Systemic Administration of the 5-HT1b Antagonist SB-216641 Prior to Acute Stress Exposure in Rats Mildly Prevents Stress-induced Behavioral Performance Dysregulations

Abstract ID 127259 Poster Board 115 FDA-approved pharmacotherapies that treat or prevent the vast array of behavioral performance dysregulations observed in ASR (acute stress reactions) and/or ASD (acute stress disorder) are sorely needed. Previous findings from our lab revealed that chemogenetically-mediated inhibition of the anterior cingulate cortex resulted in behavioral performance dysregulations in rats that were similar to those induced by our rodent model of military-relevant complex traumatic stress (MRCTS). Because this subregion is heavily populated by serotonin receptors, including 5-HT1b receptors, we hypothesized that systemic administration of the 5-HT1b antagonist SB-216641(SB) prior to acute stress exposure would prevent subsequent behavioral performance dysregulations in rats. Briefly, adult male Sprague-Dawley rats were administered SB (1.8 or 5.6 mg/kg, i.p.) or its vehicle solution and then exposed to MRCTS procedures (e.g., predator exposure, inescapable foot shock, underwater immersion) or left undisturbed in their home-cages. At 2-h and 24-h post-stress exposure, all rats were evaluated on a behavioral test battery that included the elevated plus maze, open field, and acoustic startle response tests. Two-way ANOVAs (between-subject factors of exposure type and dose; performed separately for each timepoint) were conducted. Exploration in potentially aversive areas of these tests (i.e., open arms or center arena) showed an SB-mediated inverse U-shaped function that achieved statistical significance in the elevated plus maze (stress x dose: at 2-h, n.s.; at 24-h, p < 0.05) but not in the open field test. General exploration was significantly reduced at 2-h and 24-h (p < 0.0001) in the elevated plus maze and in the open field (p < 0.01) - effects that were not prevented by SB administration. Likewise, acoustic startle responding was significantly dysregulated by acute stress exposure at both timepoints (p < 0.05) but was not prevented by SB administration. In fact, at 2-h there was a nonsignificant trend suggesting that SB administration dose-dependently increased startle responses, an effect that achieved significance at 24-h (p = 0.0016) in both control and stress-exposed groups. Cumulatively, the present findings suggest a mildly beneficial effect of low-dose SB administration for prevention of stress-induced behavioral performance dysregulations. These findings highlight the complexity with which the 5-HT1b system mediates the three-way interaction (time x stress x drug administration) that determines stressor-induced outcomes, and the challenges that remain in the search for effective pharmacotherapies for ASR and ASD. 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.