a greater degree than females under both control (<i>p</i>&lt;0.001) and stressed (<i>p</i>&lt;0.0001) conditions; however, there was a lack of a significant effect of 1MT treatment in both conditions. Together, the present results demonstrate limited efficacy of 1MT for the prevention of stress-related decrements in behavioral performance in rats. Importantly, the present data demonstrate that sex differences are present under basal &amp; stressed conditions. Trends in low dose-treated groups also highlight that MRCTS exposure influences the kynurenine pathway to some degree. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. Research was conducted under an IACUC-approved animal use protocol in an AAALAC International-accredited facility with a Public Health Services Animal Welfare Assurance and in compliance with the Animal Welfare Act and other federal statutes and regulations relating to laboratory animals.