Project Summary/Abstract: 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. We have novel preliminary data demonstrating that the paraventricular nucleus of the thalamus (PVT) regulates dopamine neuron activity. We posit that the PVT therefore represents a potential therapeutic target for the treatment of PTSD as well as comorbid psychosis. The PVT receives a particularly dense innervation from orexin containing neurons in the hypothalamus. Thus, the orexin system is well positioned to regulate PVT activity and may be a novel target for pharmacological intervention. One such drug, Suvorexant, an orexin receptor antagonist, is currently FDA- approved for the treatment of insomnia. We will test the hypothesis that Suvorexant can reverse deficits in rodents displaying circuit level alterations and corresponding behavioral deficits relevant to comorbid psychosis in PTSD. Specifically, we will examine whether orexin receptor antagonists can reverse stress-induced behavioral (Aim 1) or neurophysiological/neurochemical (Aim 2) deficits associated with PTSD. We will then determine the role of discrete PVT projections to the nucleus accumbens in comorbid psychosis (Aim 3). This proposal with therefore identify a potential novel therapeutic target and inform the development of more effective treatment approaches for PTSD and comorbid psychosis.