Abstract
Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.
Highlights
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops following exposure to a traumatic event and is characterized by flashbacks to the traumatic event, avoidance of event-related stimuli, hypervigilance, and cognitive deficits[1]
Following two-day inescapable shock, we found a main effect of stress on ventral tegmental area (VTA) dopamine neuron population activity (Fig. 1; two-way ANOVA; factors: stress × drug; F(1,35) = 7.731; t = 2.781; P = 0.009, n = 6/group)
After demonstrating the ability of both orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) receptor antagonists to alleviate stress-induced increases in VTA dopamine neuron activity, we examined the ability of the OX1R antagonist, SB334867, and the OX2R antagonist, EMPA to reverse stress-induced deficits in pre-pulse inhibition of startle (PPI)
Summary
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops following exposure to a traumatic event and is characterized by flashbacks to the traumatic event, avoidance of event-related stimuli, hypervigilance, and cognitive deficits[1]. 80–90% of individuals diagnosed with PTSD receive a comorbid psychiatric diagnosis, including depression, anxiety, and psychosis[2,3,4,5]. While PTSD and comorbid depression and anxiety have been extensively studied, less is known about psychosis in PTSD patients, despite the fact that up to 64% of individuals with PTSD are diagnosed with comorbid psychosis[5,6]. The pathology appears to lie in upstream brain regions that regulate dopamine neuron activity[10,11]. One such region of interest, known to regulate dopamine system function, is the
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