Psychotic symptoms are highly prevalent in PTSD patients and are typically treated with dopamine D2 receptor antagonists; however, these drugs are associated with significant adverse effects. During the previous funding period, we demonstrated that Suvorexant, an FDA-approved dual orexin receptor antagonist, can reverse stress- induced neurophysiological and behavioral correlates of psychosis in rats. This current proposal expands those studies to provide a circuit-based framework for understanding potential sites of therapeutic intervention for comorbid psychosis in PTSD. Specifically, we will examine a circuit by which the insular cortex, a brain region consistently associated with PTSD and psychosis in human subjects, may regulate dopamine system function (Aim 1) and determine whether manipulation of a circuit involving the projection from insular cortex to OFC can reverse stress-induced alterations in dopamine system function and behavior (Aim 2). We will then examine how orexin receptor modulation alters insular cortex function in control and stressed rats (Aim 3). This proposal will therefore identify a potential novel therapeutic target and inform the development of more effective treatment approaches for PTSD and comorbid psychosis.

Psychotic symptoms are observed in up to 60% of patients with PTSD. Unfortunately, these patient have limited therapeutic options. Here we propose to examine key brain regions known to be altered in PTSD and psychosis with the goal of developing novel treatments. Specifically, we will examine the role of the insular cortex, a complex anatomical hub that plays a critical role linking sensory experiences with emotional valence, in psychosis like physiology and behavior. We will initially determine how the insular cortex regulates dopamine system function, before examining whether targeting circuits from this region can reverse stress-induced deficits in rodents. Finally, we will investigate the utility of a novel pharmacological target, the orexin system, in order to identify and refine novel treatments for comorbid psychosis in PTSD.