Effects of chronic prazosin, an alpha-1 adrenergic antagonist, on anxiety-like behavior and cortisol levels in a chronic unpredictable stress model in zebrafish (Danio rerio)

Abstract

Post-traumatic stress disorder (PTSD) is often associated with significant neuroendocrine dysfunction and a variety of other symptoms. Today, there are limited efficacious treatment options for PTSD, none of which directly target the dysfunction observed with the hypothalamic-pituitary-adrenal (HPA) axis. The development of new pharmacological treatments is expensive and time consuming; thus, there is utility in repurposing compounds already approved for use in other conditions. One medication in particular that has shown promise for the alleviation of PTSD symptoms is prazosin, an alpha-1 adrenergic receptor antagonist used to treat hypertension. While there have been many studies indicating the efficacy of prazosin in the treatment of PTSD symptoms, no studies fully elucidate mechanisms elicited by this treatment, nor is it clear if prazosin normalizes neuroendocrine dysfunction associated with trauma exposure. The use of zebrafish (Danio rerio) has been growing in popularity, in part, due to the homology of the stress response system with mammals. In this study, the zebrafish model was utilized to determine behavioral and biological changes induced by chronic unpredictable stress (CUS) and how these effects could be modulated by chronic prazosin treatment. The results indicated that 7d of CUS increased anxiety-like behavior in the novel tank test and decreased basal levels of cortisol. Chronic (7d) prazosin treatment decreased anxiety-like behaviors overall but did not appear to affect CUS-induced changes in behavior and basal cortisol levels. This suggests that the clinical effectiveness of prazosin may not normalize dysregulated stress responses prevalent in many patients with PTSD, but that prazosin-induced relief from anxiety in stress-related conditions may involve an alternative mechanism other than by normalizing neuroendocrine dysfunction.